112 results on '"Kevin F Gibson"'
Search Results
2. Randomized Phase IIa Clinical Study of an Anti-αvβ6Monoclonal Antibody in Idiopathic Pulmonary Fibrosis
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Ganesh Raghu, Majd Mouded, Antje Prasse, Christopher Stebbins, Guolin Zhao, Guochen Song, Million Arefayene, Shelia M. Violette, Diana Gallagher, and Kevin F. Gibson
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Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine - Published
- 2022
3. Nurse-Led Palliative Care Clinical Trial Improves Knowledge and Preparedness in Caregivers of Patients with Idiopathic Pulmonary Fibrosis
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Melinda S Veatch, Margaret Rosenzweig, Kathleen O. Lindell, Sara Klein, Daniel J. Kass, Mehdi Nouraie, and Kevin F. Gibson
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Palliative care ,business.industry ,Palliative Care ,Symptom burden ,MEDLINE ,medicine.disease ,Nurse's Role ,Idiopathic Pulmonary Fibrosis ,humanities ,Poor quality ,Nurse led ,Idiopathic pulmonary fibrosis ,Quality of life (healthcare) ,Caregivers ,Preparedness ,Quality of Life ,medicine ,Humans ,Intensive care medicine ,business ,Aged ,Original Research - Abstract
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).
- Published
- 2021
4. Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease
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Gillian C. Goobie, Christopher Carlsten, Kerri A. Johannson, Nasreen Khalil, Veronica Marcoux, Deborah Assayag, Hélène Manganas, Jolene H. Fisher, Martin R. J. Kolb, Kathleen O. Lindell, James P. Fabisiak, Xiaoping Chen, Kevin F. Gibson, Yingze Zhang, Daniel J. Kass, Christopher J. Ryerson, and S. Mehdi Nouraie
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Male ,Air Pollutants ,Canada ,Carbon Monoxide ,Nitrates ,Sulfates ,Pulmonary Fibrosis ,Correction ,Environmental Exposure ,Middle Aged ,Cohort Studies ,Air Pollution ,Ammonium Compounds ,Internal Medicine ,Humans ,Female ,Particulate Matter ,Prospective Studies ,Lung ,Aged - Abstract
ImportanceParticulate 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.ObjectiveTo investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD.Design, Setting, and ParticipantsIn 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.ExposuresExposure 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 MeasuresMultivariable 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).ResultsMedian 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 RelevanceThis 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.
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- 2022
5. PM
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Gillian C, Goobie, Xiaoyun, Li, Christopher J, Ryerson, Christopher, Carlsten, Kerri A, Johannson, James P, Fabisiak, Kathleen O, Lindell, Xiaoping, Chen, Kevin F, Gibson, Daniel J, Kass, S Mehdi, Nouraie, and Yingze, Zhang
- Abstract
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
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- 2022
6. A Phase IIb Randomized Clinical Study of an Anti-α
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Ganesh, Raghu, Majd, Mouded, Daniel C, Chambers, Fernando J, Martinez, Luca, Richeldi, Lisa H, Lancaster, Mark J, Hamblin, Kevin F, Gibson, Ivan O, Rosas, Antje, Prasse, Guolin, Zhao, Michael, Serenko, Natasha, Novikov, Amy, McCurley, Prashant, Bansal, Christopher, Stebbins, Million, Arefayene, Stella, Ibebunjo, Shelia M, Violette, Diana, Gallagher, and Jürgen, Behr
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Treatment Outcome ,Double-Blind Method ,Immunoglobulin G ,Humans ,Antibodies, Monoclonal ,Idiopathic Pulmonary Fibrosis - Published
- 2022
7. PM2.5 and constituent component impacts on global DNA methylation in patients with idiopathic pulmonary fibrosis
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Gillian C. Goobie, Xiaoyun Li, Christopher J. Ryerson, Christopher Carlsten, Kerri A. Johannson, James P. Fabisiak, Kathleen O. Lindell, Xiaoping Chen, Kevin F. Gibson, Daniel J. Kass, S. Mehdi Nouraie, and Yingze Zhang
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Health, Toxicology and Mutagenesis ,General Medicine ,Toxicology ,Pollution - Published
- 2023
8. Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency
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Buqu Hu, Wenlan Zang, Naftali Kaminski, Maor Sauler, Erica L. Herzog, Michael J. Becich, Stephen R. Wisniewski, Yingze Zhang, Milica Vukmirovic, Ronald G. Collman, Joseph K. Leader, Alison Morris, Kevin F. Gibson, Charlie Strange, Jonas C. Schupp, Taylor Adams, Karen C. Patterson, Edward S. Chen, Antun Mihaljinec, Harry Hochheiser, Jen-Hwa Chu, Frank C. Sciurba, Xiting Yan, Robert A. Sandhaus, and Giuseppe DeIuliis
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Genotype ,Neutrophils ,Disease ,Transcriptome ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,alpha 1-Antitrypsin Deficiency ,Gene expression ,medicine ,Humans ,Gene Regulatory Networks ,Prospective Studies ,Gene ,030304 developmental biology ,0303 health sciences ,Alpha 1-antitrypsin deficiency ,medicine.diagnostic_test ,business.industry ,Gene Expression Profiling ,Middle Aged ,medicine.disease ,Bronchoalveolar lavage ,030228 respiratory system ,Immunology ,Female ,business ,Bronchoalveolar Lavage Fluid - Abstract
BackgroundAlpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.MethodsWe performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects’ clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.ResultWe observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.ConclusionsWe successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals’ genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.
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- 2020
9. The Pulmonary Fibrosis Foundation Patient Registry. Rationale, Design, and Methods
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Ganesh Raghu, Steven D. Nathan, Kevin R. Flaherty, Kevin F. Gibson, Cindy Burg, Imre Noth, Mridu Gulati, Gregory P. Cosgrove, Bonnie R Wang, Jack Stauffer, Lisa Lancaster, Scott Staszak, Wendi R. Mason, Rex Edwards, Elizabeth A. Freiheit, Joao A. de Andrade, Bill Schmidt, Paul J. Wolters, Yicheng Ma, Cathie Spino, and Kathleen O. Lindell
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Vital capacity ,Electronic data capture ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Informed consent ,Diffusing capacity ,Pulmonary fibrosis ,medicine ,Humans ,Prospective Studies ,Registries ,030212 general & internal medicine ,Aged ,Retrospective Studies ,Lung ,Patient registry ,business.industry ,Editorials ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,medicine.anatomical_structure ,030228 respiratory system ,Emergency medicine ,Lung Diseases, Interstitial ,business - Abstract
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.
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- 2020
10. PM 2.5 and Constituent Component Impacts on Global DNA Methylation in Patients with Idiopathic Pulmonary Fibrosis
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Gillian C. Goobie, Xiaoyun Li, Christopher J. Ryerson, Chris Carlsten, Kerri A. Johannson, James P. Fabisiak, Kathleen O. Lindell, Xiaoping Chen, Kevin F. Gibson, Daniel J. Kass, Mehdi Nouraie, and Yingze Zhang
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- 2022
11. Association of Particulate Matter Exposure with Lung Function and Mortality in Fibrotic Interstitial Lung Disease: A Multinational Cohort Study
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Gillian C. Goobie, Chris Carlsten, Kerri A. Johannson, Nasreen Khalil, Veronica Marcoux, Deborah Assayag, Hélène Manganas, Jolene H. Fisher, Martin Kolb, Kathleen O. Lindell, James P. Fabisiak, Xiaoping Chen, Kevin F. Gibson, Yingze Zhang, Daniel J. Kass, Christopher J. Ryerson, and Mehdi Nouraie
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
12. Comparative Profiling of Serum Protein Biomarkers in Rheumatoid Arthritis–Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis
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Ted R. Mikuls, Mehdi Nouraie, Karen Fernandez, Bryant R. England, Lisa Harlow, Dana P. Ascherman, Nitya Ramreddy, Kevin F. Gibson, Paul F. Dellaripa, Jean Chen, Andreas M. Reimold, Yingze Zhang, Ivan O. Rosas, Daniel J. Kass, Marilyn K. Glassberg, Chester V. Oddis, and Gail S. Kerr
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Immunology ,Arthritis ,Enzyme-Linked Immunosorbent Assay ,behavioral disciplines and activities ,Proinflammatory cytokine ,Arthritis, Rheumatoid ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Registries ,Aged ,030203 arthritis & rheumatology ,business.industry ,Interstitial lung disease ,Blood Proteins ,Middle Aged ,respiratory system ,medicine.disease ,Blood proteins ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,body regions ,030228 respiratory system ,Rheumatoid arthritis ,Cohort ,Regression Analysis ,Biomarker (medicine) ,Female ,Lung Diseases, Interstitial ,business ,Biomarkers - Abstract
Objective Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF. Methods Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling. Results Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD. Conclusion Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF.
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- 2020
13. The Role of Palliative Care in Reducing Symptoms and Improving Quality of Life for Patients with Idiopathic Pulmonary Fibrosis: A Review
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Richard H. Zou, Kathleen O. Lindell, Daniel J. Kass, and Kevin F. Gibson
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Quality of life ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Palliative care ,Referral ,medicine.medical_treatment ,Population ,Idiopathic pulmonary fibrosis ,Review ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,Respiratory Care ,medicine ,Pulmonary rehabilitation ,030212 general & internal medicine ,Intensive care medicine ,education ,lcsh:RC705-779 ,education.field_of_study ,business.industry ,lcsh:Diseases of the respiratory system ,medicine.disease ,Chronic cough ,030228 respiratory system ,medicine.symptom ,business - Abstract
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.
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- 2020
14. GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis
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Robert Lafyatis, Erica L. Herzog, Tracy Tabib, Changwan Ryu, Daniel J. Kass, Mao Jiang, Mark G. Roth, Yingze Zhang, John F. McDyer, Spencer A. Winters, X. Chen, John Sembrat, Mehdi Nouraie, Mauricio Rojas, Yanxia Chu, Kevin F. Gibson, Jonathan K. Alder, Rubin M. Tuder, and Nayra Cardenes
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Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Growth Differentiation Factor 15 ,Physiology ,Disease ,SASP ,Severity of Illness Index ,Bleomycin ,Mice ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Physiology (medical) ,Animals ,Humans ,Medicine ,Lung ,Aged ,business.industry ,Gene Expression Profiling ,aging ,Cell Biology ,Middle Aged ,Telomere ,respiratory system ,medicine.disease ,Survival Analysis ,Idiopathic Pulmonary Fibrosis ,Respiratory Function Tests ,MIC-1 ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Alveolar Epithelial Cells ,Case-Control Studies ,NAG-1 ,Biomarker (medicine) ,Female ,GDF15 ,Transcriptome ,business ,Bronchoalveolar Lavage Fluid ,Research Article - Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ( Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.
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- 2019
15. A novel protein signature from plasma extracellular vesicles for non-invasive differential diagnosis of idiopathic pulmonary fibrosis
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Nagarjun V. Konduru, K. Cai, K.V. Alzate, Kevin F. Gibson, Hiroshi Iwamoto, Li L, Joan W. Miller, de Frías Fp, Lynette M. Sholl, A.K. Pal, de Frías Sp, Adduri Rs, Yingze Zhang, Cherian S, Noboru Hattori, R. Vasireddy, Daniel J. Kass, David A. Schwartz, Yasushi Horimasu, Ivan O. Rosas, and Daniela Nicastro
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Pathology ,medicine.medical_specialty ,Lung ,business.industry ,Lung biopsy ,respiratory system ,medicine.disease ,respiratory tract diseases ,Transcriptome ,Idiopathic pulmonary fibrosis ,medicine.anatomical_structure ,Usual interstitial pneumonia ,Proteome ,medicine ,Differential diagnosis ,business ,Hypersensitivity pneumonitis - Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown etiology often leading to respiratory failure. Over half of IPF patients present with discordant features of usual interstitial pneumonia on high-resolution computed tomography at diagnosis which warrants surgical lung biopsy to exclude the possibility of other interstitial lung diseases (ILDs). Therefore, there is a need for non-invasive biomarkers for expediting the differential diagnosis of IPF. Methods: Using mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in a cohort of subjects with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects (HS). A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. We evaluated the concordance between plasma EV proteome and the lung transcriptome data. Lastly, we compared the molecular pathways overrepresented in IPF by differentially expressed proteins and transcripts from EVs and lung tissues, respectively. Results: The five-protein signature derived from mass spectrometry data showed area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from HS, respectively. We also found that the EV protein expression profiles mirrored their corresponding mRNA expressions in IPF lungs. Further, we observed an overlap in the EV proteome- and lung mRNA-associated molecular pathways. Conclusions: We discovered a plasma EV-based protein signature for differential diagnosis of IPF and validated this signature in an independent cohort. The signature needs to be tested in large prospective cohorts to establish its clinical utility.
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- 2021
16. Differential Expression of Amino Acid Metabolites in the Plasma of Patients with Pulmonary Sarcoidosis Is Associated with Clinical Behavior
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Kevin F. Gibson, Y. Zhang, Seyed Mehdi Nouraie, Daniel J. Kass, Jared Chiarchiaro, Stephen B Strock, W. Bhatti, Kristen L. Veraldi, and Richard H. Zou
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chemistry.chemical_classification ,medicine.medical_specialty ,Endocrinology ,Pulmonary sarcoidosis ,Chemistry ,Internal medicine ,medicine ,Differential expression ,Amino acid - Published
- 2020
17. Extracellular Matrix Biomarkers Predict Lung Function and Rate of Decline in Pulmonary Sarcoidosis
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D.J. Leeming, Daniel J. Kass, J.M.B. Sand, Seyed Mehdi Nouraie, Gillian C Goobie, Kevin F. Gibson, Y. Zhang, H. Jessen, and M. Karsdal
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Extracellular matrix ,Pathology ,medicine.medical_specialty ,Pulmonary sarcoidosis ,business.industry ,medicine ,business ,Lung function - Published
- 2020
18. S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension
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Yingze Zhang, Jose D. Herazo-Maya, Hubert J. Ford, Hongyi Pan, Jen-Hwa Chu, Argyrios Tzouvelekis, Ferhaan Ahmad, Erica L. Herzog, Naftali Kaminski, Changwan Ryu, Kevin F. Gibson, Benjamin M. Cherry, Wassim H. Fares, Percy K. Adonteng-Boateng, and Qin Li
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Pulmonary and Respiratory Medicine ,Cardiac output ,medicine.medical_specialty ,Lung ,business.industry ,030204 cardiovascular system & hematology ,medicine.disease ,Peripheral blood mononuclear cell ,Gastroenterology ,Pulmonary hypertension ,World health ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Internal medicine ,Cohort ,Medicine ,Biomarker (medicine) ,business - Abstract
BACKGROUND AND OBJECTIVE Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH. METHODS Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality. RESULTS The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts. CONCLUSION S100A12 levels are increased in PH patients and are associated with increased mortality.
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- 2018
19. INVASIVE AND NONINVASIVE DIAGNOSIS OF CARDIAC SARCOIDOSIS: A CASE SERIES
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Kevin F. Gibson, Tiffany Brazile, Melissa Saul, and Seyed Mehdi Nouraie
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Pulmonary and Respiratory Medicine ,Series (stratigraphy) ,medicine.medical_specialty ,business.industry ,Medicine ,Radiology ,Cardiac sarcoidosis ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine ,business - Published
- 2021
20. Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis
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Mridu Gulati, Wajahat Z. Mehal, Jaden Faunce, Caitlin Brandsdorfer, Jose D. Herazo-Maya, Varvara Kirillov, Jonathan Puchalski, Daniel F Bogenhagen, Christina Blaul, Erica L. Herzog, Anjelica L. Gonzalez, Glenda Trujillo, Raimund I. Herzog, Kathleen O. Lindell, Martin D. Slade, Huanxing Sun, Changwan Ryu, Kevin F. Gibson, Naftali Kaminski, Yonglin Chen, Julia Winkler, Argyrios Tzouvelekis, Danielle Antin-Ozerkis, Tony Woolard, Hongyi Pan, Carol Feghali-Bostwick, Charles S. Dela Cruz, and Awo Osafo-Addo
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Mitochondrial DNA ,Mitochondrion ,Biology ,Critical Care and Intensive Care Medicine ,DNA, Mitochondrial ,Disease-Free Survival ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,medicine ,Extracellular ,Humans ,Fibroblast ,Aged ,Innate immune system ,medicine.diagnostic_test ,Editorials ,Original Articles ,Fibroblasts ,respiratory system ,Prognosis ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immunology ,Cancer research ,Female ,Myofibroblast ,Biomarkers - Abstract
Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.We aimed to define an association between mtDNA and fibroblast responses in IPF.We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.
- Published
- 2017
21. BASELINE EXERTIONAL OXYGEN NEEDS IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS AT A SPECIALTY REFERRAL CENTER
- Author
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Noorien Mamoor, Kathleen O. Lindell, Waqas Bhatti, Kevin F. Gibson, Jessica Bon, Daniel J. Kass, Susanne Kushnerick, Frank C. Sciurba, Seyed Mehdi Nouraie, and X. Chen
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Specialty ,Critical Care and Intensive Care Medicine ,medicine.disease ,Idiopathic pulmonary fibrosis ,Internal medicine ,Medicine ,Referral center ,In patient ,Cardiology and Cardiovascular Medicine ,business ,Baseline (configuration management) - Published
- 2020
22. Microbiome in lung explants of idiopathic pulmonary fibrosis: a case–control study in patients with end-stage fibrosis
- Author
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Kevin F. Gibson, Shulin Qin, Kristen L. Veraldi, Adam Fitch, Joseph M. Pilewski, Barbara A. Methé, Daniel J. Kass, Bryan J. McVerry, Mauricio Rojas, Alison Morris, Kelvin Li, Georgios D Kitsios, John Sembrat, Kathleen O. Lindell, and John F. McDyer
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Cystic Fibrosis ,Pulmonary Fibrosis ,Cystic fibrosis ,Article ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Fibrosis ,RNA, Ribosomal, 16S ,medicine ,Humans ,Microbiome ,Lung ,medicine.diagnostic_test ,business.industry ,Microbiota ,Case-control study ,Respiratory infection ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,030228 respiratory system ,Case-Control Studies ,business - Abstract
The microbiome has been proposed to play a role in the progression of idiopathic pulmonary fibrosis (IPF) based on bronchoalveolar lavage analyses, but the microbiome of lung tissue in IPF has not been explored. In a case–control study of lung explants analysed by 16S rRNA gene sequencing, we could not reliably detect bacterial DNA in basilar tissue samples from patients with either chronic or acute exacerbations of IPF, in contrast to control candidate-donor lungs or cystic fibrosis explants. Thus, our data do not indicate microbiome alterations in regions of IPF lung with advanced fibrosis.
- Published
- 2017
23. Referral to Palliative Care Infrequent in Patients with Idiopathic Pulmonary Fibrosis Admitted to an Intensive Care Unit
- Author
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Kevin F. Gibson, Melissa Saul, Michael P. Donahoe, Kathleen O. Lindell, Zhan Liang, Mehdi Nouraie, Leslie A. Hoffman, and Daniel J. Kass
- Subjects
Male ,medicine.medical_specialty ,Palliative care ,Referral ,law.invention ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,DLCO ,law ,Critical care nursing ,Diffusing capacity ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Referral and Consultation ,General Nursing ,Aged ,Retrospective Studies ,Medical Audit ,business.industry ,Palliative Care ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,Intensive care unit ,Idiopathic Pulmonary Fibrosis ,Hospitalization ,Intensive Care Units ,Anesthesiology and Pain Medicine ,030228 respiratory system ,Female ,business - Abstract
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.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.Retrospective review.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.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.Due to high mortality associated with ICU admission, patients and families should be informed about palliative care early following diagnosis of IPF.
- Published
- 2017
24. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial
- Author
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Thomas G. O'Riordan, Jenny Zhang, Emmanuel Moreau, Paul W. Noble, Kevin F. Gibson, Jin Woo Song, Fernando J. Martinez, Victoria Smith, Harold R. Collard, Athol U. Wells, Vincent Cottin, Selina Bayly, Qi Gong, Kevin K. Brown, Ganesh Raghu, Scott D. Patterson, Wim A. Wuyts, Timothy P.M. Whelan, Jason W. Chien, David J. Lederer, and Robert J. Kaner
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Indoles ,Pyridones ,Population ,Antibodies, Monoclonal, Humanized ,Placebo ,Disease-Free Survival ,Drug Administration Schedule ,law.invention ,03 medical and health sciences ,FEV1/FVC ratio ,Idiopathic pulmonary fibrosis ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Progression-free survival ,Enzyme Inhibitors ,Adverse effect ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Middle Aged ,Interim analysis ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Surgery ,Treatment Outcome ,030104 developmental biology ,Female ,Amino Acid Oxidoreductases ,business - Abstract
Summary Background Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. Methods In this randomised, double-blind, phase 2 trial, we recruited patients aged 45–85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196. Findings Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention-to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12·6 months and 15·4 months for simtuzumab and placebo, respectively; stratified HR 1·13, 95% CI 0·88–1·45; p=0·329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11·7 months and 14·3 months for simtuzumab and placebo, respectively; stratified HR 1·03, 95% CI 0·74–1·43; p=0·851), or in the 75th percentile or higher (median progression-free survival 11·6 months and 16·9 months for simtuzumab and placebo, respectively; stratified HR 1·20, 95% CI 0·72–2·00; p=0·475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. Interpretation Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF. Funding Gilead Sciences Inc.
- Published
- 2017
25. Risk factors for disease progression in idiopathic pulmonary fibrosis
- Author
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Qi Gong, John S. Sundy, Kevin K. Brown, Athol U. Wells, Paul W. Noble, Brett Ley, Scott D. Patterson, Kevin F. Gibson, Timothy P.M. Whelan, Stephen M. Humphries, Vincent Cottin, David A. Lynch, Emmanuel Moreau, Victoria C. Smith, Fernando J. Martinez, David J. Lederer, Robert J. Kaner, Krista Goodman, Jin Woo Song, Ganesh Raghu, and Thomas G. O'Riordan
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Vital capacity ,Population ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,FEV1/FVC ratio ,0302 clinical medicine ,Clinical Trials, Phase II as Topic ,Risk Factors ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Treatment Failure ,Respiratory system ,education ,Aged ,Randomized Controlled Trials as Topic ,Retrospective Studies ,education.field_of_study ,business.industry ,Retrospective cohort study ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Respiratory Function Tests ,Clinical trial ,030228 respiratory system ,Disease Progression ,Female ,business ,Predictive modelling - Abstract
In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.
- Published
- 2019
26. Evaluating the Role of Support Group Participation on Palliative Care Referral and Mortality in Idiopathic Pulmonary Fibrosis
- Author
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Kevin F. Gibson, Daniel J. Kass, Richard H. Zou, Kathleen O. Lindell, Margaret Rosenzweig, Seyed Mehdi Nouraie, X. Chen, and Naftali Kaminski
- Subjects
medicine.medical_specialty ,Idiopathic pulmonary fibrosis ,Palliative care ,Referral ,business.industry ,medicine.medical_treatment ,medicine ,Intensive care medicine ,medicine.disease ,business ,Support group - Published
- 2019
27. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis
- Author
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Wei Chen, Humberto E. Trejo Bittar, Kevin F. Gibson, Robert Lafyatis, Eleanor Valenzi, John Sembrat, Tracy Tabib, Kristina L. Buschur, Panayiotis V. Benos, Christina Morse, Ana L. Mora, Mauricio Rojas, Yale Jiang, and Daniel J. Kass
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Fatty Acid-Binding Proteins ,Pathogenesis ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine ,Macrophage ,Humans ,Myofibroblasts ,Lung ,Cell Proliferation ,Inhibin-beta Subunits ,Stochastic Processes ,Innate immune system ,c-Mer Tyrosine Kinase ,business.industry ,Sequence Analysis, RNA ,Monocyte ,Macrophages ,Epithelial Cells ,respiratory system ,MERTK ,Fibroblasts ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Immunity, Innate ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immune System ,Osteopontin ,Single-Cell Analysis ,business ,Macrophage proliferation - Abstract
A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs.Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
- Published
- 2019
28. Differential Expression of Plasma Metabolites in Patients with Pulmonary Sarcoidosis is Associated with Clinical Behavior
- Author
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Kevin F. Gibson, Daniel J. Kass, Mehdi Nouraie, Jared Chiarchiaro, Yingze Zhang, Stephen B Strock, and Kristen L. Veraldi
- Subjects
medicine.medical_specialty ,business.industry ,Gastroenterology ,stomatognathic diseases ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Metabolomics ,030228 respiratory system ,Prednisone ,hemic and lymphatic diseases ,Internal medicine ,medicine ,In patient ,030212 general & internal medicine ,Analysis of variance ,Metabolon ,Biomarker discovery ,Differential expression ,business ,medicine.drug - Abstract
Introduction: We hypothesized that a comprehensive metabolomic analysis of plasma from sarcoid patients (pts) would identify potential biomarkers of disease severity. Methods & Results: This study is a cross-sectional analysis of sarcoid pts seen at our Center between February 2003 and July 2014. Plasma from 60 pulmonary sarcoid patients and 40 aged-matched donor controls were tested (Table 1) was subjected to metabolomic profiling (Metabolon) for 893 known biochemicals. Following normalization to volume extracted, log transformation and imputation of missing values, if any, with the minimum observed value for each compound, ANOVA contrasts and Welch’s two-sample t-test were used to identify biochemicals that differed significantly between experimental groups. Differential expression of chemicals that were decreased in sarcoid included steroids, but notably not prednisone, which is consistent with steroid treatment and adrenal suppression. Differential expression of chemicals that were increased in sarcoid mapped to amino acid metabolism. In sarcoid pts only, based on Pearson correlations, one amino acid, N-acetylthreonine, was associated with FVC (R=−0.38, P Conclusion: Metabolomics profiling for biomarker discovery in sarcoid is feasible, and candidate biomarkers should be prioritized for further testing.
- Published
- 2018
29. Identification of Cell Populations with Increase Expression of Markers of Cell Senescence in Explanted IPF Lungs
- Author
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Nina Morse, Tamara Cruz, Tracy Tabib, Mauricio Rojas, Wei Chen, Robert Lafyatis, Kristina L. Buschur, Takis Benos, Kevin F. Gibson, John Sembrat, Ana L. Mora, Humberto Trejo, and Lan Tu
- Subjects
Senescence ,medicine.anatomical_structure ,business.industry ,Cell ,medicine ,Identification (biology) ,business ,Cell biology - Published
- 2018
30. Lessons learned when recruiting for an early Idiopathic Pulmonary Fibrosis (IPF) palliative care intervention
- Author
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Kevin F. Gibson, Margaret Rosenzweig, Kathleen O. Lindell, Sara Klein, Mehdi Nouraie, Melinda Klesen, and Daniel J. Kass
- Subjects
Idiopathic pulmonary fibrosis ,medicine.medical_specialty ,Palliative care ,business.industry ,Intervention (counseling) ,medicine ,medicine.disease ,Intensive care medicine ,business - Published
- 2018
31. Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase
- Author
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SeungHye Han, Courtney Snavely, Bill B. Chen, Shristi Rajbhandari, Dexter L. Gulick, Jacob A. Jerome, Rama K. Mallampalli, Travis Lear, Kevin F. Gibson, and Chunbin Zou
- Subjects
Lipopolysaccharides ,Inflammasomes ,Ubiquitin-Protein Ligases ,Immunology ,Interleukin-1beta ,NALP3 ,Biochemistry ,F-box protein ,Cell Line ,Proinflammatory cytokine ,AIM2 ,Ubiquitin ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Humans ,Molecular Biology ,SKP Cullin F-Box Protein Ligases ,biology ,F-Box Proteins ,Interleukin-18 ,Ubiquitination ,Inflammasome ,Cell Biology ,Immunity, Innate ,Ubiquitin ligase ,Cell biology ,Proteolysis ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Interleukin 18 ,Carrier Proteins ,medicine.drug - Abstract
The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, the NALP3 inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1β and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1β in cells. Here we show that LPS increases the NALP3 protein lifespan without significantly altering steady-state mRNA in human cells. LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. A unique small molecule inhibitor of FBXO3 restores FBXL2 levels, resulting in decreased NALP3 protein levels in cells and, thereby, reducing the release of IL-1β and IL-18 in human inflammatory cells after NALP3 activation. Our findings uncover NALP3 as a molecular target for FBXL2 and suggest that therapeutic targeting of the inflammasome may serve as a platform for preclinical intervention.
- Published
- 2015
32. Palliative Care and Location of Death in Decedents With Idiopathic Pulmonary Fibrosis
- Author
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Kathleen O. Lindell, Leslie A. Hoffman, Joseph M. Pilewski, Melissa Saul, Naftali Kaminski, Kevin F. Gibson, Zhan Liang, and Margaret Rosenzweig
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Time Factors ,Palliative care ,Referral ,medicine.medical_treatment ,Specialty ,Critical Care and Intensive Care Medicine ,Idiopathic pulmonary fibrosis ,Quality of life (healthcare) ,Correspondence ,medicine ,Humans ,Lung transplantation ,Intensive care medicine ,Referral and Consultation ,Aged ,Aged, 80 and over ,Terminal Care ,business.industry ,Palliative Care ,Interstitial lung disease ,Middle Aged ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Community hospital ,Emergency medicine ,Quality of Life ,Female ,Cardiology and Cardiovascular Medicine ,business ,Lung Transplantation - Abstract
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.
- Published
- 2015
33. A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis
- Author
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Patrick Hess, Brenda Juan Guardela, Kevin F. Gibson, Naftali Kaminski, Markus Rey, Edgar Weber, Simon de Bernard, Axel Klenk, Yasmina Bauer, Sylvie Poirey, Kathleen O. Lindell, Bérengère Renault, John Tedrow, Magdalena Birker-Robaczewska, and Oliver Nayler
- Subjects
Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,NELL1 ,Clinical Biochemistry ,Gene Expression ,Biology ,Bleomycin ,MMP7 ,Rats, Sprague-Dawley ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Correspondence ,Gene expression ,medicine ,Animals ,Humans ,Lung ,Molecular Biology ,Original Research ,Epithelial Cells ,Genomic signature ,Genomics ,Cell Biology ,Fibroblasts ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,FHL2 ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Protein Biosynthesis ,Immunology ,Signal Transduction - Abstract
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.
- Published
- 2015
34. Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis
- Author
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Kevin F. Gibson, Imre Noth, Kevin R. Flaherty, Katia Rothhaar, Michael J. Klemsz, Sarah Frye, Terrence Chew, Naftali Kaminski, Wade Lange, and David S. Wilkes
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Vital capacity ,Vital Capacity ,Administration, Oral ,Placebo ,Gastroenterology ,Cohort Studies ,Idiopathic pulmonary fibrosis ,Internal medicine ,Humans ,Medicine ,Dosing ,Adverse effect ,Lung ,Serum Albumin ,Aged ,business.industry ,Complement C1q ,Middle Aged ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Respiratory Function Tests ,respiratory tract diseases ,Clinical trial ,Matrix Metalloproteinase 7 ,Cohort ,Female ,Immunotherapy ,Patient Safety ,business ,Collagen Type V ,Biomarkers ,Cohort study - Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. IPF appears to be heterogeneous in pathobiology with ∼40% of IPF patients found to have elevated levels of circulating antibodies to the autoantigen type V collagen (col(V)).Following a targeted, precision medicine approach, we conducted a phase 1 study to test the safety and explore potential efficacy of IW001, a col(V) oral immunotherapeutic developed to treat antibody-positive IPF patients. We divided 30 antibody-positive IPF patients into three cohorts for daily dosing over a 24-week period.All patients completed treatment without serious adverse events, acute exacerbations or IPF-related hospitalisations. A decline in lung function occurred in the lowest-dose cohort that was comparable to that reported in placebo arms of published IPF trials. In contrast, the highest-dose cohort showed a trend toward stabilisation of forced vital capacity and matrix metalloproteinase 7, and a reduction in binding of C1q to anti-col(V) antibodies.IW001 may modulate the immune response to col(V) and may represent a new therapeutic for col(V)- reactive IPF patients.
- Published
- 2015
35. The Pulmonary Histopathology of Anti-KS Transfer RNA Synthetase Syndrome
- Author
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Kevin F. Gibson, Frank Schneider, Samuel A. Yousem, David Bi, Chester V. Oddis, and Rohit Aggarwal
- Subjects
Adult ,Male ,Connective Tissue Disorder ,medicine.medical_specialty ,Pathology ,Aspartate-tRNA Ligase ,Antisynthetase syndrome ,RNA, Transfer, Amino Acyl ,Pathology and Forensic Medicine ,Amino Acyl-tRNA Synthetases ,Diagnosis, Differential ,Fibrosis ,Usual interstitial pneumonia ,Humans ,Medicine ,Registries ,Lung ,Myositis ,Autoantibodies ,Retrospective Studies ,business.industry ,Interstitial lung disease ,General Medicine ,Middle Aged ,medicine.disease ,Review Literature as Topic ,Medical Laboratory Technology ,medicine.anatomical_structure ,Female ,Histopathology ,Lung Diseases, Interstitial ,business - Abstract
Context The clinical spectrum of the antisynthetase syndromes (AS) has been poorly defined, although some frequently present with pulmonary manifestations. The anti-KS anti–asparaginyl-transfer RNA synthetase syndrome is one in which pulmonary interstitial lung disease is almost always present and yet the histopathologic spectrum is not well described. Objective To define the morphologic manifestations of pulmonary disease in those patients with anti-KS antiasparaginyl syndrome. Design We reviewed the connective tissue disorder registry of the University of Pittsburgh and identified those patients with anti-KS autoantibodies who presented with interstitial lung disease and had surgical lung biopsies. Results The 5 patients with anti-KS antisynthetase syndrome were usually women presenting with dyspnea and without myositis, but with mechanic's hands (60%) and Raynaud phenomenon (40%). They most often presented with a usual interstitial pneumonia pattern of fibrosis (80%), with the final patient displaying organizing pneumonia. Conclusions Pulmonary interstitial lung disease is a common presentation in patients with the anti-KS–antisynthetase syndrome, who are often women with rather subtle or subclinical connective tissue disease, whereas the literature emphasizes the nonspecific interstitial pneumonia pattern often diagnosed clinically. Usual interstitial pneumonia and organizing pneumonia patterns of interstitial injury need to be added to this clinical differential diagnosis.
- Published
- 2015
36. S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension
- Author
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Argyrios, Tzouvelekis, Jose D, Herazo-Maya, Changwan, Ryu, Jen-Hwa, Chu, Yingze, Zhang, Kevin F, Gibson, Percy K, Adonteng-Boateng, Qin, Li, Hongyi, Pan, Benjamin, Cherry, Ferhaan, Ahmad, Hubert J, Ford, Erica L, Herzog, Naftali, Kaminski, and Wassim H, Fares
- Subjects
Adult ,Male ,Hypertension, Pulmonary ,S100A12 Protein ,Middle Aged ,Prognosis ,Article ,Cohort Studies ,Case-Control Studies ,Leukocytes, Mononuclear ,Humans ,Female ,Cardiac Output ,Lung ,Biomarkers ,Aged - Abstract
Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH.Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality.The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P0.001) and negatively correlated with cardiac output (r = -0.58, P0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P0.001) cohorts.S100A12 levels are increased in PH patients and are associated with increased mortality.
- Published
- 2017
37. Insights from RNA-sequencing of bronchoalveolar lavage cells in a large sarcoidosis cohort
- Author
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Taylor Adams, Buqu Hu, Scott M. O'Neal, Tony Woolard, Panagiotis V. Benos, Michael J. Becich, Yingze Zhang, David R. Moller, Erica L. Herzog, Joseph K. Leader, Robert M. Senior, Mridu Gulati, Hubertus D. Luijk, Nachelle Aurelien, Laura L. Koth, Alison Morris, Harry Hochheiser, Xiting Yan, Naftali Kaminski, Stephen R. Wisniewski, Kevin F. Gibson, Wenlan Zang, Giuseppe DeIuliis, Joe G. N. Garcia, Antun Mihaljinec, Wonder P. Drake, Milica Vukmirovic, Lisa A. Maier, and Edward S. Chen
- Subjects
medicine.diagnostic_test ,cDNA library ,business.industry ,medicine.disease ,Phenotype ,Transcriptome ,Exon ,Bronchoalveolar lavage ,Gene expression ,Immunology ,medicine ,Sarcoidosis ,business ,Gene - Abstract
Introduction: We analyzed the transcriptome of bronchoalveolar lavage cells (BAL) in a large cohort of well characterized sarcoidosis subjects by RNA-sequencing to better understand disease progression and severity, and potentially identify novel molecular phenotypes. Methods: BAL was performed on subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (GRADS) as described (Moller et al., Ann Am Thorac Soc, 2015 PMID: 26193069). cDNA libraries were prepared from 1ug of RNA and sequenced by Ion Torrent Proton Sequencer. Cufflinks calculated Fragments per Kilobase of exon per Million (FPKM) values. Non-parametric correlation methods and Metacore identified significant genes and pathways. Weighted gene co-expression network analysis (WGCNA) revealed correlation networks between gene expression and clinical traits. Multiple hypothesis testing was controlled at FDR Results: 199 samples from 24 stage I, 33 stage II-III treated, 40 stage II-III untreated, 17 stage IV treated, and 12 stage IV untreated subjects were available (53.2% females, 23.1% blacks). Correlation analysis revealed that 65 genes were increased with advanced Scadding stage and 24 were decreased (FDR Conclusion: RNA-sequencing of BAL in sarcoidosis patients identified novel genes associated with features of disease. Preliminary analysis suggests the presence of molecular disease endotypes.
- Published
- 2017
38. Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study
- Author
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Yingze Zhang, Philip L. Molyneaux, Juan C. Osorio, Kevin F. Gibson, Imre Noth, Antje Prasse, Kathleen O. Lindell, Joe G.N. Garcia, William O.C.M. Cookson, Ziv Bar-Joseph, Brenda Juan-Guardela, Melinda Klesen, Ivan O. Rosas, Jose D. Herazo-Maya, Xiting Yan, Miriam F. Moffatt, Toby M. Maher, Qin Li, Jiehuan Sun, Erica L. Herzog, George Michel, Nachelle Aurelien, Heather Lynn, Hongyu Zhao, Naftali Kaminski, Julian A. Villalba, Argyrios Tzouvelekis, Cristobal Risquez, Medical Research Council (MRC), Royal Brompton & Harefield NHS Foundation Trust, and National Institute for Health Research
- Subjects
Male ,Vital capacity ,Time Factors ,Respiratory System ,Vital Capacity ,PROTEIN ,SERUM ,Cohort Studies ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Risk Factors ,Pulmonary fibrosis ,030212 general & internal medicine ,Prospective cohort study ,Oligonucleotide Array Sequence Analysis ,Hazard ratio ,ASSOCIATION ,Middle Aged ,Prognosis ,3. Good health ,PROGNOSTIC VALUE ,SURVIVAL ,MAST-CELLS ,Female ,Risk assessment ,Life Sciences & Biomedicine ,Cohort study ,Pulmonary and Respiratory Medicine ,EXPRESSION ,Genetic Markers ,medicine.medical_specialty ,Risk Assessment ,Article ,03 medical and health sciences ,Critical Care Medicine ,Internal medicine ,General & Internal Medicine ,medicine ,Humans ,Genetic Testing ,Intensive care medicine ,Aged ,Proportional Hazards Models ,Science & Technology ,Proportional hazards model ,business.industry ,MORTALITY ,Gene Expression Profiling ,medicine.disease ,POLYMORPHISM ,Idiopathic Pulmonary Fibrosis ,030228 respiratory system ,Leukocytes, Mononuclear ,Linear Models ,business ,FORCED VITAL CAPACITY - Abstract
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
- Published
- 2017
39. PaTH: towards a learning health system in the Mid-Atlantic region
- Author
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William Shirey, Sonye K. Danoff, Bari Dzomba, Mitch Parker, Mike Jacobs, Lisa Khorey, Mary Mueller, Chad Pettengill, Anne E.F. Dimmock, Harold P Lehmann, G. Daniel Martich, Diana Gumas, Charles D. Borromeo, Mark G. Weiner, Thomas Abendroth, Richard Rauscher, Jeremy Kahn, Joseph Y. Cheung, Anne Boland Docimo, Gerald Naccarelli, Arthur Berg, Art Feldman, Nae-Yuh Wang, Sally C. Morton, Michael J. Becich, Anuradha Paranjape, Jeanne M. Clark, Sandeep Jain, Erdlen Frank, Sam Meiselman, Wishwa N. Kapoor, Rachel Hess, Rebecca Bascom, Jeremy U. Espino, Maribel Valentin, Daniel E. Ford, Jennifer L. Kraschnewski, Kathleen M. McTigue, Harold Paz, Daniel A. Notterman, Waqas Amin, Wenke Hwang, Francis Cordova, Robert Oberteuffer, Christopher N. Sciamanna, Theresa A Heinrich, Kruti Mohan, Aaron A. Sorensen, Kathleen O. Lindell, Chris Ryan, Kevin F. Gibson, Cynthia H. Chuang, Saman Nazarian, and Fu-Chiang Tsui
- Subjects
Knowledge management ,Best practice ,Information Dissemination ,Health Informatics ,Health informatics ,patient reported outcomes (PROs) ,Computer Communication Networks ,Nursing ,Patient-Centered Care ,patient-centered outcomes research (PCORI) ,Outcome Assessment, Health Care ,Electronic Health Records ,Humans ,Medicine ,Mid-Atlantic Region ,business.industry ,clinical data research network (CDRN) ,Focus on Building a Network for Patient-Centered Outcomes Research ,electronic health records (EHRs) ,Outreach ,Data sharing ,I2B2 ,distributed cohort query ,Informatics ,Medical Record Linkage ,business ,PATH (variable) - Abstract
The PaTH (University of Pittsburgh/UPMC, Penn State College of Medicine, Temple University Hospital, and Johns Hopkins University) clinical data research network initiative is a collaborative effort among four academic health centers in the Mid-Atlantic region. PaTH will provide robust infrastructure to conduct research, explore clinical outcomes, link with biospecimens, and improve methods for sharing and analyzing data across our diverse populations. Our disease foci are idiopathic pulmonary fibrosis, atrial fibrillation, and obesity. The four network sites have extensive experience in using data from electronic health records and have devised robust methods for patient outreach and recruitment. The network will adopt best practices by using the open-source data-sharing tool, Informatics for Integrating Biology and the Bedside (i2b2), at each site to enhance data sharing using centrally defined common data elements, and will use the Shared Health Research Information Network (SHRINE) for distributed queries across the network.
- Published
- 2014
40. Bosentan for Sarcoidosis-Associated Pulmonary Hypertension
- Author
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Robert P. Baughman, Daniel A. Culver, Peter J. Engel, Maria Padilla, Kevin F. Gibson, Elyse E. Lower, and Francis Cordova
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Critical Care and Intensive Care Medicine ,Placebo ,medicine.disease ,Pulmonary hypertension ,Bosentan ,Pulmonary function testing ,medicine.anatomical_structure ,Internal medicine ,medicine.artery ,Heart catheterization ,Pulmonary artery ,Vascular resistance ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Pulmonary wedge pressure ,medicine.drug - Abstract
Background Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH. Methods This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy. Results Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean ± SD fall in PA mean pressure (−4 ± 6.6 mm Hg, P = .0105) and PVR (−1.7 ± 2.75 Wood units, P = .0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1 ± 3.7 mm Hg, P > .05) or PVR (0.1 ± 1.42 Wood units, P > .05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by > 2 L after 16 weeks of therapy. Conclusions This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH. Trial registry ClinicalTrials.gov ; No: NCT00581607; URL: www.clinicaltrials.gov
- Published
- 2014
41. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression
- Author
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Yingze Zhang, Joanne I. Adamkewicz, Lixin Shao, Kathleen O. Lindell, Victoria Smith, Kevin F. Gibson, Thomas G. O'Riordan, Susan K. Lyman, Jason W. Chien, Naftali Kaminski, and Thomas J. Richards
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Cart ,medicine.medical_specialty ,Vital capacity ,Pathology ,Lysyl oxidase ,Gastroenterology ,Cohort Studies ,Idiopathic pulmonary fibrosis ,Risk Factors ,Internal medicine ,medicine ,Humans ,Pathological ,Aged ,Immunoassay ,Carbon Monoxide ,LOXL2 ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Disease Progression ,Regression Analysis ,Female ,Amino Acid Oxidoreductases ,business ,Biomarkers ,Cohort study - Abstract
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.
- Published
- 2013
42. The Lung Microbiome in Idiopathic Pulmonary Fibrosis. What Does It Mean and What Should We Do about It?
- Author
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Ronald G. Collman, Alison Morris, and Kevin F. Gibson
- Subjects
Pulmonary and Respiratory Medicine ,Lung microbiome ,Idiopathic pulmonary fibrosis ,Pathology ,medicine.medical_specialty ,business.industry ,medicine ,Critical Care and Intensive Care Medicine ,medicine.disease ,business - Published
- 2014
43. Plasma B Lymphocyte Stimulator and B Cell Differentiation in Idiopathic Pulmonary Fibrosis Patients
- Author
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Marc C. Levesque, Eva Csizmadia, Leo E. Otterbein, Naftali Kaminski, Kevin F. Gibson, Makoto Soejima, Jessica Bon, Frank C. Sciurba, Michael P. Donahoe, Jiangning Tan, Louis J. Vuga, Daniel J. Kass, Joseph M. Pilewski, Steven R. Duncan, and Jianmin Xue
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Lymphocyte ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Article ,Pathogenesis ,Idiopathic pulmonary fibrosis ,Immune system ,B-Cell Activating Factor ,Humans ,Immunology and Allergy ,Medicine ,Restrictive lung disease ,B-cell activating factor ,B cell ,Aged ,Aged, 80 and over ,CD20 ,B-Lymphocytes ,biology ,business.industry ,Cell Differentiation ,Middle Aged ,respiratory system ,Flow Cytometry ,medicine.disease ,Immunohistochemistry ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,medicine.anatomical_structure ,biology.protein ,Female ,business - Abstract
We hypothesized B cells are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive, restrictive lung disease that is refractory to glucocorticoids and other nonspecific therapies, and almost invariably lethal. Accordingly, we sought to identify clinically associated B cell–related abnormalities in these patients. Phenotypes of circulating B cells were characterized by flow cytometry. Intrapulmonary processes were evaluated by immunohistochemistry. Plasma B lymphocyte stimulating factor (BLyS) was assayed by ELISA. Circulating B cells of IPF subjects were more Ag differentiated, with greater plasmablast proportions (3.1 ± 0.8%) than in normal controls (1.3 ± 0.3%) (p < 0.03), and the extent of this differentiation correlated with IPF patient lung volumes (r = 0.44, p < 0.03). CD20+ B cell aggregates, diffuse parenchymal and perivascular immune complexes, and complement depositions were all prevalent in IPF lungs, but much less prominent or absent in normal lungs. Plasma concentrations of BLyS, an obligate factor for B cell survival and differentiation, were significantly greater (p < 0.0001) in 110 IPF (2.05 ± 0.05 ng/ml) than among 53 normal (1.40 ± 0.04 ng/ml) and 90 chronic obstructive pulmonary disease subjects (1.59 ± 0.05 ng/ml). BLyS levels were uniquely correlated among IPF patients with pulmonary artery pressures (r = 0.58, p < 0.0001). The 25% of IPF subjects with the greatest BLyS values also had diminished 1-y survival (46 ± 11%), compared with those with lesser BLyS concentrations (81 ± 5%) (hazard ratio = 4.0, 95% confidence interval = 1.8–8.7, p = 0.0002). Abnormalities of B cells and BLyS are common in IPF patients, and highly associated with disease manifestations and patient outcomes. These findings have implications regarding IPF pathogenesis and illuminate the potential for novel treatment regimens that specifically target B cells in patients with this lung disease.
- Published
- 2013
44. P015 <break /> Variable Advance Care Planning in Patients in the PaTH Idiopathic Pulmonary Fibrosis Cohort
- Author
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Kevin F. Gibson, Cynthia H. Chuang, Michael Green, Kathleen O. Lindell, Sonye K. Danoff, Rebecca Bascom, Harold P Lehmann, Anne E.F. Dimmock, and Francis Cordova
- Subjects
Advance care planning ,Variable (computer science) ,Idiopathic pulmonary fibrosis ,Pediatrics ,medicine.medical_specialty ,business.industry ,Cohort ,Medicine ,In patient ,General Medicine ,business ,medicine.disease ,PATH (variable) - Published
- 2016
45. P016 <break /> Impact of Idiopathic Pulmonary Fibrosis on Executive Functioning: A Cross-Sectional Analysis
- Author
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Francis Cordova, Sonye K. Danoff, Kathleen O. Lindell, Rebecca Bascom, Kevin F. Gibson, Cynthia H. Chuang, Harold P Lehmann, and Anne E.F. Dimmock
- Subjects
medicine.medical_specialty ,Idiopathic pulmonary fibrosis ,Cross-sectional study ,business.industry ,Internal medicine ,medicine ,General Medicine ,medicine.disease ,business - Published
- 2016
46. P107 <break /> Implementing PCORI Methodology Standards for Patient Engagement in the PaTH Idiopathic Pulmonary Fibrosis Cohort
- Author
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Francis Cordova, James Carns, Kevin F. Gibson, Cynthia H. Chuang, Rebecca Bascom, Kathleen O. Lindell, Anne E.F. Dimmock, Mary-Beth Scholand, Sonye K. Danoff, and James Uhrig
- Subjects
medicine.medical_specialty ,Idiopathic pulmonary fibrosis ,business.industry ,Patient-centered outcomes ,Cohort ,Physical therapy ,medicine ,Patient engagement ,General Medicine ,medicine.disease ,business ,Intensive care medicine - Abstract
Introduction: By statutory mandate, the United States Patient Centered Outcomes Research Institute’s (PCORI) aims to “improve clinical decision-making by supporting research…. with patients and their caregivers at the center of this process.” We analyzed the PCORI-funded PaTH Idiopathic Pulmonary Fibrosis (PaTH IPF) cohort’s …
- Published
- 2016
47. New molecular targets for the treatment of sarcoidosis
- Author
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Jared Chiarchiaro, Bill B. Chen, and Kevin F. Gibson
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung ,Sarcoidosis ,business.industry ,Mortality rate ,Disease ,medicine.disease ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Chronic granulomatous disease ,medicine.anatomical_structure ,030228 respiratory system ,Rheumatoid arthritis ,Psoriasis ,Immunology ,Molecular targets ,Medicine ,Humans ,business - Abstract
Purpose of review Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. Recent findings Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. Summary Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease.
- Published
- 2016
48. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia
- Author
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David McKean, Diana Zelenika, Megan S. Devine, Christine Kim Garcia, David A. Schwartz, Keith P Smith, Philip L. Molyneaux, Yingze Zhang, Pamela Russell, Harold R. Collard, Kevin K. Brown, Elizabeth A. Regan, Barry J. Make, Hannah C. Ainsworth, Annie Pardo, Mark P. Steele, Steve D. Groshong, Gunnar Gudmundsson, Carl D. Langefeld, Naftali Kaminski, Toby M. Maher, Karl Kossen, Brian M. Freed, Yoichiro Kamatani, Moisés Selman, Weiming Zhang, Elissa Murphy, Miriam F. Moffatt, Dinesha Walek, Rachel Z. Blumhagen, David A. Lynch, Helgi J Isaksson, Cheryl Markin, Mark Lathrop, Gregory P. Cosgrove, Kenneth B. Beckman, Jerry Daniel, Janet Talbert, James E. Loyd, James D. Crapo, Paul J. Wolters, Julia Powers, Scott D. Seiwert, Brent S. Pedersen, Marvin I. Schwarz, Roland M. du Bois, Tasha E. Fingerlin, Ivana V. Yang, Williamson Z. Bradford, Athol U. Wells, Lisa Lancaster, Dong Soon Kim, and Kevin F. Gibson
- Subjects
0301 basic medicine ,Adult ,Male ,Linkage disequilibrium ,Locus (genetics) ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Linkage Disequilibrium ,Pulmonary fibrosis ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,medicine ,Genetics ,HLA-DQ beta-Chains ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,RNA-Seq ,Allele ,Idiopathic interstitial pneumonia ,Genotyping ,Genetics (clinical) ,Aged ,Imputation ,Genetics & Heredity ,0604 Genetics ,Sequence Analysis, RNA ,Gene Expression Profiling ,Middle Aged ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,3. Good health ,030104 developmental biology ,030228 respiratory system ,Gene Expression Regulation ,Genetic Loci ,HLA association ,Chromosomes, Human, Pair 6 ,Female ,Gene expression ,Research Article ,Genome-Wide Association Study ,HLA-DRB1 Chains - Abstract
Background Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. Results We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 Pmeta = 3.7 × 10−09). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10−7 and DQB1*06:02 P = 6.1 × 10−8). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q
- Published
- 2016
49. The palliative care needs of patients with idiopathic pulmonary fibrosis: A qualitative study of patients and family caregivers
- Author
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Kevin F. Gibson, Margaret Rosenzweig, Dio Kavalieratos, Kathleen O. Lindell, and Laura Tycon
- Subjects
Pulmonary and Respiratory Medicine ,Advance care planning ,Male ,medicine.medical_specialty ,Palliative care ,Specialty ,Disease ,Critical Care and Intensive Care Medicine ,Article ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,medicine ,Humans ,Family ,030212 general & internal medicine ,Intensive care medicine ,Aged ,Quality of Health Care ,Aged, 80 and over ,Family caregivers ,business.industry ,Palliative Care ,Middle Aged ,medicine.disease ,Focus group ,Idiopathic Pulmonary Fibrosis ,030228 respiratory system ,Caregivers ,Female ,Thematic analysis ,Cardiology and Cardiovascular Medicine ,business ,Needs Assessment - Abstract
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.
- Published
- 2016
50. Myositis-associated usual interstitial pneumonia has a better survival than idiopathic pulmonary fibrosis
- Author
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Samuel A. Yousem, Frank Schneider, Chester V. Oddis, Christine McBurney, Kathleen O. Lindell, Kevin F. Gibson, Carl R. Fuhrman, and Rohit Aggarwal
- Subjects
Adult ,Male ,medicine.medical_specialty ,Vital capacity ,Biopsy ,Lung biopsy ,Comorbidity ,Kaplan-Meier Estimate ,Gastroenterology ,Cohort Studies ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Rheumatology ,Usual interstitial pneumonia ,Internal medicine ,Cause of Death ,medicine ,Humans ,Pharmacology (medical) ,Registries ,Survival analysis ,Aged ,Proportional Hazards Models ,Retrospective Studies ,030203 arthritis & rheumatology ,Myositis ,business.industry ,Proportional hazards model ,Hazard ratio ,Interstitial lung disease ,respiratory system ,Middle Aged ,medicine.disease ,Prognosis ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,030228 respiratory system ,Female ,Radiology ,business ,Respiratory Insufficiency ,Tomography, X-Ray Computed - Abstract
Objective To compare the survival outcomes between myositis-associated usual interstitial pneumonia (MA-UIP) and idiopathic pulmonary fibrosis (IPF-UIP). Methods Adult MA-UIP and IPF-UIP patients were identified using CTD and IPF registries. The MA-UIP cohort included myositis or anti-synthetase syndrome patients with interstitial lung disease while manifesting UIP on high-resolution CT chest and/or a lung biopsy revealing UIP histology. IPF subjects met American Thoracic Society criteria and similarly had UIP histopathology. Kaplan-Meier survival curves compared cumulative and pulmonary event-free survival (event = transplant or death) between (i) all MA-UIP and IPF-UIP subjects, (ii) MA-UIP with biopsy proven UIP (n = 25) vs IPF-UIP subjects matched for age, gender and baseline forced vital capacity (±10%). Cox proportional hazards ratios compared the survival controlling for co-variates. Results Eighty-one IPF-UIP and 43 MA-UIP subjects were identified. The median cumulative and event-free survival time in IPF vs MA-UIP was 5.25/1.8 years vs 16.2/10.8 years, respectively. Cumulative and event-free survival was significantly worse in IPF-UIP vs MA-UIP [hazards ratio of IPF-UIP was 2.9 (95% CI: 1.5, 5.6) and 5.0 (95% CI: 2.8, 8.7) (P < 0.001), respectively]. IPF-UIP event-free survival (but not cumulative) remained significantly worse than MA-UIP with a hazards ratio of 6.4 (95% CI: 3.0, 13.8) after controlling for age at interstitial lung disease diagnosis, gender, ethnicity and baseline forced vital capacity%. Respiratory failure was the most common cause of death in both groups. A sub-analysis of 25 biopsy-proven MA-UIP subjects showed similar results. Conclusion MA-UIP patients demonstrated a significant survival advantage over a matched IPF cohort, suggesting that despite similar histological and radiographic findings at presentation, the prognosis of MA-UIP is superior to that of IPF-UIP.
- Published
- 2016
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