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Rationale: The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF.Objectives: To understand the gene expression patterns of acute exacerbations of IPF.Methods: RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation (IPF-AEx), and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed with Spotfire and Genomica. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2, and CCNA2 were performed by real-time quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry and in situ terminal deoxynucleotidyltransferase dUTP nick end-labeling assays were performed on the same tissues used for the microarray. ELISA for alpha-defensins was performed on plasma from control subjects, patients with stable IPF, and patients with IPF-AEx.Measurements and Main Results: Gene expression patterns in IPF-AEx and IPF samples were similar for the genes that distinguish IPF from control lungs. Five hundred and seventy-nine genes were differentially expressed (false discovery rate < 5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence of an infectious or overwhelming inflammatory etiology. CCNA2 and alpha-defensins were among the most up-regulated genes. CCNA2 and alpha-defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. alpha-Defensin protein levels were increased in the peripheral blood of patients with IPF-AEx.Conclusions: Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder. [ABSTRACT FROM AUTHOR]

Dyspnea is the most common and activity-limiting symptom for those with chronic obstructive pulmonary disease (COPD). Treatment is complex, palliative care (PC) dyspnea relief interventions are poorly understood, and PC remains underutilized in COPD despite national guidelines and recommendations. The purpose of this rapid review was to explore the concept of dyspnea and role of PC through the lens of providers, caregivers, and patients with COPD. A systematic approach for synthesis was used to identify 13 articles published between January 2018 and October 2023. Team members compared data via visualization and theme clustering to identify key conclusions describing operationalization of dyspnea, management, and PC implications. Dyspnea operationalization was challenging, with inconsistent measurement and terminology. Dyspnea was a significant burden in COPD and contributed to complexity of treatment. Opioids were used most often to treat dyspnea, but provider perspectives and biases can influence treatment decisions and perceptions of opioid therapy by the patient and caregiver. Evidence-based clinical practice guidelines and policies are needed to clarify the use of opioid therapy for dyspnea management to reduce stigmatization and barriers to treatment. Provider education should emphasize a multipronged approach to treatment of dyspnea in COPD with integration of PC early in the care continuum., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 by The Hospice and Palliative Nurses Association. All rights reserved.)

Patients with interstitial lung diseases (ILD) often have hypoxemia at rest and/or with exertion, for which supplemental oxygen is commonly prescribed. The number of patients with ILD who require supplemental oxygen is unknown, although estimates suggest it could be as much as 40%; many of these patients may require high-flow support (>4 L/min). Despite its frequent use, there is limited evidence for the impact of supplemental oxygen on clinical outcomes in ILD, with recommendations for its use primarily based on older studies in patients with chronic obstructive pulmonary disease. Oxygen use in ILD is rarely included as an outcome in clinical trials. Available evidence suggests that supplemental oxygen in ILD may improve quality of life and some exercise parameters in patients whose hypoxemia is a limiting factor; however, oxygen therapy also places new burdens and barriers on some patients that may counter its beneficial effects. The cost of supplemental oxygen in ILD is also unknown but likely represents a significant portion of overall healthcare costs in these patients. Current Centers for Medicare and Medicaid reimbursement policies provide only a modest increase in payment for high oxygen flows, which may negatively impact access to oxygen services and equipment for some patients with ILD. Future studies should examine clinical and quality-of-life outcomes for oxygen use in ILD. In the meantime, given the current limited evidence for supplemental oxygen and considering cost factors and other barriers, providers should take a patient-focused approach when considering supplemental oxygen prescriptions in patients with ILD.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious illness with an unpredictable disease course and survival rates comparable with some cancers. Patients with IPF suffer considerable symptom burden, declining quality of life, and high health care resource utilization. Patients and caregivers report many unmet needs, including a desire for more education regarding diagnosis and assistance with navigating disease trajectory. Compelling evidence suggests that palliative care (PC) provides an extra layer of support for patients with serious illness., Research Question: The purpose of this survey was to gain perspectives regarding PC for patients with IPF by board-certified pulmonologists in South Carolina (SC)., Study Design and Methods: A 24-item survey was adapted (with permission) from the Pulmonary Fibrosis Foundation PC Survey instrument. Data were analyzed and results are presented., Results: Pulmonologists ( n  = 32, 44%) completed the survey; 97% practice in urbanized settings. The majority agreed that PC and hospice do not provide the same service. There were varying views about comfort in discussing prognosis, disease trajectory, and addressing advance directives. Options for ambulatory and inpatient PC are limited and early PC referral does not occur. None reported initiating a PC referral at time of initial IPF diagnosis., Interpretation: Pulmonologists in SC who participated in this survey are aware of the principles of PC in providing comprehensive care to patients with IPF and have limited options for PC referral. PC educational materials provided early in the diagnosis can help facilitate and guide end-of-life planning and discussions. Minimal resources exist for patients in underserved communities., Competing Interests: No competing financial interests exist., (© Kathleen Oare Lindell et al., 2023; Published by Mary Ann Liebert, Inc.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM 2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM 2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM 2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (β = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM 2.5 , sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM 2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gillian C. Goobie reports financial support was provided by Pulmonary Fibrosis Foundation. Gillian C. Goobie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Kathleen O. Lindell reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Daniel J. Kass reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. S. Mehdi Nouraie reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. Christopher J. Ryerson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: funding grants. Christopher J. Ryerson reports a relationship with Hoffmann-La Roche Limited that includes:. Kerri A. Johannson reports a relationship with Boehringer Ingelheim Canada Ltd that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Three Lakes Foundation that includes: consulting or advisory and funding grants. Kerri A. Johannson reports a relationship with Hoffmann-La Roche Limited that includes: consulting or advisory. James P. Fabisiak reports a relationship with Heinz Endowments that includes: funding grants. Daniel J. Kass reports a relationship with National Institutes of Health that includes: funding grants. Yingze Zhang reports a relationship with National Institutes of Health that includes: funding grants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear., Objective: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD., Design, Setting, and Participants: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022., Exposures: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements., Main Outcomes and Measures: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts)., Results: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 μg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes., Conclusions and Relevance: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes., Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide ( D LCO ) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history., Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (β = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (β = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC β = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO β = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC β = -0.80, 95% CI -1.37 to -0.24, p=0.003)., Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes., Competing Interests: Conflict of interest: G.C. Goobie receives research funding and support through the Pulmonary Fibrosis Foundation Scholars Award Program and the University of British Columbia Clinician Investigator Program. C.J. Ryerson, D. Assayag and M.R.J. Kolb report personal fees and grants from Boehringer Ingelheim and Hoffman La Roche outside the submitted work. K.A. Johannson reports personal fees, nonfinancial support and other support from Boehringer Ingelheim and the Three Lakes Foundation, personal fees from Hoffman-La Roche Ltd, and grants from the University Hospital Foundation, the University of Calgary Cumming School of Medicine, and the Pulmonary Fibrosis Society of Calgary. V. Marcoux reports grants and personal fees from Boehringer Ingelheim Canada, Hoffman La-Roche Ltd and AstraZeneca, and grants from the University of Saskatchewan and the Royal University Hospital Foundation. M.R.J. Kolb also reports personal fees and grants from GSK, Gilead, Actelion, Respivert, Genoa, Alkermes, Pharmaxis, Prometric, Indalo and Third Pole. H. Manganas reports grants from Hoffman-La Roche Ltd, Galapagos and BMS, and personal fees and research grants from Boehringer Ingelheim. D. Assayag also reports personal fees and grants from Novartis. J.H. Fisher reports grants from the Canadian Pulmonary Fibrosis Foundation, and personal fees from Boehringer Ingelheim and AstraZeneca, outside of the submitted work. D.J. Kass is supported in part by AR060780, HL133232, UL1 TR001857 and AR076024 (NIH grants), Boehringer Ingelheim grants, and receives collaborative research funding from Regeneron Pharmaceuticals, outside of the submitted work. Y. Zhang is supported in part by AR076024 (NIH grant). S. Keil, E. Schikowski, N. Khalil, X. Chen, K.F. Gibson and K.O. Lindell report no competing interests. S.M. Nouraie receives grant support from Boehringer Ingelheim USA., (Copyright ©The authors 2022.)

Background: Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals: This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods: An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary-critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results: The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1 ) delivery models, 2 ) comprehensive symptom assessment and management, 3 ) advance care planning and goals of care discussions, 4 ) caregiver support, 5 ) health disparities, 6 ) mass casualty events and emergency preparedness, and 7 ) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions: This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary-critical care clinicians and policymakers for its proactive integration.

Background: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients., Methods: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review., Results: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres., Conclusions: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease., Competing Interests: Conflict of interest This project was supported by National Heart, Lung, and Blood Institute Grant R01HL135062 (JA), R01 HL133184 (JM), UPMC Immune Transplant and Therapy Center, UPMC Genomics Research Center, Kathleen Ford Fund for Lung Transplant Research, The Richard P. Simmons Chair for Interstitial Lung Disease, and the Simmons Genetics Research Fund., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

COPD is the fourth leading cause of death in the United States and is a serious respiratory illness characterized by years of progressively debilitating breathlessness, high prevalence of associated depression and anxiety, frequent hospitalizations, and diminished well-being. Despite the potential to confer significant quality-of-life benefits for patients and their care partners and to improve end-of-life (EOL) care, specialist palliative care is rarely implemented in COPD, and when initiated, it often occurs only at the very EOL. Primary palliative care delivered by frontline clinicians is a feasible model, but is not integrated routinely in COPD. In this review, we discuss the following: (1) the role of specialist and primary palliative care for patients with COPD and the case for earlier integration into routine practice; (2) the domains of the National Consensus Project Guidelines for Quality Palliative Care applied to people living with COPD and their care partners; and (3) triggers for initiating palliative care and practical ways to implement palliative care using case-based examples. This review solidifies that palliative care is much more than hospice and EOL care and demonstrates that early palliative care is appropriate at any point during the COPD trajectory. We emphasize that palliative care should be integrated long before the EOL to provide comprehensive support for patients and their care partners and to prepare them better for the EOL., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P  = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P  = 0.04). Greater disadvantage was associated with reduced baseline DL CO in both cohorts, but it was not associated with baseline FVC or FVC or DL CO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

Purpose of Review: Pulmonary fibrosis is an incurable lung disease that leads to significant morbidity. In many patients, pulmonary fibrosis is progressive causing debilitating dyspnea that impairs patients' ability to perform everyday tasks and maintain independence. Informal caregivers provide invaluable support for patients with pulmonary fibrosis; however, support for the caregiver is inadequate. The purpose of this scoping review is to identify unmet needs for caregivers of pulmonary fibrosis patients., Recent Findings: During the past 18 months, there has been an increase in studies about the impact of pulmonary fibrosis on the caregiver or carer of the patient with pulmonary fibrosis. These carers experience caregiver burden which includes negative psychological and physical effects on caregiver health because of the challenge in caring for someone with pulmonary fibrosis. Caregivers describe the need for help navigating the healthcare system. This includes supportive and informational needs, lack of access to comprehensive patient-centred care, geographically accessible specialty centres and psychological support for both patient and caregiver., Summary: Caregivers of pulmonary fibrosis patients have numerous unmet care needs that include education about the disease, symptom management, financial assistance, access to specialty centres, advanced care planning and psychological support. This resulting caregiver burden can be alleviated with comprehensive support tailored throughout the disease course., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Patients with idiopathic pulmonary fibrosis (IPF) and their caregivers experience stress, symptom burden, poor quality of life, and inadequate preparedness for end-of-life (EOL) care planning as the disease progresses. The hypothesis for this study was that the early introduction of palliative care in the course of IPF would improve knowledge and preparation for EOL, patient-reported outcomes, and advance care planning in patients with IPF and their caregivers. Objectives: We sought to determine the feasibility, acceptability, and efficacy of a nurse-led early palliative care intervention entitled "A Program of SUPPORT" (Symptom management, Understanding the disease, Pulmonary rehabilitation, Palliative care, Oxygen therapy, Research participation, and Transplantation) in patients with IPF and their caregivers. Methods: Patients with IPF (diagnosed in the year previous to their initial center visit) from the University of Pittsburgh Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease at University of Pittsburgh Medical Center-together with their caregivers-were randomized to receive the intervention "A Program of SUPPORT" or usual care. This included a total of three research visits aligned with their clinic visit over a period of 6 to 8 months. We measured feasibility, acceptability, and efficacy of this intervention. Results: A total of 136 patient/caregiver dyads were eligible, and a total of 76 dyads were enrolled and participated. Participants were predominately White males >65 years old. Thirteen percent did not have an identified caregiver. Feasibility was limited; 56% of eligible dyads were enrolled. Eligible dyads (24%) were interested in participating but too fatigued to stay after their clinic visit. There was high attrition (20% of participants died before the study was completed). "A Program of SUPPORT" was acceptable to participants. Efficacy demonstrated a significant improvement in caregiver's knowledge, disease preparedness, and confidence in caring for the patient as well as an improvement in knowledge and advance care planning completion in patient participants. Conclusions: Patients with IPF and their caregivers have unmet needs regarding knowledge of their disease, self-management strategies, and preparedness for EOL planning. This nurse-led intervention demonstrated acceptability and efficacy in knowledge and advance care planning completion in patients and in knowledge, disease preparedness, and confidence in caregivers. Future research should identify additional strategies, including telemedicine resources to reach additional patients and their caregivers earlier in their disease course. Clinical trial registered with clinicaltrials.gov (NCT02929017).

Background: In the past two decades, many advances have been made to our understanding of interstitial lung disease (ILD) and the way we approach its treatment. Despite this, many questions remain unanswered, particularly those related to how the disease and its therapies impact outcomes that are most important to patients. There is currently a lack of guidance on how to best define and incorporate these patient-centered outcomes in ILD research. Objectives: To summarize the current state of patient-centered outcomes research in ILD, identify gaps in knowledge and research, and highlight opportunities and methods for future patient-centered research agendas in ILD. Methods: An international interdisciplinary group of experts was assembled. The group identified top patient-centered outcomes in ILD, reviewed available literature for each outcome, highlighted important discoveries and knowledge gaps, and formulated research recommendations. Results: The committee identified seven themes around patient-centered outcomes as the focus of the statement. After a review of the literature and expert committee discussion, we developed 28 research recommendations. Conclusions: Patient-centered outcomes are key to ascertaining whether and how ILD and interventions used to treat it affect the way patients feel and function in their daily lives. Ample opportunities exist to conduct additional work dedicated to elevating and incorporating patient-centered outcomes in ILD research.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a median survival of 3-4 years from time of initial diagnosis, similar to the time course of many malignancies. A hallmark of IPF is its unpredictable disease course, ranging from long periods of clinical stability to acute exacerbations with rapid decompensation. As the disease progresses, patients with chronic cough and progressive exertional dyspnea become oxygen dependent. They may experience significant distress due to concurrent depression, anxiety, and fatigue, which often lead to increased symptom burden and decreased quality of life. Despite these complications, palliative care is an underutilized, and often underappreciated, resource before end-of-life care in this population. While there is growing recognition about early palliative care in IPF, current data suggest referral patterns vary widely based on institutional practices. In addition to focusing on symptom management, there is emphasis on supplemental oxygen use, pulmonary rehabilitation, quality of life, and end-of-life care. Importantly, increased use of support groups and national foundation forums have served as venues for further disease education, communication, and advanced care planning outside of the hospital settings. The purpose of this review article is to discuss the clinical features of IPF, the role of palliative care in chronic disease management, current data supporting benefits of palliative care in IPF, its role in symptom management, and practices to help patients and their caregivers achieve their best quality of life.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with an unpredictable course and a median survival of three to four years. This timeline challenges providers to approach diagnosis, oxygen therapy, rehabilitation, transplantation, and end-of-life discussions in limited encounters. There is currently no widely accepted guideline for determining when IPF patients should be referred to palliative care (PC). Objective: We sought to describe the patient and clinical factors associated with PC referral, as well as its impact on mortality and location of death. We also aimed to examine temporal trends in PC referral in this population. Materials and Methods: Patient data were retrospectively extracted from the health system repository of our specialty referral center for all new IPF patients evaluated between 2000 and 2016 ( n  = 828). Exclusion criteria included transplant recipients and patients who did not have IPF. Results: One hundred twelve (13.5%) IPF patients received formal PC referral. Recipients were older at diagnosis (72 years vs. 69 years, p  < 0.001), had higher frequency of Charlson Comorbidity Index ≥1 (55% vs. 42%, p  = 0.011), resided closer to our institution (16 miles vs. 54 miles, p  < 0.001), and had a higher number of total outpatient visits (7 vs. 4, p  < 0.001). PC was associated with less in-hospital death (44% vs. 60%, p  = 0.006) and more in-home and hospice death (56% vs. 40%, p  = 0.006). Conclusions: IPF patients referred to PC were older with more severe comorbidities, resided closer to our specialty referral center, and had more outpatient follow-up. This was associated with more in-home and hospice deaths. The patient-provider relationship and frequency of follow-up visits likely play important roles in the introduction of end-of-life discussions.

More than 1.5 million adults in the United States use supplemental oxygen for a variety of respiratory disorders to improve their quality of life and prolong survival. This document describes recommendations from a multidisciplinary workshop convened at the ATS International Conference in 2017 with the goal of optimizing home oxygen therapy for adults. Ideal supplemental oxygen therapy is patient-specific, provided by a qualified clinician, includes an individualized prescription and therapeutic education program, and offers oxygen systems that are safe, promote mobility, and treat hypoxemia. Recently, patients and clinicians report a growing number of problems with home oxygen in the United States. Oxygen users experience significant functional, mechanical, and financial problems and a lack of education related to their oxygen equipment-problems that impact their quality of life. Health care providers report a lack of readily accessible resources needed to prescribe oxygen systems correctly and efficiently. Patients with certain lung diseases are affected more than others because of physically unmanageable or inadequate portable systems. Analysis is needed to quantify the unintended impact that the Centers for Medicare and Medicaid Services Competitive Bidding Program has had on patients receiving supplemental oxygen from durable medical equipment providers. Studies using effectiveness and implementation research designs are needed to develop and evaluate new models for patient education, identify effective ways for stakeholders to interface, determine the economic benefit of having respiratory therapists perform in-home education and follow-up testing, and collaborate with technology companies to improve portable oxygen devices. Generation of additional evidence of the benefit of supplemental oxygen across the spectrum of advanced lung diseases and the development of clinical practice guidelines should both be prioritized.

A Purpose of Review: Interstitial lung diseases (ILDs) cause unpredictable degrees of fibrosis and inflammation in the lungs leading to functional decline and varying symptom burden for patients. Some patients may live for years and be responsive to therapy and others disease trajectory may be shorter and similar to patients with lung cancer. This ultimately affects the patient's quality of life as well as their caregiver(s)., B Recent Findings: Nonpharmacological therapies play an important role in treatment of interstitial lung disease. These include symptom management, pulmonary rehabilitation, oxygen therapy, and palliative care. While ILDs are associated with high morbidity and mortality, different models of care exist globally. New tools help clinicians identify and address palliative care needs in daily practice and specialty nurses and ILD centers can optimize care., C Summary: This paper provides an overview of nonpharmacological therapies available for patients with interstitial lung disease., Competing Interests: Compliance with Ethical Standards Conflict of Interest Kathleen Lindell declare no conflict of interest.

Introduction: Idiopathic pulmonary fibrosis (IPF), a progressive life-limiting lung disease affects approximately 128 000 newly diagnosed individuals in the USA annually. IPF, a disease of ageing associated with intense medical and financial burden, is expected to grow in incidence globally. Median survival from diagnosis is 3.8 years, and many of these patients succumb to a rapid death within 6 months. Despite the fatal prognosis, we have found that patients and caregivers often fail to understand the poor prognosis as the disease relentlessly progresses. Based on feedback from patients and families living with IPF, we developed the S-Symptom Management, U-Understanding the Disease, P-Pulmonary Rehabilitation, P-Palliative Care, O-Oxygen Therapy, R-Research Considerations and T-Transplantation ('SUPPORT') intervention to increase knowledge of the disease, teach self-management strategies and facilitate preparedness with end of life (EOL) planning., Methods: This study is a randomised trial to test the efficacy of SUPPORT intervention compared with routine care in patients with IPF and their caregivers delivered after three clinical visits. We are recruiting a cohort of 64 new IPF patient/caregiver dyads (32 for each dyad)., Results: The trial will evaluate whether the SUPPORT intervention decreases stress, improves symptom burden, quality of life, preparedness and advance care planning for patients and caregivers, quality of dying and death for caregivers if the patient dies during the course of the study, as well as assess the impact of primary palliative care on healthcare resource use near the EOL., Conclusion: By increasing knowledge of the disease, teaching self-management strategies and facilitating preparedness with EOL planning, we will address a critical gap in the care of patients with IPF., Trial Registration Number: NCT02929017; Pre-results., Competing Interests: Competing interests: None declared.

Rationale: Pulmonary clinicians and patients anecdotally report barriers to home supplemental oxygen services including inadequate supply, unacceptable portable options, and equipment malfunction. Limited evidence exists to describe or quantify these problems., Objectives: To describe the frequency and type of problems experienced by supplemental oxygen users in the United States., Methods: The Patient Supplemental Oxygen Survey, a self-report questionnaire, was posted on the American Thoracic Society Public Advisory Roundtable and patient and health care-affiliated websites. Respondents were invited to complete the questionnaire, using targeted e-mail notifications. Data were analyzed using descriptive statistics, paired t tests, and χ 2 analysis., Results: In total, 1,926 responses were analyzed. Most respondents reported using oxygen 24 h/d, for 1-5 years, and 31% used high flow with exertion. Oxygen use varied, with only 29% adjusting flow rates based on oximeter readings. The majority (65%) reported not having their oxygen saturation checked when equipment was delivered. Sources of instruction included the delivery person (64%), clinician (8%), and no instruction (10%). Approximately one-third reported feeling "very" or "somewhat" unprepared to operate their equipment. Fifty-one percent of the patients reported oxygen problems, with the most frequent being equipment malfunction, lack of physically manageable portable systems, and lack of portable systems with high flow rates. Most respondents identified multiple problems (average, 3.6 ± 2.3; range, 1-12) in addition to limitations in activities outside the home because of inadequate portable oxygen systems (44%). Patients living in Competitive Bidding Program areas reported oxygen problems more often than those who did not (55% [389] vs. 45% [318]; P = 0.025). Differences in sample characteristics and oxygen problems were noted across diagnostic categories, with younger, dyspneic, high-flow users, and respondents who did not receive oxygen education, relating more oxygen problems. Respondents reporting oxygen problems also experienced increased health care resource utilization., Conclusions: Supplemental oxygen users experience frequent and varied problems, particularly a lack of access to effective instruction and adequate portable systems. Initiatives by professional and patient organizations are needed to improve patient education, and to promote access to equipment and services tailored to each patient's needs.

Background: The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes., Methods: We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital-Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4-6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models., Findings: The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03-4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53-3·09; p<0·0001) or transplant-free survival (2·04, 1·52-2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16-8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort., Interpretation: The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies., Funding: The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Palliative care has been recommended as a means to assist patients with idiopathic pulmonary fibrosis (IPF) in managing symptom burden and advanced care planning. Timing of referral is important because although most patients display a gradually progressive course, a minority experience acute deterioration, an outcome associated with high mortality., Aim: To describe characteristics of IPF patients referred to a specialty lung disease center over a 10-year period who experienced acute deterioration and subsequent intensive care unit (ICU) admission, including frequency and timing of referral to palliative care., Design: Retrospective review., Setting/participants: We identified 106 patients admitted to the ICU with acute deterioration due to a respiratory or nonrespiratory cause. Variables examined included demographics, date of first center visit, forced vital capacity, diffusing capacity of the lung for carbon monoxide (DLCO), and palliative care referral., Results: ICU admission occurred early (median 9.5 months) and, for 34%, within four months of their first center visit. For nearly one-half of these patients, ICU admission occurred before their third clinic visit. Only 4 (3.8%) patients received a palliative care referral before ICU admission. The majority (77%) died during ICU admission. With exception of the relationship between DLCO% predicted at first visit and time to ICU admission (r = 0.32, p = 0.005), no variables identified those most likely to experience acute deterioration., Conclusion: Due to high mortality associated with ICU admission, patients and families should be informed about palliative care early following diagnosis of IPF.

Objectives: To explore the perceptions of palliative care (PC) needs in patients with idiopathic pulmonary fibrosis (IPF) and their caregivers., Background: IPF carries a poor prognosis with most patients succumbing to their illness at a rate comparable to aggressive cancers. No prior studies have comprehensively explored perceptions of PC needs from those currently living with the disease, caring for someone living with the disease, and who cared for a deceased family member., Methods: Thematic analysis of focus group content was obtained from thirteen participants., Results: Four themes described frustration with the diagnostic process and education received, overwhelming symptom burden, hesitance to engage in advance care planning, and comfort in receiving care from pulmonary specialty center because of resources., Conclusions: Findings support that patients and caregivers have informational needs and high symptom burden, but limited understanding of the potential benefits of PC. Future studies are needed to identify optimal ways to introduce early PC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: There is controversy about how to manage requests by patients or surrogates for treatments that clinicians believe should not be administered., Purpose: This multisociety statement provides recommendations to prevent and manage intractable disagreements about the use of such treatments in intensive care units., Methods: The recommendations were developed using an iterative consensus process, including expert committee development and peer review by designated committees of each of the participating professional societies (American Thoracic Society, American Association for Critical Care Nurses, American College of Chest Physicians, European Society for Intensive Care Medicine, and Society of Critical Care)., Main Results: The committee recommends: (1) Institutions should implement strategies to prevent intractable treatment conflicts, including proactive communication and early involvement of expert consultants. (2) The term "potentially inappropriate" should be used, rather than futile, to describe treatments that have at least some chance of accomplishing the effect sought by the patient, but clinicians believe that competing ethical considerations justify not providing them. Clinicians should explain and advocate for the treatment plan they believe is appropriate. Conflicts regarding potentially inappropriate treatments that remain intractable despite intensive communication and negotiation should be managed by a fair process of conflict resolution; this process should include hospital review, attempts to find a willing provider at another institution, and opportunity for external review of decisions. When time pressures make it infeasible to complete all steps of the conflict-resolution process and clinicians have a high degree of certainty that the requested treatment is outside accepted practice, they should seek procedural oversight to the extent allowed by the clinical situation and need not provide the requested treatment. (3) Use of the term "futile" should be restricted to the rare situations in which surrogates request interventions that simply cannot accomplish their intended physiologic goal. Clinicians should not provide futile interventions. (4) The medical profession should lead public engagement efforts and advocate for policies and legislation about when life-prolonging technologies should not be used., Conclusions: The multisociety statement on responding to requests for potentially inappropriate treatments in intensive care units provides guidance for clinicians to prevent and manage disputes in patients with advanced critical illness.

Background: Palliative care, integrated early, may reduce symptom burden in patients with idiopathic pulmonary fibrosis (IPF). However, limited information exists on timing and clinical practice. The purpose of this study was to describe the time course of events prior to death in patients with IPF managed at a specialty center with a focus on location of death and timing of referral for palliative care., Methods: Data were retrospectively extracted from the health system's data repository and obituary listings. The sample included all decedents, excluding lung transplant recipients, who had their first visit to the center between 2000 and 2012., Results: Median survival for 404 decedents was 3 years from diagnosis and 1 year from first center visit. Of 277 decedents whose location of death could be determined, > 50% died in the hospital (57%). Only 38 (13.7%) had a formal palliative care referral and the majority (71%) was referred within 1 month of their death. Decedents who died in the academic medical center ICU were significantly younger than those who died in a community hospital ward (P = .04) or hospice (P = .001)., Conclusions: The majority of patients with IPF died in a hospital setting and only a minority received a formal palliative care referral. Referral to palliative care occurred late in the disease. These findings indicate the need to study adequacy of end-of-life management in IPF and promote earlier discussion and referral to palliative care.

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1-treated primary human lung fibroblasts and transforming growth factor-β1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease.

We evaluated whether lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen in pathological stroma, was detectable in serum from idiopathic pulmonary fibrosis (IPF) patients, and assessed its relationship with IPF disease progression. Patients from the ARTEMIS-IPF (n=69) and the Genomic and Proteomic Analysis of Disease Progression in IPF (GAP) (n=104) studies were analysed. Baseline serum LOXL2 (sLOXL2) levels were compared with baseline clinical and physiological surrogates of disease severity, and the association with IPF disease progression was assessed using a classification and regression tree (CART) method. sLOXL2 correlated weakly with forced vital capacity and carbon monoxide diffusion capacity (r -0.24-0.05) in both cohorts. CART-determined thresholds were similar: ARTEMIS-IPF 800 pg·mL(-1) and GAP 700 pg·mL(-1). In ARTEMIS-IPF, higher sLOXL2 (>800 pg·mL(-1)) was associated with increased risk for disease progression (hazard ratio (HR) 5.41, 95% CI 1.65-17.73). Among GAP subjects with baseline spirometric data (n=70), higher sLOXL2 levels (>700 pg·mL(-1)) were associated with more disease progression events (HR 1.78, 95% CI 1.01-3.11). Among all GAP subjects, higher sLOXL2 levels were associated with increased risk for mortality (HR 2.28, 95% CI 1.18-4.38). These results suggest that higher sLOXL2 levels are associated with increased risk for IPF disease progression. However, due to multiple limitations, these results require validation.

We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of "The costimulatory signal during T cell activation" Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient's age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4(+)CD28(+) T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.

Importance: Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials., Objective: To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF., Design, Setting, and Participants: Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings., Main Outcomes and Measures: The primary end point was all-cause mortality., Results: The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01)., Conclusions and Relevance: Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.

Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations., Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF., Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti-heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies., Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0-8.6; P < 0.0001). HSP70 protein, antigen-antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression., Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course., Objectives: The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF., Methods: Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested., Measurements and Main Results: High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort., Conclusions: Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

Background: Patients were recruited from the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, located within the University of Pittsburgh Medical Center. Idiopathic pulmonary fibrosis results in scarring of the lung and respiratory failure, and has a median survival of 3 to 5 years from the time of diagnosis. The purpose of this study was to determine whether patients with idiopathic pulmonary fibrosis and their care partners could be more optimally managed by a disease-management intervention entitled "Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management," which nurses delivered using the format of a support group. We hypothesized that participation would improve perceptions of health-related quality of life (HRQoL) and decrease symptom burden., Methods: Subjects were 42 participants randomized to an experimental (10 patient/care partner dyads) or control (11 patient/care partner dyads) group. Experimental group participants attended the 6-week program, and controls received usual care. Before and after the program, all participants completed questionnaires designed to assess symptom burden and HRQoL. Patients and care partners in the intervention group were also interviewed in their home to elicit information on their experience after participating in the Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management., Results: After the intervention, experimental group patients rated their HRQoL less positively (P = .038) and tended to report more anxiety (P = .077) compared with controls. Care partners rated their stress at a lower level (P = .018) compared with controls. Course evaluations were uniformly positive. Post-study qualitative interviews with experimental group participants suggested benefits not exemplified by these scores. Patient participants felt less isolated, were able to put their disease into perspective, and valued participating in research and helping others., Conclusion: Further exploration of the impact of disease-management interventions in patients with advanced lung disease and their care partners is needed using both qualitative and quantitative methodology. Disease-management interventions have the potential to positively affect patients with advanced lung disease and their care partners.

Background: Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF., Methodology/principal Findings: Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4(+)CD28(+)cells, the unusual CD4(+)CD28(null) lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4+/-0.8% vs. 60.0+/-7.4%, p<0.0001) and granzyme B (4.5+/-2.8% vs.74.9+/-6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9+/-1.1% vs. 3.3+/-0.6% p<0.0001). Infiltration of CD4(+)CD28(null) T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (r(s) = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56+/-6% among 78 IPF patients with CD4(+)CD28(+)/CD4(total)>or=82%, compared to 9+/-9% among those with more extensive CD28 down-regulation (CD4(+)CD28(+)/CD4(total)<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1., Conclusions/significance: Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4(+)CD28(null) cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression., Methods and Findings: We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins-MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A-that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%-100%) and specificity of 98.1% (95% CI 89.9%-100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%-100%) and specificity of 87.2% (95% CI 72.6%-95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%)., Conclusions: Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.