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Rationale: Distinguishing connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging. Objectives: To identify proteins that separate and classify patients with CTD-ILD and those with IPF. Methods: Four registries with 1,247 patients with IPF and 352 patients with CTD-ILD were included in analyses. Plasma samples were subjected to high-throughput proteomics assays. Protein features were prioritized using recursive feature elimination to construct a proteomic classifier. Multiple machine learning models, including support vector machine, LASSO (least absolute shrinkage and selection operator) regression, random forest, and imbalanced Random Forest, were trained and tested in independent cohorts. The validated models were used to classify each case iteratively in external datasets. Measurements and Main Results: A classifier with 37 proteins (proteomic classifier 37 [PC37]) was enriched in the biological process of bronchiole development and smooth muscle proliferation and immune responses. Four machine learning models used PC37 with sex and age score to generate continuous classification values. Receiver operating characteristic curve analyses of these scores demonstrated consistent areas under the curve of 0.85-0.90 in the test cohort and 0.94-0.96 in the single-sample dataset. Binary classification demonstrated 78.6-80.4% sensitivity and 76-84.4% specificity in the test cohort and 93.5-96.1% sensitivity and 69.5-77.6% specificity in the single-sample classification dataset. Composite analysis of all machine learning models confirmed 78.2% (194 of 248) accuracy in the test cohort and 82.9% (208 of 251) in the single-sample classification dataset. Conclusions: Multiple machine learning models trained with large cohort proteomic datasets consistently distinguished CTD-ILD from IPF. Many of the identified proteins are involved in immune pathways. We further developed a novel approach for single-sample classification, which could facilitate honing the differential diagnosis of ILD in challenging cases and improve clinical decision making.

Background: Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD)., Methods: A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure., Results: The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery p interaction =0.013; replication p interaction =0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD., Conclusion: Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression., Competing Interests: Conflict of interest: D. Zhang reports consulting fees from Boehringer Ingelheim, and grant support from the Stony Wold-Herbert Fund and Parker B. Francis Foundation. A. Adegunsoye reports consulting fees from Genentech, Inogen, Medscape, PatientMpower and Boehringer Ingelheim, lecture honoraria from Boehringer Ingelheim, and grant support from the NHLBI. J.M. Oldham reports consulting fees from Boehringer Ingelheim, Lupin Pharmaceuticals, AmMax Bio, Roche and Veracyte, advisory board participation with Endeavor Biomedicines, and grant support from the NHLBI; J.M. Oldham also has a patent “TOLLIP TT genotype for NAC use in IPF” issued, and is an associate editor of CHEST, as well as a member of the programme committee for the American Thoracic Society. I. Noth reports consulting fees from Boehringer Ingelheim and Sanofi, data safety monitoring board participation with Yale, and grant support from Veracyte and the NIH. M.E. Strek reports honoraria from Boehringer Ingelheim, Fibrogen and the American College of Chest Physicians, advisory board participation with Fibrogen, and grant support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation; M.E. Strek also reports being a member of the scientific review committee of the Pulmonary Fibrosis Foundation. P.J. Wolters reports grant support from Boehringer Ingelheim, Roche, Sanofi, Pliant and the NIH, and consulting fees from Blade Therapeutics. C.K. Garcia reports grant support from the NIH, DOD and Boehringer Ingelheim, lecture honoraria from Three Lakes Foundation, Stanford, UPenn, UCSF and Cedar-Sinai. C.A. Newton reports consulting fees from Boehringer Ingelheim and grant support from the NHLBI; C.A. Newton is also a member of the scientific review committee for the Pulmonary Fibrosis Foundation, member of the editorial board for CHEST and member of the planning committee for the American Thoracic Society. J. Kozlitina, N. Garcia, M. Poonawalla, R. Strykowski, A.L. Linderholm, B. Ley and S-F. Ma have nothing to disclose., (Copyright ©The authors 2023.)

Background: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown., Methods: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD)., Results: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs., Conclusions: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD., Competing Interests: Competing interests: EAH is the founder of VIDA Diagnostics, a company that is commercialising lung image analysis software developed, in part, at the University of Iowa. SK reports receipt of grant support from the NIH and Cardiovascular Medical Research and Education Fund and payments/honoria from Children’s Hospital of Philadelphia, University of California, San Francisco, University of Minnesota, PVRI and Stanford University, and support for attending meetings from the Pulmonary Hypertension Association, American Thoracic Society study section, Duke University, World Symposium on Pulmonary Hypertension, PVRI, Children’s Hospital of Philadelphia, University of Miami, Wake Forest University, Aspen Lung Conference and NIH Study Section. SK reports participation on a data safety monitoring board for United Therapeutics and editorial board for the European Respiratory Journal. IN reports receipt of personal fees and other support from Boehringer Ingelheim, HLR/Genentech, Sanofi Aventis, Global Blood Therapeutics and Veracyte outside the scope of this work. CKG reports support from the Department of Defense, Boehringer Ingelheim and AstraZeneca outside the scope of this work. RGB reports receipt of grants from the Alpha-1 Foundation and the COPD Foundation outside the scope of this work. AP reports grant support from the NHLBI and American Lung Association and consulting fees from Regeneron and Boehringer Ingelheim outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hiatus hernia (HH) is prevalent in adults with pulmonary fibrosis. We hypothesised that HH would be associated with markers of lung inflammation and fibrosis among community-dwelling adults and stronger among MUC5B (rs35705950) risk allele carriers., Methods: In the Multi-Ethnic Study of Atherosclerosis, HH was assessed from cardiac and full-lung computed tomography (CT) scans performed at Exam 1 (2000-2002, n=3342) and Exam 5 (2010-2012, n=3091), respectively. Percentage of high attenuation areas (HAAs; percentage of voxels with attenuation between -600 and -250 HU) was measured from cardiac and lung scans. Interstitial lung abnormalities (ILAs) were examined from Exam 5 scans (n=2380). Regression models were used to examine the associations of HH with HAAs, ILAs and serum matrix metalloproteinase-7 (MMP-7), and adjusted for age, sex, race/ethnicity, educational attainment, smoking, height, weight and scanner parameters for HAA analysis., Results: HH detected from Exam 5 scans was associated with a mean percentage difference in HAAs of 2.23% (95% CI 0.57-3.93%) and an increase of 0.48% (95% CI 0.07-0.89%) per year, particularly in MUC5B risk allele carriers (p-value for interaction=0.02). HH was associated with ILAs among those <80 years of age (OR for ILAs 1.78, 95% CI 1.14-2.80) and higher serum MMP-7 level among smokers (p-value for smoking interaction=0.04)., Conclusions: HH was associated with more HAAs over time, particularly among MUC5B risk allele carriers, and ILAs in younger adults, and may be a risk factor in the early stages of interstitial lung disease., Competing Interests: Conflicts of interest: J.S. Kim reports a K23 grant from the National Heart, Lung, and Blood Institute related to the current study; is the recipient of a Pulmonary Fibrosis Foundation Scholar's Award; and has participated on a data safety monitoring board for a UVA Convalescent Plasma Trial. J. Kim has nothing to disclose. X. Yin has nothing to disclose. G.T. Hiura has nothing to disclose. M.R. Anderson reports a grant from the National Heart, Lung, and Blood Institute related to the current study. E.A. Hoffman reports National Institutes of Health grant funding to the University of Iowa, related to the current study; and is a founder and shareholder of VIDA Diagnostics, a company commercialising lung image analysis software developed, in part, at the University of Iowa. G. Raghu has nothing to disclose. I. Noth reports having received grants from the National Heart, Lung, and Blood Institute; and consulting fees from Boehringer Ingelheim, Genentech and Confo, in the 36 months prior to manuscript submission. A. Manichaikul reports a grant from the National Heart, Lung, and Blood Institute related to the current study. S.S. Rich has nothing to disclose. B.M. Smith reports National Institutes of Health grant R01-HL130506, paid to their institution related to the current study; and further grants to their institution from the National Institutes of Health, Canadian Institutes of Health Research and Fonds de Recherche du Québec, in the 36 months prior to manuscript submission. A.J. Podolanczuk reports a grant from the National Heart, Lung, and Blood Institute related to the current study; further grant funding from the American Lung Association; consulting fees from Regeneron, Boehringer Ingelheim, Imvaria and the National Association for Continuing Education; and participation on an ILD-related advisory board for Boehringer Ingelheim, all in the 36 months prior to manuscript submission. C.K. Garcia reports a grant from the National Heart, Lung, and Blood Institute related to the current study; as well as investigator-initiated research support from the Department of Defense and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from the Three Lakes Foundation and Stanford University, all in the 36 months prior to manuscript submission; as well as stock or stock options in Pliant Therapeutics; and a collaboration with AstraZeneca regarding genomic sequencing in 2020. R.G. Barr reports having received grants from the National Heart, Lung, and Blood Institute and the COPD Foundation. M.R. Prince has nothing to disclose. E.C. Oelsner has nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: The coagulation cascade may play a role in the pathogenesis of interstitial lung disease through increased production of thrombin and fibrin deposition. Whether circulating coagulation cascade factors are linked to lung inflammation and scarring among community-dwelling adults is unknown. Objectives: To test the hypothesis that higher baseline D-dimer concentrations are associated with markers of early lung injury and scarring. Methods: Using the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( n = 6,814), we examined associations of baseline D-dimer concentrations with high attenuation areas from examination 1 (2000-2002; n = 6,184) and interstitial lung abnormalities from examination 5 computed tomographic (CT) scans (2010-2012; n = 2,227), and serum MMP-7 (matrix metalloproteinase-7) and SP-A (surfactant protein-A) from examination 1 ( n = 1,098). We examined longitudinal change in forced vital capacity (FVC) from examinations 3-6 (2004-2018, n = 3,562). We used linear logistic regression and linear mixed models to examine associations and adjust for potential confounders. Results: The mean (standard deviation) age of the cohort was 62 (10) years, and the D-dimer concentration was 0.35 (0.69) ug/ml. For every 10% increase in D-dimer concentration, there was an increase in high attenuation area percentage of 0.27 (95% confidence interval (CI), 0.08-0.47) after adjustment for covariates. Associations were stronger among those older than 65 years ( P values for interaction < 0.001). A 10% increase in D-dimer concentration was associated with an odds ratio of 1.05 for interstitial lung abnormalities (95% CI, 0.99-1.11). Higher D-dimer concentrations were associated with higher serum MMP-7 and a faster decline in FVC. D-dimer was not associated with SP-A. Conclusions: Higher D-dimer concentrations were associated with a greater burden of lung parenchymal abnormalities detected on CT scan, MMP-7, and FVC decline among community-dwelling adults.

Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012; n = 6,541), the Framingham Heart Study (2005-2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002-2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Background: OSA, a common comorbidity in interstitial lung disease (ILD), could contribute to a worsened course if untreated. It is unclear if adherence to CPAP therapy improves outcomes., Research Question: Does adherence to CPAP therapy improve outcomes in patients with concurrent interstitial lung disease and OSA?, Study Design and Methods: We conducted a 10-year retrospective observational multicenter cohort study, assessing adult patients with ILD who had undergone polysomnography. Subjects were categorized based on OSA severity into no/mild OSA (apnea-hypopnea index score < 15) or moderate/severe OSA (apnea-hypopnea index score ≥ 15). All subjects prescribed and adherent to CPAP were deemed to have treated OSA. Cox regression models were used to examine the association of OSA severity and CPAP adherence with all-cause mortality risk and progression-free survival (PFS)., Results: Of 160 subjects that met inclusion criteria, 131 had OSA and were prescribed CPAP. Sixty-six patients (41%) had no/mild untreated OSA, 51 (32%) had moderate/severe untreated OSA, and 43 (27%) had treated OSA. Subjects with no/mild untreated OSA did not differ from those with moderate/severe untreated OSA in mean survival time (127 ± 56 vs 138 ± 93 months, respectively; P = .61) and crude mortality rate (2.9 per 100 person-years vs 2.9 per 100 person-years, respectively; P = .60). Adherence to CPAP was not associated with improvement in all-cause mortality risk (hazard ratio [HR], 1.1; 95% CI, 0.4-2.9; P = .79) or PFS (HR, 0.9; 95% CI, 0.5-1.5; P = .66) compared with those that were nonadherent or untreated. Among subjects requiring supplemental oxygen, those adherent to CPAP had improved PFS (HR, 0.3; 95% CI, 0.1-0.9; P = .03) compared with nonadherent or untreated subjects., Interpretation: Neither OSA severity nor adherence to CPAP was associated with improved outcomes in patients with ILD except those requiring supplemental oxygen., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. Objectives: To perform a genome-wide association study (GWAS) of ILAs. Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( P  = 2.6 × 10 -27 ) and subpleural ILAs ( P  = 1.6 × 10 -29 ). We discovered novel genome-wide associations near IPO11 (rs6886640, P  = 3.8 × 10 -8 ) and FCF1P3 (rs73199442, P  = 4.8 × 10 -8 ) with ILAs, and near HTRE1 (rs7744971, P  = 4.2 × 10 -8 ) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five ( DPP9 , DSP , FAM13A , IVD , and MUC5B ) were significantly associated ( P  < 0.05/12) with ILAs. Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. IPF is a complex disease, with environmental and genetic factors variably contributing to disease susceptibility and outcomes. A host of common gene variants with modest effect size impart disease risk in patients with sporadic IPF, while rare variants with large effect size influence disease risk in those with familial interstitial pneumonia. In this review, we highlight several common and rare variants underpinning IPF risk and call attention to recently published studies informing our understanding of this risk., (Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Rationale: Honeycombing on chest computed tomography (CT) has been described in diverse forms of interstitial lung disease (ILD); however, its prevalence and association with mortality across the spectrum of ILD remains unclear. Objective: To determine the prevalence and prognostic value of CT honeycombing and characterize associated mortality patterns across diverse ILD subtypes in a multicenter cohort. Methods: This was an observational cohort study of adult participants with multidisciplinary or adjudicated ILD diagnosis and documentation of chest CT imaging at index diagnosis across five U.S. hospitals (one tertiary and four nontertiary medical centers). Participants were stratified based on presence or absence of CT honeycombing. Vital status was determined from review of medical records and social security death index. Transplant-free survival was analyzed using univariate and multivariable Cox regression. Results: The sample comprised 1,330 participants (mean age, 66.8 yr; 50% men) with 4,831 person-years of follow-up. The prevalences of CT honeycombing were 42.0%, 41.9%, 37.6%, and 28.6% in chronic hypersensitivity pneumonitis, connective tissue disease-related ILD (CTD-ILD), idiopathic pulmonary fibrosis (IPF), and unclassifiable/other ILDs, respectively. Among those with CT honeycombing, cumulative mortality hazards were similar across ILD subtypes, except for CTD-ILD, which had a lower mortality hazard. Overall, the mean survival time was shorter among those with CT honeycombing (107 mo; 95% confidence interval [CI], 92-122 mo) than those without CT honeycombing (161 mo; 95% CI, 147-174 mo). CT honeycombing was associated with an increased mortality rate (hazard ratio, 1.72; 95% CI, 1.38-2.14) even after adjustment for center, sex, age, forced vital capacity, diffusing capacity, ILD subtype, and use of immunosuppressive therapy (hazard ratio, 1.62; 95% CI, 1.29-2.02). CT honeycombing was associated with an increased mortality rate within non-IPF ILD subgroups (chronic hypersensitivity pneumonitis, CTD-ILD, and unclassifiable/other ILD). In IPF, however, mortality rates were similar between those with and without CT honeycombing. Conclusions: CT honeycombing is prevalent in diverse forms of ILD and uniquely identifies a progressive fibrotic ILD phenotype with a high mortality rate similar to IPF. CT honeycombing did not confer additional risk in IPF, which is already known to be a progressive fibrotic ILD phenotype regardless of the presence of CT honeycombing.

Fibrotic interstitial lung diseases (ILDs) have a high mortality rate with an unpredictable disease course and clinical features that frequently overlap. Recent data indicate important roles for genomics in the mechanisms underlying susceptibility and progression of pulmonary fibrosis. The impact of these genomic markers on pharmacotherapy and their contribution to outcomes is increasingly recognized. Interstitial lung abnormalities, frequently considered representative of early ILD, have been consistently associated with the MUC5B promoter polymorphism, a common gene variant. Other rare gene variant mutations, including TERT, TERC, SFTPC, and DKC1, may be present in patients with familial interstitial pneumonia and are frequently associated with a usual interstitial pneumonia pattern of fibrosis. The minor allele of the MUC5B rs35705950 genotype is prevalent in several sporadic forms of ILD, including idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. Gene mutations that characterize familial pulmonary fibrosis may be present in patients with connective tissue disease-related ILD, such as rheumatoid arthritis-ILD. Additionally, shorter telomere lengths and mutations in telomere biology-related genes have been demonstrated in both familial and sporadic ILD, with significant implications for disease progression, lung function, and survival. An improved understanding of the impact of genetic and genomic risk factors on disease progression would better guide personalized therapeutic choices in persons with fibrotic ILD., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD., Competing Interests: Conflict of interest: C.A. Newton reports grants from the National Institutes of Health (KL2TR001103), during the conduct of the study. Conflict of interest: J.M. Oldham reports grants from the National Heart, Lung, and Blood Institute (NHLBI), and personal fees from Genentech and Boehringer Ingelheim, outside the submitted work. Conflict of interest: B. Ley has nothing to disclose. Conflict of interest: V. Anand has nothing to disclose. Conflict of interest: A. Adegunsoye reports speaking fees and honoraria for advisory boards with Boehringer Ingelheim related to idiopathic pulmonary fibrosis (IPF) within the last 12 months. Conflict of interest: G. Liu has nothing to disclose. Conflict of interest: K. Batra has nothing to disclose. Conflict of interest: J. Torrealba reports personal fees for expert panel work from Roche–Ventana and AbbVie, outside the submitted work. Conflict of interest: J. Kozlitina has nothing to disclose. Conflict of interest: C. Glazer is a member of a speaker bureau for Genentech. There is no discussion of therapy in this paper. Conflict of interest: M.E. Strek reports grants and personal fees for advisory board work and speaker fees from Boehringer Ingelheim, and grants from Genentech-Roche, Gilead and MedImmune, outside the submitted work. Conflict of interest: P.J. Wolters reports grants from Medimmune and Genentech, and personal fees from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: I. Noth reports personal fees for consultancy from Boehringer Ingelheim, Genentech, Sanofi Aventis and Global Blood Therapeutics, outside the submitted work, and has a patent pending on TOLLIP and IPF pharmacogenomics. Conflict of interest: C.K. Garcia reports grants from the National Institutes of Health (R01 HL09309) during the conduct of the study and was previously a member of the advisory board for Pliant Therapeutics., (Copyright ©ERS 2019.)

Rationale: Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking., Objectives: We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD., Methods: MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity-related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts., Measurements and Main Results: Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12-2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17-1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15-2.53; P = 0.008, respectively) when compared with subjects with MLN <10 mm. Patients with MLN enlargement had lower lung function and decreased plasma concentrations of soluble CD40L (376 pg/ml vs. 505 pg/ml, P = 0.001) compared with those without MLN enlargement. Plasma IL-10 concentration >45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21-14.68; P = 0.024). Independent analysis of external datasets confirmed these findings., Conclusions: MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.

We studied whether African-American race is associated with younger age and decreased survival time at diagnosis of interstitial lung disease (ILD).We performed a multicentre, propensity score-matched analysis of patients with an ILD diagnosis followed at five US hospitals between 2006 and 2016. African-Americans were matched with patients of other races based on a time-dependent propensity score calculated from multiple patient, physiological, diagnostic and hospital characteristics. Multivariable logistic regression models were used. All-cause mortality and hospitalisations were compared between race-stratified patient cohorts with ILD, and sensitivity analyses were performed.The study included 1640 patients with ILD, 13% of whom were African-American, followed over 5041 person-years. When compared with patients of other races, African-Americans with ILD were younger at diagnosis (56 years versus 67 years), but in the propensity-matched analyses had greater survival (hazard ratio 0.46, 95% CI 0.28-0.77; p=0.003) despite similar risk of respiratory hospitalisations (relative risk 1.04, 95% CI 0.83-1.31; p=0.709), and similar GAP-ILD (gender-age-physiology-ILD) scores at study entry. Sensitivity analyses in a separate cohort of 9503 patients with code-based ILD diagnosis demonstrated a similar association of baseline demographic characteristics with all-cause mortality.We conclude that African-Americans demonstrate a unique phenotype associated with younger age at ILD diagnosis and perhaps longer survival time., Competing Interests: Conflict of interest: R. Vij received a grant from Genentech to study the genomics of autoimmune interstitial lung diseases. Conflict of interest: I. Noth received honoraria for advisory boards from Boehringer Ingelheim, InterMune and Anthera within the last 12 months related to IPF. He has also received speaking honoraria from GSK and consulting fees for Immuneworks. He also has study contracts with the NIH, Stromedix, Sanofi and BI for the conduct of clinical trials in IPF. Conflict of interest: M.M. Churpek is supported by a career development award from the National Heart, Lung, and Blood Institute (K08 HL121080), has received honoraria from Chest for invited speaking engagements and also has a patent pending (ARCD.P0535US.P2) for risk stratification algorithms for hospitalised patients. Conflict of interest: M.E Strek received institutional funding for interstitial lung disease research from Genentech, Gilead and MedImmune, and serves on a data monitoring committee for Boehringer Ingelheim. Conflict of interest: J.M. Oldham received speaking and advisory board fees from Genentech and Boehringer Ingelheim., (Copyright ©ERS 2018.)

Background: The current interstitial lung disease (ILD) classification has overlapping clinical presentations and outcomes. Cluster analysis modeling is a valuable tool in identifying distinct clinical phenotypes in heterogeneous diseases. However, this approach has yet to be implemented in ILD., Methods: Using cluster analysis, novel ILD phenotypes were identified among subjects from a longitudinal ILD cohort, and outcomes were stratified according to phenotypic clusters compared with subgroups according to current American Thoracic Society/European Respiratory Society ILD classification criteria., Results: Among subjects with complete data for baseline variables (N = 770), four clusters were identified. Cluster 1 (ie, younger white obese female subjects) had the highest baseline FVC and diffusion capacity of the lung for carbon monoxide (Dlco). Cluster 2 (ie, younger African-American female subjects with elevated antinuclear antibody titers) had the lowest baseline FVC. Cluster 3 (ie, elderly white male smokers with coexistent emphysema) had intermediate FVC and Dlco. Cluster 4 (ie, elderly white male smokers with severe honeycombing) had the lowest baseline Dlco. Compared with classification according to ILD subgroup, stratification according to phenotypic clusters was associated with significant differences in monthly FVC decline (Cluster 4, -0.30% vs Cluster 2, 0.01%; P < .0001). Stratification by using clusters also independently predicted progression-free survival (P < .001) and transplant-free survival (P < .001)., Conclusions: Among adults with diverse chronic ILDs, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might better predict meaningful clinical outcomes than current ILD diagnostic criteria., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: A substantial proportion of cases of usual interstitial pneumonia (UIP) are due to connective tissue disease (CTD)-associated interstitial lung disease (ILD). The purpose of this study was to determine whether specific CT findings can help differentiate a UIP pattern of CTD-ILD from a UIP pattern of idiopathic pulmonary fibrosis (IPF) and whether these signs are associated with survival., Materials and Methods: Adults visiting an ILD clinic from 2006 to 2015 enrolled in a research registry with a multidisciplinary diagnosis of CTD-ILD or IPF and a UIP pattern at high-resolution CT were included in the study. In these subjects with CT findings of UIP due to either IPF or CTD-ILD, three CT findings anecdotally associated with CTD-ILD were assessed for diagnostic accuracy: the "straight-edge" sign, the "exuberant honeycombing" sign, and the "anterior upper lobe" sign. Survival assessments were performed with univariate and multivariable techniques., Results: The subjects included 63 patients who had CTD-ILD and 133 patients who had IPF with a UIP pattern at CT. All three CT signs were significantly more common in subjects with CTD-ILD than those with IPF (prevalence, 22.2-25.4% for CTD-ILD, 6.0-12.8% for IPF; p = 0.028 to < 0.001). The highest specificity (94.0%) and sensitivity (25.4%) were seen for the straight-edge sign. No CT sign was associated with survival in multivariable analysis., Conclusion: Although UIP is usually associated with IPF, the index of suspicion for CTD-ILD should be raised in the care of patients with any of the three CT signs. A thorough workup for CTD-ILD should be pursued, including referral to the rheumatology department.

Objective: The objective of this study is to determine the CT findings and patterns of interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can predict survival for patients with IPAF., Materials and Methods: The study included 136 subjects who met the criteria for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74 of these subjects had pathologic samples available for review within 1 year of chest CT examination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest CT findings associated with survival was performed using standard univariate and multivariate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data were visually presented using the Kaplan-Meier survival curve estimator., Results: Most subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was inconsistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smoking (p < 0.01), male sex (p < 0.01), and older age (p < 0.001). Approximately one-fourth of the subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis rather than the customary CT patterns ascribed to lung disease resulting from connective tissue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on CT (hazard ratio, 2.17; 95% CI, 1.05-4.47) and pulmonary artery enlargement on CT (hazard ratio, 2.08; 95% CI, 1.02-4.20) were independent predictors of survival., Conclusion: IPAF most often presents with a UIP pattern on CT and is associated with worse survival when concomitant honeycombing or pulmonary artery enlargement is present.

Background: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown., Methods: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models., Results: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement., Conclusions: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose of Review: Interstitial lung disease (ILD) is comprised of a heterogeneous group of disorders with highly variable natural histories and response to therapies. Pharmacogenetics focuses on the variability in drug response because of the presence of genetic factors that influence drug metabolism or disease activity. In this article, we review relevant drug-specific and disease-specific polymorphisms that may influence therapeutic response, and then highlight a recently identified drug-gene interaction in patients with idiopathic pulmonary fibrosis (IPF)., Recent Findings: The emergence of high-throughput genomic technology has allowed for identification of gene polymorphisms associated with susceptibility to specific disease states, including IPF and several connective tissue diseases known to cause ILD. IPF risk loci span a diverse group of genes, while most associated with connective tissue disease are critical to immune signaling. A recent pharmacogenetic analysis of patients enrolled in an IPF clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy., Summary: Though few pharmacogenetic investigations have been conducted in patients with ILD to date, ample opportunities for pharmacogenetic exploration exist in this patient population. Such exploration will advance our understanding of specific ILDs and help usher in an era of personalized medicine.

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort., (Copyright ©ERS 2015.)

TERT and MUC5B polymorphisms have been associated consistently with idiopathic pulmonary fibrosis (IPF) in recent genomewide genetic studies. However, it remains unclear how both loci contribute to the susceptibility to different entities of sporadic interstitial lung disease (ILD). We sought to test the associations of the 2 polymorphisms with IPF and non-IPF ILD entities in a white population. Associations between 2 polymorphisms in TERT (rs2736100) and MUC5B (rs35705950) and IPF or non-IPF sporadic ILD were tested using 227 patients with ILD and 689 control subjects. Genotypic data were also correlated with pulmonary functions measured in patients with ILD. As a result, rs2736100 and rs35705950 were associated significantly and independently with ILD as a single phenotype (Odds ratio [OR], 1.29; 95% confidence interval [CI], 1.04-1.60; P = 2 × 10(-2); and OR, 2.22; 95% CI, 1.69-2.92; P = 7 × 10(-9); respectively). When considering IPF and "other ILD" (non-IPF) separately, rs35705950 had a stronger association with IPF (OR, 3.2; 95% CI, 2.21-4.63; P = 1.2 × 10(-10)) than with other ILD (OR, 1.72; 95% CI, 1.22-2.42; P = 1.2 × 10(-3)). In contrast, rs2736100 was associated with other ILD (OR, 1.43; 95% CI, 1.11-1.85; P = 6.2 × 10(-3)) but not with IPF (OR, 1.08; 95% CI, 0.78-1.49; P > 0.05). Rs35705950 correlated significantly with increased pulmonary function (P < 0.05). It was also associated with ILD without airflow obstruction in both the IPF and other ILD groups (P < 0.01 for both), and conferred the highest risk for IPF without airflow obstruction (OR, 4.46; 95% CI, 2.60-7.66; P = 4.5 × 10(-9)). Our study suggests that although both loci confer independent risks for ILD, rs35705950 may, in particular, contribute differentially to IPF and other ILD entities. Our study further highlights the genetic and phenotypic heterogeneity of ILD., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Patients with interstitial lung disease (ILD) may have features of an autoimmune disorder that do not meet the diagnostic criteria for connective tissue diseases. We determined the prevalence and characteristics of autoimmune-featured ILD (AIF-ILD) and compared these with those of idiopathic pulmonary fibrosis (IPF) and known connective tissue disease-related ILD (CTD-ILD)., Methods: Patients with ILD who did not meet the criteria for a connective tissue disease were defined as having AIF-ILD if they had a sign or symptom suggestive of a connective tissue disease and a serologic test reflective of an autoimmune process. Clinical characteristics, high-resolution CT images, and lung biopsy specimens were analyzed and compared with those of patients with IPF and CTD-ILD. Survival was evaluated using a Kaplan-Meier curve., Results: Two hundred subjects completed the questionnaire and serologic testing. AIF-ILD was identified in 32%, IPF in 29%, and CTD-ILD in 19%. Gender, age, and race differed among groups (P < .01). Sixty-two percent of patients with AIF-ILD had a typical usual interstitial pneumonia (UIP) pattern on CT images. In 31 patients with AIF-ILD, lung biopsy specimens showed UIP in 81% and nonspecific interstitial pneumonia in 6%. Patients with AIF-ILD and IPF had similar survival, worse than those with CTD-ILD (P < .01). Antinuclear antibody (ANA) titers ≥ 1:1280 were associated with improved survival in patients with AIF-ILD (P = .02)., Conclusions: Systematic evaluation of symptoms and serologic tests in ILD can identify AIF-ILD. A UIP pattern on CT images and histopathology is common in AIF-ILD. Although survival for patients with AIF-ILD is poor, ANA titers ≥ 1:1280 are associated with improved survival.

Context: Gastroesophageal reflux disease (GERD) is common in patients with respiratory disorders and interstitial lung fibrosis from diverse disease processes. However, a cause-effect relationship has not been well demonstrated. It is hypothesized that there might be more than a coincidental association between GERD and interstitial lung damage. There is still confusion about the diagnostic steps necessary to confirm the presence of GERD, and about the role of effective control of GERD in the natural history of these respiratory disorders., Objectives: To determine the prevalence of GERD in patients with respiratory disorders and lung involvement; the sensitivity of symptoms in the diagnosis of GERD; and the role of esophageal function tests (manometry and 24- hour pH monitoring) in the diagnosis and treatment of these patients., Methods: Prospective study based on a database of 44 patients (29 females) with respiratory disorders: 16 patients had idiopathic pulmonary fibrosis, 11 patients had systemic sclerosis associated interstitial lung disease, 2 patients had polymyositis associated interstitial lung disease, 2 patients had Sjögren associated interstitial lung disease, 2 patients had rheumatoid artrithis associated interstitial lung disease, 1 patient had undifferentiated connective tissue diseases associated interstitial lung disease and 10 patients had sarcoidosis. The average forced vital capacity (% predicted) was 64.3%. All patients had esophageal function tests., Results: Thirty patients (68%) had pathologic reflux (average DeMeester score: 45, normal <14.7). The average number of reflux episodes recorded 20 cm above the lower esophageal sphincter was 24. Sensitivity and specificity of heartburn were 70% and 57%, of regurgitation 43% and 57%, and of dysphagia 33% and 64%. Twelve patients with GERD underwent a laparoscopic fundoplication which was tailored to the manometric profile: three patients in which peristalsis was normal had a total fundoplication (360°) and nine patients in which the peristalsis was absent had a partial anterior fundoplication (180°)., Conclusions: The results of our study show that: (a) abnormal reflux was present in about 2/3 of patients with respiratory disorders (idiophatic pulmonary fibrosis, connective tissue disorders and sarcoidosis), and it extended to the upper esophagus in most patients; (b) the sensitivity and specificity of reflux symptoms was very low; and (c) esophageal function tests were essential to establish the diagnosis of abnormal reflux, to characterize the esophageal function and guide therapy. Long term follow-up will be necessary to determine if control of reflux alters the natural history of these respiratory disorders.