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Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia, a form of interstitial lung disease characterized by abnormal wound healing in the lung that leads to progressive scarring and loss of lung function. Comorbidities are highly prevalent in IPF and often lead to further complications and worse outcomes. In fact, undetected and untreated comorbidities are independently associated with poor outcomes. IPF not only affects patient quality of life (QOL) but also requires significant cost for delivering care. Given the potential for rapid progression of IPF and the associated risk for mortality, early diagnosis is critical for retaining the highest lung function and QOL for as long as possible. Delayed diagnosis of IPF is associated with increased costs in terms of investigations performed, and delayed referral can result in lower survival rates independent of disease severity or associated prognostic factors. Significant progress has been made in understanding IPF pathogenesis, which has, in turn, led to the development of novel therapeutic options that improve outcomes, extend life, and minimize disease burden on patients' daily lives. For patients with IPF in the absence of underlying liver disease, pirfenidone and nintedanib are licensed for the treatment of IPF. Additionally, a number of investigational therapeutic options are currently in development. The extent of clinical effectiveness compared with the cost of therapy has led to a lack of consensus on the cost-vs-benefit analyses for the drugs.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a variable clinical course and high mortality. We used data from a large national US registry of patients with IPF to investigate relationships between patient characteristics, including markers of disease severity, and mortality. Methods The analysis cohort comprised patients enrolled in the IPF-PRO Registry from its inception on 5 June 2014 to 26 October 2017. The primary criterion for inclusion in this registry is that patients must be diagnosed or confirmed with IPF at the enrolling centre within 6 months. Associations between patient characteristics and markers of disease severity at enrolment and mortality outcomes were investigated using univariable, multivariable and adjustment models. Results Among 662 patients enrolled, 111 patients died or had a lung transplant over a follow-up period of 30 months. The probability of being free of both events at month 30 was 50.6% (95% CI: 40.0, 60.2). When patient characteristics and markers of disease severity were jointly examined in a multivariable analysis, oxygen use at rest (hazard ratio [HR] 2.44 [95% CI: 1.45, 4.10]), lower forced vital capacity (FVC) % predicted (HR 1.28 [95% CI: 1.10, 1.49] per 10% decrease) and diffusion capacity for carbon monoxide (DLco) % predicted (HR 1.25 [95% CI: 1.04, 1.51] per 10% decrease) were significantly associated with increased risk of death or lung transplant. The risk of death or lung transplant increased with increasing age in patients ≥62 years old (HR 1.18 [95% CI: 0.99, 1.40] per 5-year increase), and decreased with increasing age in patients

Detailed understanding of longitudinal behavior, response to therapy, and applicable biomarkers for interstitial lung diseases (ILDs) is lacking. There is a need for a large multicenter registry that provides researchers and clinicians access to well-characterized data not limited to patients with idiopathic pulmonary fibrosis. The Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) is a database that collects baseline and longitudinal demographic and clinical information about patients with ILDs in the United States. The objective of this study is to describe the patient population, data collection process, and opportunities for retrospective and prospective research with the PFF-PR. Individuals 18 years or older who had ILD diagnosed and who were seen at PFF-PR centers who provided informed consent were eligible to participate. Baseline and longitudinal demographic, spirometric, radiographic, morbidity, and mortality data are recorded into a secure electronic data capture system. Starting in 2016, the PFF-PR has collected data on 2,003 patients at 42 clinical sites in the United States. At the time of enrollment, the mean age of participants was 68 years old. Most (62%) of participants were male, and 58% had a positive smoking history. The mean forced vital capacity was 69% predicted, and the mean diffusing capacity of the lung for carbon monoxide was 43% predicted. Forty-one percent of patients were using supplemental oxygen, and 39% were on antifibrotic therapy. Reasons for attrition were mostly death or transplant, with low rates of loss to follow-up or withdrawal. The PFF-PR is a large multicenter United States-based registry that provides researchers and clinicians access to well-characterized ILD patient data.

Idiopathic pulmonary fibrosis (IPF) is a rare and serious condition that is associated with high health-care resource use. The goal of this study was to estimate hospital-related resource use and costs by using a national, prospective registry of patients who were diagnosed with IPF or who had their diagnosis confirmed at the enrolling center in the past 6 months in the United States.Participants enrolled between June 5, 2014, and April 12, 2016, in the ongoing Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry were included (N = 300). Time to first hospitalization was analyzed by using Kaplan-Meier methods. Annualized costs were estimated for hospitalizations, ICU admissions, and ED visits.At enrollment, most participants were male (75%), white (95%), commercially insured (64%), smokers (68%), had an FVC between 50% and 80% predicted (66%), and received antifibrotic drugs (55%). During the first 12 months of follow-up, participants averaged 0.11 ED visit, 0.42 hospitalization, 0.08 ICU admission, 2.18 hospital days, and 0.45 ICU day. Probability of hospitalization was 18% and 30% at 6 and 12 months, respectively, and was highest for those with FVC 50% predicted/diffusing lung capacity for carbon monoxide 30% predicted. Mean annual costs (95% CI) for ICU admission and inpatient care were $10,098 ($4,732-$16,662) and $13,975 ($8,482-$20,918), respectively, per patient.IPF is associated with a substantial economic burden incurred by patients requiring hospital care. Future research in IPF should focus on improving clinical outcomes while reducing cost of care in hospitals.ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov.

Background Limited data are available on the association between clinically measured disease severity markers and quality of life (QOL) in idiopathic pulmonary fibrosis (IPF). The study examined the associations between objective disease severity metrics and QOL in a contemporary IPF population. Methods This study evaluated baseline data from patients enrolled in the multicenter, US-based Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry between June 2014 and July 2018. Disease severity metrics included FVC % predicted, diffusing capacity for carbon monoxide (Dlco) % predicted, supplemental oxygen use with activity, supplemental oxygen use at rest, and two summary scores (the Gender-Age-Lung Physiology index, based on gender, age, and % predicted values for Dlco and FVC; and the Composite Physiologic Index, based on % predicted values for Dlco, FVC, and FEV1). Multivariable adjusted regression models were used to examine cross-sectional associations between each severity measure and St. George's Respiratory Questionnaire (SGRQ) total score. Results Among 829 patients with complete SGRQ data, the median (interquartile range) SGRQ score at enrollment was 40 (26-53), with higher scores indicating worse QOL. Modest SGRQ impairments were observed with increasing Gender-Age-Lung Physiology score (2.9 [1.8-4.0] per 1-point increase] and with increasing Composite Physiologic Index scores (3.0 [2.4-3.6] per 5-point increase). Substantial SGRQ impairments were observed for oxygen use with activity (15.6 [12.9-18.2]), oxygen use at rest (16.2 [13.0-19.4]), and decreasing Dlco (5.0 [4.0-6.1] per 10% decrease in % predicted). Conclusions Objective measures of disease severity, including severity scores, physiologic parameters, and supplemental oxygen use, are associated with worse QOL in patients with IPF. Trial Registry ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which diagnosis and management remain challenging. Defining the circulating proteome in IPF may identify targets for biomarker development. We sought to quantify the circulating proteome in IPF, determine differential protein expression between subjects with IPF and controls, and examine relationships between protein expression and markers of disease severity. Methods This study involved 300 patients with IPF from the IPF-PRO Registry and 100 participants without known lung disease. Plasma collected at enrolment was analysed using aptamer-based proteomics (1305 proteins). Linear regression was used to determine differential protein expression between participants with IPF and controls and associations between protein expression and disease severity measures (percent predicted values for forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DLco]; composite physiologic index [CPI]). Multivariable models were fit to select proteins that best distinguished IPF from controls. Results Five hundred fifty one proteins had significantly different levels between IPF and controls, of which 47 showed a |log2(fold-change)| > 0.585 (i.e. > 1.5-fold difference). Among the proteins with the greatest difference in levels in patients with IPF versus controls were the glycoproteins thrombospondin 1 and von Willebrand factor and immune-related proteins C-C motif chemokine ligand 17 and bactericidal permeability-increasing protein. Multivariable classification modelling identified nine proteins that, when considered together, distinguished IPF versus control status with high accuracy (area under receiver operating curve = 0.99). Among participants with IPF, 14 proteins were significantly associated with FVC % predicted, 23 with DLco % predicted, 14 with CPI. Four proteins (roundabout homolog-2, spondin-1, polymeric immunoglobulin receptor, intercellular adhesion molecule 5) demonstrated the expected relationship across all three disease severity measures. When considered in pathways analyses, proteins associated with the presence or severity of IPF were enriched in pathways involved in platelet and haemostatic responses, vascular or platelet derived growth factor signalling, immune activation, and extracellular matrix organisation. Conclusions Patients with IPF have a distinct circulating proteome and can be distinguished using a nine-protein profile. Several proteins strongly associate with disease severity. The proteins identified may represent biomarker candidates and implicate pathways for further investigation. Trial registration ClinicalTrials.gov (NCT01915511).

Over the past decade, several large registries of patients with idiopathic pulmonary fibrosis (IPF) have been established. These registries are collecting a wealth of longitudinal data on thousands of patients with this rare disease. The data collected in these registries will be complementary to data collected in clinical trials because the patient populations studied in registries have a broader spectrum of disease severity and comorbidities and can be followed for a longer period of time. Maintaining the quality and completeness of registry databases presents administrative and resourcing challenges, but it is important to ensuring the robustness of the analyses. Data from patient registries have already helped improve understanding of the clinical characteristics of patients with IPF, the impact that the disease has on their quality of life and survival, and current practices in diagnosis and management. In the future, analyses of biospecimens linked to detailed patient profiles will provide the opportunity to identify biomarkers linked to disease progression, facilitating the development of precision medicine approaches for prognosis and therapy in patients with IPF.

To evaluate the adherence and effectiveness of a home-based exergame program for patients with idiopathic pulmonary fibrosis (IPF).Patients with IPF were randomly assigned to a relatively unsupervised Wii Fit exergame intervention group or Wii video game control group (with no active whole-body movement involved). Participants in both groups were instructed to play their respective games 30 min/d, 3 d/wk for 12 wk. In addition, they were asked to perform their usual exercise/physical activities. Outcome measures were 6-min walk distance (6MWD), exercise-related dyspnea, and St George's Respiratory Questionnaire (SGRQ).The 20 participants differed significantly between intervention and control groups in baseline characteristics (forced vital capacity = 2.0 ± 0.5 vs 3.1 ± 0.7 L; forced expiratory volume in 1 sec = 1.7 ± 0.4 vs 2.5 ± 0.6 L, respectively). Participant adherence rate to the exergame program was very low (20%). There was no significant improvement in the outcome measures in either group. In fact, both the intervention and control groups had a deterioration in 6MWD (-22 ± 56 m vs -60 ± 111 m), respectively and SGRQ scores (3 ± 9 vs 1 ± 11), respectively.The home-based exergame intervention for patients with IPF did not show improvement in functional performance, dyspnea, or health-related quality of life at the completion of the 12-wk program in our 2 heterogeneous groups. In addition to the low adherence rate, insufficient frequencies and durations of exergaming may contribute to the lack of improvement. A lack of effectiveness of home-based pulmonary rehabilitation using exergaming for patients with IPF appears consistent with prior observational studies that used more traditional modes of home-based exercise.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.

Background Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes. Methods An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity. Results All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001). Conclusions Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)–dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2(−/−) and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.

Background Few data are available on the extent to which clinical practice is aligned with international guidelines for the management of idiopathic pulmonary fibrosis (IPF). We investigated the extent to which management guidelines for IPF have been implemented in the US IPF-PRO Registry and associations between implementation of guidelines and clinical outcomes. Methods We assessed the implementation of eight recommendations in clinical practice guidelines within the 6 months after enrollment: visit to a specialized clinic; pulmonary function testing; use of oxygen in patients with resting hypoxemia and exercise-induced hypoxemia; referral for pulmonary rehabilitation; treatment of gastro-esophageal reflux disease; initiation of anti-fibrotic therapy; referral for lung transplant evaluation. An implementation score was calculated as the number of recommendations achieved divided by the number for which the patient was eligible. Associations between implementation score and outcomes were analyzed using logistic regression and Cox proportional hazards models. Results Among 727 patients, median (Q1, Q3) implementation score was 0.6 (0.5, 0.8). Patients with an implementation score >0.6 had greater disease severity than those with a lower score. Implementation was lowest for referral for pulmonary rehabilitation (19.5%) and lung transplant evaluation (22.3%). In unadjusted models, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization, but no significant associations were observed in adjusted models. Conclusions Management guidelines were more likely to be implemented in patients with IPF with greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and clinical outcomes.

Purpose: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF), which slows disease progression. Management of patients with IPF receiving nintedanib can be complicated by tolerability issues, comorbidities, and concomitant medications. We developed consensus recommendations on the management of dosing, adverse events and comorbidities in patients with IPF treated with nintedanib. Methods: A modified Delphi process using 3 questionnaires was used to survey 14 pulmonologists experienced in using nintedanib. Panelists rated their agreement with statements on a Likert scale from −5 (strongly disagree) to +5 (strongly agree). Consensus was predefined as a mean score of ⩽−2.5 or ⩾+2.5 with a standard deviation not crossing zero. Results: The panelists’ recommendations were largely aligned with clinical trial data, real-world evidence, and the prescribing information, and provided additional guidance regarding minimizing gastrointestinal effects, periodic monitoring for liver dysfunction, caution with respect to concomitant administration of cytochrome P450 3A4 and P-glycoprotein 1 inhibitors and inducers and anticoagulants, and management of comorbidities. The panelists unanimously agreed that adverse event management should be individualized, based on careful consideration of the risks and benefits of each possible intervention and discussion with the patient. Conclusions: These consensus recommendations provide additional guidance on the appropriate management of IPF with nintedanib, for use alongside evidence-based literature and the prescribing information.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. Patient characteristics associated with diagnostic delays are not well described.MethodsSubjects who had not been diagnosed with IPF prior to referral and received a new diagnosis of IPF at an enrolling centre for the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry were characterised as having a longer (>1 year) or shorter (≤1 year) time from symptom onset to diagnosis and from first imaging evidence of fibrosis to diagnosis. Patient characteristics, evaluations and time to death or lung transplant were compared between these cohorts.ResultsAmong 347 patients with a symptom onset date, 49% were diagnosed with IPF >1 year after symptom onset. These patients were slightly younger and had more cardiac comorbidities than patients diagnosed ≤1 year after symptom onset. Among 454 patients with a date for imaging evidence of fibrosis, 78% were diagnosed with IPF ≤1 year later. A greater proportion of patients with >1 year versus ≤1 year from imaging evidence of fibrosis to diagnosis had cardiac comorbidities and gastro-oesophageal reflux. There was no significant difference in time to death or lung transplant between groups by time to diagnosis.ConclusionsThe time from symptom onset to diagnosis remains over 1 year in approximately half of the patients with IPF, but once imaging evidence is obtained, most of the patients are diagnosed within a year. Cardiac conditions and gastro-oesophageal disorders were more commonly reported in patients with a longer time to diagnosis.

BackgroundNumerous publications suggest an association between herpes virus infection and idiopathic pulmonary fibrosis (IPF). These reports have employed immunohistochemistry, in situ hybridization and/or PCR, which are susceptible to specificity artifacts.MethodsWe investigated the possible association between IPF and viral RNA expression using next-generation sequencing, which has the potential to provide a high degree of both sensitivity and specificity. We quantified viral RNA expression for 740 viruses in 28 IPF patient lung biopsy samples and 20 controls. Key RNA-seq results were confirmed using Real-time RT-PCR for select viruses (EBV, HCV, herpesvirus saimiri and HERV-K).ResultsWe identified sporadic low-level evidence of viral infections in our lung tissue specimens, but did not find a statistical difference for expression of any virus, including EBV, herpesvirus saimiri and HERV-K, between IPF and control lungs.ConclusionsTo the best of our knowledge, this is the first publication that employs RNA-seq to assess whether viral infections are linked to the pathogenesis of IPF. Our results do not address the role of viral infection in acute exacerbations of IPF, however, this analysis patently did not support an association between herpes virus detection and IPF.

Introduction Cellular senescence has been linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). CCN1 is a matricellular protein that has been shown to induce cellular senescence and contribute to lung fibrosis in pre-clinical models. In this report, we determined plasma CCN1 levels in patients with IPF and its potential role in clinical outcomes. Methods and Results We evaluated 88 patients diagnosed with IPF at the University of Alabama at Birmingham. CCN1 levels were measured in plasma specimens by ELISA. The primary outcome measure was transplant-free survival (TFS) duration. High-CCN1 levels were associated with a lower transplant-free survival independent of %FVC and %DLCO compared to patients with low plasma CCN1 (HR = 2.15; 95%CI 1.04–4.45, p = 0.04). Conclusion This study demonstrates that plasma levels of CCN1 may be predictive of survival in IPF. Given the plausible role of CCN1 in cellular senescence and pathobiology of IPF, the predictive value of CCN1 in disease progression among patients with IPF warrants further investigation.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with poor prognosis and limited therapeutic options. The 2011 ATS/ERS/JRS/ALAT consensus statement provided a number of recommendations for the management of IPF patients. The primary objective of this study was to determine if "bundling" these recommendations in the management of patients with IPF impacts clinical outcomes. Methods We conducted a single center, retrospective cohort study of 284 patients diagnosed with IPF. The proposed bundle of care (BOC) components were: (1) visits to a specialized interstitial lung diseases clinic with evaluation of pulmonary function tests at least twice yearly; (2) referral to pulmonary rehabilitation yearly; (3) timed walk test yearly; (4) echocardiogram yearly; and (5) gastroesophageal reflux therapy. Each component of the BOC was given a score of "1" per year of follow up, and the average sum of the scores (ranging from 0 to 5) was determined for the entire period of follow-up (BOC S ), as well as during the first year of follow-up (BOC Y1 ). The primary outcome measure was transplant-free survival. Results Age, gender, smoking status, BMI, %FVC, %D L CO did not differ between levels of BOC S and BOC Y1 . Lowest BOC S (≤1) was associated with a lower transplant-free survival independent of age and %FVC compared to patients with the highest BOC S (>4) (HR 2.274, CI 1.12–4.64, p = 0.024). Lower BOC Y1 was associated with a higher risk for transplant or death independent of age and %FVC in comparison to patients with highest BOC Y1 (≤1 vs. >4, HR 2.23, p = 0.014; >1 to 2 vs. >4, HR 1.87, p = 0.011; >2 to 3 vs. >4, HR 1.72, p = 0.019). Conclusion IPF patients with higher BOC scores had improved transplant-free survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of patients with IPF.

Introduction: IPF is a progressive and ultimately fatal interstitial lung disease with a variable clinical course. Aim: To assess relationships between clinical characteristics and death or lung transplant in patients with IPF. Methods: Data from patients with a newly established diagnosis of IPF enrolled in the US Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry from its inception on 5 June 2014 to 26 October 2017 were used to examine relationships between patient characteristics at time of enrolment and the composite outcome of all-cause death or lung transplant. Univariable associations were assessed using Cox proportional hazards models. Results: Of 662 patients enrolled, 111 events of death (91) or lung transplant (20) were observed over a follow-up period of 30 months. Older age; oxygen use at rest; oxygen use with activity; history of pulmonary hypertension; number of respiratory-related hospitalizations in the previous year; and worse disease severity based on FVC % predicted, DLco % predicted, CPI, or GAP stage were significantly associated with all-cause death or lung transplant (Table). Conclusion: Univariable analyses of data from the IPF-PRO Registry suggest that oxygen use was the strongest predictor of death or lung transplant in patients with IPF. Multivariable analyses will determine if the effect of oxygen use is independent of more well-established predictors.

A proportion of patients with interstitial lung diseases (ILDs) are at risk of developing a progressive-fibrosing phenotype, which is associated with a deterioration in lung function and early mortality. In addition to idiopathic pulmonary fibrosis (IPF), fibrosing ILDs that may present a progressive phenotype include idiopathic nonspecific interstitial pneumonia, connective tissue disease-associated ILDs, hypersensitivity pneumonitis, unclassifiable idiopathic interstitial pneumonia, ILDs related to other occupational exposures and sarcoidosis. Corticosteroids and/or immunosuppressive therapies are sometimes prescribed to patients with these diseases. However, this treatment regimen may not be effective, adequate on its own or well tolerated, suggesting that there is a pressing need for efficacious and better tolerated therapies. Currently, the only approved treatments to slow disease progression in patients with IPF are nintedanib and pirfenidone. Similarities in pathobiological mechanisms leading to fibrosis between IPF and other ILDs that may present a progressive-fibrosing phenotype provide a rationale to suggest that nintedanib and pirfenidone may be therapeutic options for patients with the latter diseases.This review provides an overview of the therapeutic options currently available for patients with fibrosing ILDs, including fibrosing ILDs that may present a progressive phenotype, and explores the status of the randomised controlled trials that are underway to determine the efficacy and safety of nintedanib and pirfenidone.

BACKGROUND The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes. METHODS The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures. RESULTS The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site. CONCLUSIONS The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov

Introduction: Previous studies have reported long delays from symptom onset to diagnosis of IPF. Aim: To assess time from symptom onset to diagnosis of IPF and compare clinical characteristics of patients who had long, typical, or short delays in diagnosis. Methods: Data from patients with newly diagnosed IPF participating in the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry were used to estimate the distribution of time from symptom onset to patients receiving a confirmed diagnosis of IPF. The cohort was stratified into quartiles of patients with a long (≥75th percentile), typical (between 25th and 75th percentile) or short (≤25th percentile) time from symptom onset to diagnosis and the clinical characteristics of these groups at enrollment into the registry were compared. Results: Of the first 424 patients enrolled, 300 patients had data available on time to diagnosis from symptom onset. Median (25th, 75th percentile) time from symptom onset to diagnosis of IPF was 12.6 (7.1, 26.3) months. There were no significant differences in clinical characteristics including age, oxygen use, pulmonary function, and 6-minute walk test distance between patients with a long, typical, or short time from symptom onset to diagnosis, except that patients with a longer time from symptom onset to diagnosis had worse symptoms based on the CASA-Q cough symptom and impact domains and worse health-related quality of life based on the SGRQ total and activity scores. Conclusion: Data from the IPF-PRO Registry suggest that while time to diagnosis of IPF appears to be shorter than previously reported, a quarter of patients were not diagnosed for ≥26 months after symptom onset.

Background: Fatigue is often reported as an adverse event (AE) in patients (pts) with IPF treated with PFD but is also an important symptom of IPF. Objective: To compare fatigue in pts with IPF receiving PFD or placebo (PBO) in the Phase III CAPACITY and ASCEND trials. Methods: All pts who received PFD 2403 mg/day (n=623) or PBO (n=624) from the pooled Phase III trials were analyzed to describe the frequency and time course of fatigue AEs using descriptive statistics and time-to-event analyses. Results: Fatigue AEs occurred in 162 pts treated with PFD (26.0%) and 119 with PBO (19.1%). Moderate and severe fatigue occurred in 67 (10.8%) and 7 (1.1%) PFD pts vs 26 (4.2%) and 5 (0.8%) PBO pts, respectively. Dose modification occurred following 17.6% of fatigue AEs with PFD (39/222) vs 7.0% (10/142) with PBO. Fatigue occurred sooner after randomization (median [IQR], 30.5 [13.0-231.0] vs 36.0 [7.0-168.0] days) and for shorter duration (64.0 [7.0-214.5] vs 109.5 [24.0-267.0] days) in the PFD vs PBO groups, respectively (Figure). There were no meaningful differences in baseline characteristics between pts with fatigue vs those without in either PFD or PBO groups. Conclusions: Fatigue AEs tended to be more frequent, shorter and slightly more severe in pts with IPF treated with PFD vs PBO. A fatigue questionnaire to quantitatively assess fatigue in pts with IPF might be considered in future IPF trials.

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic lung disease characterized by the presence of invasive myofibroblasts in the lung. Currently, there are only two FDA-approved drugs (pirfenidone and nintedanib) for the treatment of IPF. There are no defined criteria to guide specific drug therapy. New methodologies are needed not only to predict personalized drug therapy, but also to screen novel molecules that are on the horizon for treatment of IPF. We have developed a model system that exploits the invasive phenotype of IPF lung tissue. This ex vivo 3D model uses lung tissue from patients to develop pulmospheres. Pulmospheres are 3D spheroids composed of cells derived exclusively from primary lung biopsies and inclusive of lung cell types reflective of those in situ, in the patient. We tested the pulmospheres of 20 subjects with IPF and 9 control subjects to evaluate the responsiveness of individual patients to antifibrotic drugs. Clinical parameters and outcomes were also followed in the same patients. Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF.

Autoimmunity has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the repertoire of autoantigens involved in this disease and the clinical relevance of these autoimmune responses are still being explored. Our initial discovery assays demonstrated that circulating and intrapulmonary vimentin levels are increased in IPF patients. Subsequent studies showed native vimentin induced HLA-DR–dependent in vitro proliferation of CD4 T cells from IPF patients and enhanced the production of IL-4, IL-17, and TGF-β1 by these lymphocytes in contrast to normal control specimens. Vimentin supplementation of IPF PBMC cultures also resulted in HLA-DR–dependent production of IgG with anti-vimentin specificities. Circulating anti-vimentin IgG autoantibody levels were much greater in IPF subjects from the University of Alabama at Birmingham (n = 102) and the University of Pittsburgh (U. Pitt., n = 70) than in normal controls. Anti-vimentin autoantibody levels in IPF patients were HLA biased and inversely correlated with physiological measurements of lung function (i.e., forced expiratory volumes and diffusing capacities). Despite considerable intergroup differences in transplant-free survival between these two independent IPF cohorts, serious adverse outcomes were most frequent among the patients within each population that had the highest anti-vimentin autoantibody levels (University of Alabama at Birmingham: hazard ratio 2.5, 95% confidence interval 1.2–5.3, p = 0.012; University of Pittsburgh: hazard ratio 2.7, 95% confidence interval 1.3–5.5, p = 0.006). These data show that anti-vimentin autoreactivity is prevalent in IPF patients and is strongly associated with disease manifestations. These findings have implications with regard to the pathogenesis of this enigmatic disease and raise the possibility that therapies specifically directed at these autoimmune processes could have therapeutic efficacy.

Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking.In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period.At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P0.99).As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.).

The Pulmonary Biospecimen Repository (PBR) at the University of Alabama at Birmingham (UAB) was launched in 2009. The purpose of the UAB PBR is to provide investigators within the pulmonary community at UAB and elsewhere with clinical samples derived from multiple lung diseases, including transplant recipients, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, and asthma. Cell and fluid samples isolated from bronchoalveolar lavage (BAL), plasma, and serum are collected and stored; samples are assessed routinely for viability. Each sample is linked directly with the respective patient information via the Pulmonary Translational Research and Clinical Database, a Health Insurance Portability and Accountability Act compliant database that includes detailed information allowing for the study of specific patient cohorts. To access samples, investigators must complete a request form, which is reviewed by the UAB PBR Steering Committee. To date, more than 800 patients have provided approximately 7,000 BAL, serum and plasma fluid, and cell samples. Over the past 4 years, nearly 800 of these samples have been distributed to investigators at UAB and elsewhere. Future plans for the UAB PBR include expanding sample collection to additional pulmonary diseases, such as mycobacterial infections, increasing the number of sample users and obtaining external funding to ensure its continued sustainability.

BackgroundThe processes that result in progression of idiopathic pulmonary fibrosis (IPF) remain enigmatic. Moreover, the course of this disease can be highly variable and difficult to accurately predict. We hypothesized analyses of body mass index (BMI), a simple, routine clinical measure, may also have prognostic value in these patients, and might provide mechanistic insights. We investigated the associations of BMI changes with outcome, plasma adipokines, and adaptive immune activation among IPF patients.MethodsData were analyzed in an IPF discovery cohort (n = 131) from the University of Pittsburgh, and findings confirmed in patients from the University of Alabama at Birmingham (n = 148). Plasma adipokines were measured by ELISA and T-cell phenotypes determined by flow cytometry.ResultsTransplant-free one-year survivals in subjects with the greatest rates of BMI decrements, as percentages of initial BMI (>0.68%/month), were worse than among those with more stable BMI in both discovery (HR = 1.8, 95%CI = 1.1-3.2, p = 0.038) and replication cohorts (HR = 2.5, 95%CI = 1.2-5.2, p = 0.02), when adjusted for age, baseline BMI, and pulmonary function. BMI decrements >0.68%/month were also associated with greater mortality after later lung transplantations (HR = 4.6, 95%CI = 1.7-12.5, p = 0.003). Circulating leptin and adiponectin levels correlated with BMI, but neither adipokine was prognostic per se. BMI decrements were significantly associated with increased proportions of circulating end-differentiated (CD28null) CD4 T-cells (CD28%), a validated marker of repetitive T-cell activation and IPF prognoses.ConclusionsIPF patients with greatest BMI decrements had worse outcomes, and this effect persisted after lung transplantation. Weight loss in these patients is a harbinger of poor prognoses, and may reflect an underlying systemic process, such as adaptive immune activation.

Rationale: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline in lung function, resulting in significant morbidity and mortality. Current concepts of the pathogenesis of IPF primarily center on dysregulated epithelial cell repair and altered epithelial-mesenchymal communication and extracellular matrix deposition following chronic exposure to cigarette smoke or environmental toxins. In recent years, increasing attention has been directed toward the role of the intercellular junctional complex in determining the specific properties of epithelia in pulmonary diseases. Additionally, recent genomewide association studies suggest that specific genetic variants predictive of epithelial cell dysfunction may confer susceptibility to the development of sporadic idiopathic pulmonary fibrosis. A number of genetic disorders linked to pulmonary fibrosis and familial interstitial pneumonias are associated with loss of epithelial integrity. However, the potential links between extrapulmonary clinical syndromes associated with defects in epithelial cells and the development of pulmonary fibrosis are not well understood. Here, we report a case of hereditary mucoepithelial dysplasia that presented with pulmonary fibrosis and emphysema on high-resolution computed tomography. This case illustrates a more generalizable concept of epithelial disintegrity in the development of fibrotic lung diseases, which is explored in greater detail in this review article.

Rationale: Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis.Objectives: In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC.Methods: This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy.Measurements and Main Results: The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality o...

Purpose of review The lung in systemic sclerosis (scleroderma) is susceptible to fibrosis and the ensuing respiratory insufficiency contributes to significant morbidity and mortality in this disease. The lack of effective therapies for pulmonary fibrosis has spurred a re-evaluation of pathobiological paradigms and therapeutic strategies in scleroderma-associated interstitial lung disease and in idiopathic pulmonary fibrosis. The purpose of this review is to examine emerging new therapeutic targets that modulate pro-fibrotic phenotypes of tissue-resident cells and the associated aberrant tissue remodeling responses in fibrotic disorders. Recent findings Progressive forms of tissue fibrosis, including scleroderma, are characterized by an accumulation of activated mesenchymal cells and their secreted extracellular matrix proteins in association with dysrepair of epithelial and endothelial cells. Recent studies suggest that emergence of cellular phenotypes that perpetuate loss of cellular homeostasis is characteristic of many fibrosis-related clinical syndromes. Summary Therapeutic strategies that modulate the fate/phenotype of reparative structural cells, including epithelial, endothelial, and mesenchymal cells, offer new opportunities for the development of more effective drugs for the treatment of fibrosis.

Background The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. Methods Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival. Results The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years). Conclusions Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0614-x) contains supplementary material, which is available to authorized users.

FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway.

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs.

The Pulmonary Biospecimen Repository (PBR) at the University of Alabama at Birmingham (UAB) was launched in 2009. The purpose of the UAB PBR is to provide investigators within the pulmonary community at UAB and elsewhere with clinical samples derived from multiple lung diseases, including transplant recipients, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, and asthma. Cell and fluid samples isolated from bronchoalveolar lavage (BAL), plasma, and serum are collected and stored; samples are assessed routinely for viability. Each sample is linked directly with the respective patient information via the Pulmonary Translational Research and Clinical Database, a Health Insurance Portability and Accountability Act compliant database that includes detailed information allowing for the study of specific patient cohorts. To access samples, investigators must complete a request form, which is reviewed by the UAB PBR Steering Committee. To date, more than 800 patients have provided approximately 7,000 BAL, serum and plasma fluid, and cell samples. Over the past 4 years, nearly 800 of these samples have been distributed to investigators at UAB and elsewhere. Future plans for the UAB PBR include expanding sample collection to additional pulmonary diseases, such as mycobacterial infections, increasing the number of sample users and obtaining external funding to ensure its continued sustainability.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause characterized by progressive scarring of the lung parenchyma and relentless loss of lung function. The diagnosis depends on close collaboration between clinicians, radiologists, and pathologists. No therapies approved by the Food and Drug Administration are available for IPF, and an analysis of completed clinical trials has demonstrated that the clinical course of IPF is largely unpredictable. Until therapies that improve survival become available, measures to preserve function and quality of life should be considered, and gastroesophageal reflux should be treated aggressively.