RATIONALE:Familial pulmonary fibrosis (FPF), defined as fibrosing interstitial lung disease (ILD) affecting two or more family members, is associated with earlier-onset and a more aggressive disease phenotype. Imaging findings may vary between relatives, complicating diagnosis. While genetic testing exists, it is limited by accessibility and the rarity of monogenic causes. Patient-reported family history may serve as a valuable adjunct prognostic marker. OBJECTIVES:This study aimed to characterize the clinical and radiological features of patients with FPF using a multicenter ILD registry. We compared lung function and transplant-free survival between patients with FPF and sporadic ILD, overall and by radiologic pattern. METHODS:The multicenter Canadian Registry for Pulmonary Fibrosis includes patients with fibrotic ILD. Demographics, forced vital capacity (FVC%), diffusion capacity for carbon monoxide (DLCO%), and death or lung transplant data were collected. Family history was determined via physician or patient documentation. A subset underwent re-evaluation where baseline radiologic features and patterns were described. Statistical comparisons used chi-square tests, Cox proportional hazards, omnibus test and mixed models to assess outcomes. RESULTS:Of 5375 patients, 719 (13%) had FPF. Demographics were similar between FPF and sporadic ILD. When grouping idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis and unclassifiable ILD together, those with FPF were younger (P < .001), more likely female (P < .001), less likely to have smoked (P = .007), and had higher baseline DLCO% (P < .001). Antifibrotics were more often prescribed to FPF patients with fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and systemic autoimmune rheumatic disease-ILD versus their sporadic counterparts. The mean annual rate of FVC% decline was greater in patients with FPF compared to those with sporadic ILD (P = .024). FPF more frequently received referral for transplant (P < .001), but transplant-free survival did not differ between FPF and sporadic disease. In the radiologic cohort (n = 1519) those with FPF had a higher likelihood of radiologic usual interstitial pneumonia than those with sporadic ILD (P = .004). CONCLUSIONS:FPF accounts for a meaningful proportion of ILD cases and exhibits distinct clinical features in certain disease subtypes. Although survival outcomes were similar in this study, earlier onset and accelerated progression highlight the need for refined diagnostic and prognostic approaches to familial disease.

BACKGROUND:Combined pulmonary fibrosis and emphysema (CPFE) is an important phenotype in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION:What is the prevalence of CPFE? What is the predictive performance of the CPFE index and of physiologic airflow obstruction for CT imaging emphysema extents? Is the extent of emphysema on CT imaging associated with outcomes in patients with fibrotic ILD? STUDY DESIGN AND METHODS:Consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who underwent a standardized visual assessment of the baseline high-resolution CT imaging of the chest from a prospective registry were included. CPFE was defined as emphysema extent of ≥ 15% on CT imaging, with sensitivity analyses using different thresholds: ≥ 5%, ≥ 10%, and ≥ 20%. Emphysema subtypes were categorized based on their predominant distribution: centrilobular, paraseptal, or panlobular. The CPFE index was derived using measurements of spirometry and diffusion capacity of the lungs for CO2. RESULTS:The prevalence of CPFE at baseline was 20% for IPF (92/455) and 7% in non-IPF fibrotic ILD (84/1121). Both FEV1 to FVC ratio less than the lower limit of normal and < 0.70 showed poor sensitivity (IPF, 11.1%-18.9%; non-IPF fibrotic ILD, 13.1%-23.7%) for detecting emphysema on CT imaging, although high specificity (IPF, 96.2%-98.8%; non-IPF fibrotic ILD, 92.8%-95.8%). The CPFE index was correlated moderately with extent of emphysema on CT imaging in both IPF (r = 0.48) and non-IPF fibrotic ILD (r = 0.41), but with poor agreement and wide limits of agreement on Bland-Altman analysis. Extent of emphysema on CT imaging of ≥ 20% was associated consistently with differences in lung function trajectories and worse transplant-free survival in IPF and non-IPF fibrotic ILD. No significant relationships were noted between emphysema subtypes and health outcomes. INTERPRETATION:Our results show that coexisting emphysema is important in both IPF and non-IPF fibrotic ILD, with extent of emphysema on CT imaging of ≥ 20% being associated with worse health outcomes. Both physiologic and radiologic assessments are needed to identify coexistent emphysema in patients with fibrotic ILD.

Background Clinical practice guidelines define radiologic pattern categories based on the integration of multiple imaging features. However, the relative importance of each feature is unknown. Purpose To determine the relative weights of imaging features in distinguishing radiologic patterns and identify incongruencies between guideline-defined and radiologist-assigned patterns in fibrotic interstitial lung disease (ILD). Materials and Methods In this secondary analysis of the prospective Canadian Registry for Pulmonary Fibrosis (CARE-PF), consecutive patients were evaluated in multidisciplinary discussion between January 2021 and March 2022, with documentation of features and their extent at high-resolution CT. Radiologic pattern was identified according to American Thoracic Society clinical guidelines (guideline-defined pattern) and radiologist impression (radiologist-assigned pattern). Receiver operating characteristic curves were used to evaluate how continuous features distinguished usual interstitial pneumonia (UIP), fibrotic hypersensitivity pneumonitis (fHP), and nonspecific interstitial pneumonia (NSIP) patterns. Logistic regression was used to evaluate discordance between guideline-defined and radiologist-assigned patterns. A multinomial model was used to quantify the association of individual radiologic features with radiologist-assigned patterns. Results A total of 1498 patients (mean age, 66 years ± 12 [SD]; 753 male patients) were included, with radiologist-assigned patterns of UIP (36%; 544 of 1498), fHP (17%; 250 of 1498), NSIP (33%; 499 of 1498), and "no confident pattern" (14%; 205 of 1498). More honeycombing, less total ground-glass opacity (GGO), and less pure GGO distinguished UIP from non-UIP (area under the receiver operating characteristic curve [AUC], 0.75, 0.81, and 0.77, respectively); more hypoattenuating lung differentiated fHP from non-fHP (AUC, 0.84); and more total GGO and less honeycombing distinguished NSIP from non-NSIP (AUC, 0.71 and 0.70, respectively), with features with greater than 10% lung involvement commonly demonstrating specificities of 90% or greater. Certain features led radiologists to disagree with guideline-defined UIP (eg, admixed GGO, central component of disease), guideline-defined fHP (consolidation, peripheral and basal distributions), and guideline-defined NSIP (honeycombing, reticulation). Features most helpful for pattern identification according to experienced radiologists (odds ratio ≥3 or ≤0.33) were related to distribution or distinctive findings (eg, three-density sign, axillary lymphadenopathy). Conclusion Key continuous features with greater than 10% lung involvement commonly demonstrated good specificity, and radiologists emphasized disease distribution and distinctive dichotomous features when determining fibrotic ILD patterns. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Czum in this issue.

Introduction The role of gastroesophageal reflux disease (GERD) and proton pump inhibitors (PPI) in fibrotic interstitial lung disease (fILD) remains unclear. We evaluated the association of GERD and PPI use with cough severity and major pulmonary outcomes in patients with fibrotic ILD. Methods This retrospective analysis of a prospective cohort study consisted of patients with fibrotic ILD enrolled in the CAnadian REgistry for Pulmonary Fibrosis. Patients were categorized by the presence of GERD and PPI use based on patient self-report and verified by review of the medical record. We evaluated the unadjusted and adjusted association of GERD and PPI use with cough severity visual analog scale (VAS), change in lung function, and mortality. Results 2,238 patients with fILD were included, of whom 731 had idiopathic pulmonary fibrosis. GERD was present in 777 patients (35%), with 494 (64%) of these reporting PPI use. GERD was associated with worse baseline cough severity VAS [36 mm (21-59) vs 30 mm (17-55), p=0.007), with no difference between PPI users and non-users (p=0.89). There was no consistent association of GERD or PPI use with change in lung function or transplant-free survival, with PPI use tending to be associated with worse outcomes only upon adjustment for age, sex, body mass index, and smoking pack-years (HR 1.31, 95%CI 1.02-1.67, p=0.03). Conclusions GERD is associated with worse cough severity in fILD, but PPI use is not associated with less cough. Neither GERD nor PPI use was consistently associated with change in lung function or transplant-free survival.

For patients with idiopathic pulmonary fibrosis (IPF), cough impairs quality of life; effective treatments for IPF-associated cough are needed. To determine if nalbuphine extended release (ER), a κ opioid receptor agonist and μ-opioid receptor antagonist, decreases cough compared with placebo in patients with IPF-associated cough. In this randomized, double-blind, placebo-controlled phase 2b trial conducted at 52 sites in 10 countries, patients with IPF, chronic cough for at least 8 weeks, and a Cough Severity Numerical Rating Scale (0, no cough; 10, worst possible cough) score of 4 or higher were enrolled from February 2024 to February 2025, with last follow-up in April 2025. Statistical analyses were conducted from May to August 2025. Patients were randomized 1:1:1:1 to receive nalbuphine ER at doses of 27 mg, 54 mg, or 108 mg or placebo twice daily for 6 weeks. The primary outcome was the relative change from baseline in 24-hour cough frequency (coughs/h), measured with a digital cough monitor, for nalbuphine ER compared with placebo at week 6. The key secondary outcome was the relative change from baseline in the patient-reported cough frequency (Evaluating Respiratory Symptoms in IPF cough subscale; scores range from 0-4, lower scores indicate lesser cough frequency) at week 6. Of the 223 patients screened, 165 were randomized (42, 43, 40, and 40 to receive nalbuphine ER 27 mg, 54 mg, and 108 mg, and placebo, respectively) and 160 were included in the primary analysis (median age, 71 [range, 51-85] years; 28.5% female). The baseline mean (SD) cough count was 28.3 (27.4) coughs/h. In the nalbuphine ER 27 mg, 54 mg, and 108 mg twice-daily groups, the mean relative decrease in the cough count and the absolute decrease in coughs/h were 47.9% (from 24.6 to 11.9; P = .008), 53.4% (from 28.0 to 14.9; P < .001), and 60.2% (from 31.5 to 11.9; P < .001), respectively, compared with placebo (16.9%; from 29.4 to 28.1 coughs/h). For the key secondary outcome of patient-reported cough frequency at week 6, the relative and absolute changes were −31.4% (from 2.3 to 1.5; P = .14), −40.6% (from 2.6 to 1.4; P = .004), and −40.2% (from 2.4 to 1.4; P < .005) in the 27-mg, 54-mg, and 108-mg groups, respectively, compared with –21.9% (from 2.6 to 1.9) with placebo. For patients with IPF-associated chronic cough, all 3 doses of nalbuphine ER reduced objective cough frequency and the 2 higher doses improved patient-reported cough frequency at 6 weeks. ClinicalTrials.gov Identifier: NCT05964335

Introduction:Idiopathic pulmonary fibrosis (IPF) has high morbidity and mortality with limited treatment options. Goal-oriented management approaches, such as the "treatable traits" concept, have yet to be implemented in IPF. This study aims to identify specific treatment goals in IPF for potential interventions by analysing outcomes from two national registries. Methods:We used data from the INSIGHTS-IPF registry, comprising 1232 IPF patients, enrolled from 2014 to 2020 as derivation cohort. Baseline and 6-month follow-up data were examined to assess clinical progression and predict 1-year mortality. Variables included forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (D LCO), 6-min walk distance (6MWD), body mass index (BMI) and comorbidities. For validation we used data from 490 IPF patients enrolled in the Canadian Registry for Pulmonary Fibrosis (CARE-PF) and the full 2576 fibrotic interstitial lung disease (ILD) cohort of the CARE-PF registry. Results:Multivariable analysis identified FVC, D LCO, 6MWD and BMI as independent predictors of 1-year survival. We established three risk groups based on these variables: low risk (<15% 1-year mortality), intermediate risk (15-30%) and high risk (>30%). Potential treatment goals were defined based on FVC, D LCO, 6MWD and BMI, which are readily available and may be responsive to interventions. Our risk model showed equivalent accuracy in the validation cohort, both for IPF alone and the overall population. Conclusion:This study provides a novel risk model for IPF patients, which may also apply to a broader spectrum of fibrotic ILD. It is based on potentially actionable variables which deserve further evaluation as measurable treatment goals in interventional clinical trials.

Background Interstitial lung disease (ILD) consists of a large group of lung diseases with high mortality and reduced quality of life. Previous small studies have reported depression and anxiety in up to 60% of patients, but their prevalence in specific subgroups is unknown and there is little understanding of what drives these disorders. Methods Patients with ILD were identified from the Canadian Registry for Pulmonary Fibrosis. Patient reported history of depression, anxiety, and other comorbidities were recorded based on a standardized review of the clinical record at the time of ILD diagnosis. Medications used to treat depression and/or anxiety were recorded and categorized by class (selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antidepressant, antipsychotic, and benzodiazepine). Presence of a self-reported diagnosis or medication use were used to classify patients as having depression and/or anxiety. Multivariable logistic regression models tested association of presence of depression and/or anxiety with age, sex, smoking pack-years, forced vital capacity (FVC%), and diffusion capacity of the lung for carbon monoxide (DLCO%). Results The study population consisted of 3,988 patients, including 31% with idiopathic pulmonary fibrosis (IPF), 41% with connective tissue disease-associated ILD (CTD-ILD), 9% with fibrotic hypersensitivity pneumonitis (fHP), and 19% with unclassifiable ILD. Mean age was 65±12 years, 2,002 (50%) were female, mean smoking pack years was 25±22, and 649 (16%) used oxygen. Depression and/or anxiety was present in 701 (18%) patients in the total cohort, including 17% with IPF, 15% with CTD-ILD, 23% with fHP, and 22% with unclassifiable ILD. In unadjusted analysis, the presence of depression and/or anxiety was associated with female sex (OR 1.79, 95% CI 1.51 to 2.12, p<0.001) and oxygen use (OR 1.45, 95% CI 1.16 to 1.79, p<0.001). Female sex was an independent predictor of depression and/or anxiety in all ILD diagnosis subgroups (Table), with increased smoking pack-years also independently associated with presence of depression and/or anxiety in CTD-ILD and unclassifiable ILD. Conclusions Depression and/or anxiety is present in 18% of patients with fibrotic ILD and is more common in females. These findings highlight the importance of a comprehensive approach to patient care that specifically addresses the possible presence of mood disorders.

Extent of fibrosis, defined by the amount of honeycombing and traction bronchiectasis, was consistently associated with death or lung transplant across all interstitial lung disease subtypes in a dose-dependent fashion.

Background:The impact of applying different lung function reference equations and interpretation methods in fibrotic interstitial lung disease (ILD) is poorly understood. We aimed to evaluate disease severity classification, trajectories and prognostic significance of percent-predicted and z-scores of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D LCO) using the Global Lung Function Initiative (GLI) reference equations in patients with fibrotic ILD, compared to registry-recorded values. Methods:Serial lung function measurements of 5026 patients from three prospective registries were used to calculate percent-predicted and z-scores using 2012- and 2023-GLI FVC reference equations and 2017-GLI D LCO reference equations, which were compared with registry-recorded values. Differences for baseline and longitudinal assessments, classification for lung function impairment severity and progression, and association with transplant-free survival and performance of the ILD-Gender-Age-Physiology model with external validation were assessed. Results:Baseline FVC and D LCO percent-predicted values were consistently higher using the 2012- and 2023-GLI FVC and 2017-GLI D LCO reference equations compared to registry-recorded values. The agreements for all percent-predicted reference equations were good for lung function severity classification (unweighted κ for FVC 0.69-0.76, D LCO 0.70), but only moderate for the counterpart z-scores (FVC 0.41-0.50, D LCO 0.45). The largest 1-year declines were observed using the 2023-GLI FVC reference equations and the 2017-GLI D LCO reference equations. Lower baseline GLI and registry-recorded FVC and D LCO values were associated with worse transplant-free survival and had similar performance for risk stratification, except for a lack of association of baseline 2023-GLI FVC percent-predicted and z-scores for adjusted analyses in the non-White cohort. Conclusions:Use of different lung function reference equations and interpretation methods may impact disease severity classification and longitudinal trajectory in patients with fibrotic ILD, although prognostic significance is similar, except for 2023-GLI FVC in non-White patients.

Background: Guidelines have defined “typical hypersensitivity pneumonitis (HP)” imaging patterns for fibrotic HP (fHP); however, the frequency, characteristics, and outcomes of different multidisciplinary diagnoses within this pattern are unknown. Methods: Patients with a typical fHP pattern on chest computed tomography (CT) were identified from a prospective registry. Multidisciplinary diagnoses were established by consensus during a standardized multidisciplinary discussion of all available data. Pre-specified diagnostic categories of interest included fHP with an exposure identified, fHP without an exposure identified, and connective tissue disease-associated interstitial lung disease (CTD-ILD), with each diagnosis defined by >50% likelihood after multidisciplinary discussion. Clinical and radiological features and outcomes were compared across multidisciplinary diagnoses. Results: Of 164 patients with a CT pattern of typical fHP, 49 had a multidisciplinary diagnosis of fHP with a probable or possible exposure identified (30%), 56 had fHP without an exposure (34%), 36 had a CTD-ILD (22%), and 23 had another multidisciplinary diagnosis (14%) (Figure). Clinical and CT features differed across multidisciplinary diagnoses. Lung function decline and time to death or transplant were worse in fHP without a probable or possible exposure. Positive autoimmune serologies or a new rheumatologist-confirmed CTD diagnosis developed in 14% of patients with fHP without an exposure identified during follow-up of at least 4 years. Conclusion: Patients with a typical fHP pattern on CT frequently have non-HP diagnoses (most often CTD-ILD), have differences in baseline characteristics and disease behavior across multidisciplinary diagnoses, and more frequently develop features of CTD during follow-up when an initial HP exposure is not identified.

Rationale: Guidelines have defined a "typical hypersensitivity pneumonitis (HP)" imaging pattern for fibrotic HP (fHP); however, the frequency, characteristics, and outcomes of different multidisciplinary diagnoses within this pattern are unknown. Objectives: The goal of this study was to describe the frequency at which different multidisciplinary diagnoses present with a typical fHP pattern and to identify clinically relevant differences across these diagnoses. Methods: Patients with a typical fHP pattern on chest computed tomography (CT) were identified from a prospective registry. Multidisciplinary diagnoses were established by consensus during a research-dedicated standardized multidisciplinary discussion of all available data. Prespecified diagnostic categories of interest included fHP with an exposure identified, fHP without an exposure identified, and connective tissue disease-associated interstitial lung disease (CTD-ILD), with each diagnosis defined by >50% likelihood after this structured multidisciplinary discussion. Clinical and radiological features and outcomes were compared across multidisciplinary diagnoses. Measurements and Main Results: Of 164 patients with CT patterns of typical fHP, 49 had multidisciplinary diagnoses of fHP with probable or possible exposures identified (30%), 56 had fHP without exposures identified (34%), 36 had CTD-ILD (22%), and 23 had other multidisciplinary diagnoses (14%). Clinical and CT features differed across multidisciplinary diagnoses. Lung function decline and time to death or transplantation were worse in patients with fHP without probable or possible exposures. Positive autoimmune serologies or new rheumatologist-confirmed CTD diagnoses developed in 14% of patients with fHP without exposures identified during follow-up. Conclusions: Patients with a typical fHP pattern on chest CT frequently have non-HP diagnoses (most often CTD-ILD), have differences in baseline characteristics and disease behavior across multidisciplinary diagnoses, and more frequently develop features of CTD during follow-up when an initial HP exposure is not identified.

Rationale: Sarcoidosis is a multisystem disease with pulmonary manifestations in >90% of patients. Environmental exposures are associated with sarcoidosis incidence, but the impact on clinical outcomes remains understudied. Objectives: To evaluate the association of exposures to ambient particulate matter [Formula: see text]2.5 μm in diameter (PM2.5) with lung function outcomes in pulmonary sarcoidosis. Methods: PM2.5 and constituent exposures were obtained by matching monthly satellite-derived hybrid measurements to each patient's residential address obtained from the time of enrollment, averaged over 5 years before registry enrollment and censoring. Linear models evaluated associations of pollutants with baseline lung function (FEV1, FVC, FEV1/FVC ratio, and DlCO). Linear mixed effects models analyzed associations of pollutants with rates of lung function change (FEV1, FVC, and DlCO change per year of follow-up). Measurements and Main Results: Two prospectively enrolled cohorts of mostly middle-aged, White, and nonsmoking adults with specialist-diagnosed pulmonary sarcoidosis were used. The U.S. cohort (n = 400) experienced higher 5-year preenrollment median PM2.5 exposures (12.3 μg/m3) than the Canadian cohort (n = 112) (8.0 μg/m3). Each 1-μg/m3 increase in PM2.5 was associated with 0.93% predicted lower baseline FEV1 (95% confidence interval, -1.76 to -0.10; P = 0.03) and 1.53% predicted lower FVC (95% confidence interval, -2.26 to -0.79; P < 0.001) in the U.S. cohort, but the associations were not significant in the Canadian cohort. PM2.5, sulfate, nitrate, and ammonium were associated with accelerated FEV1, FVC, and DlCO decline in the U.S. cohort. Conclusions: PM2.5 was associated with worse pulmonary disease severity and progression in a higher-exposure cohort, highlighting the importance of exposure disparities in this population.

Background: Idiopathic pulmonary fibrosis (IPF) is historically quoted as having a median survival of 2-5 years, but this is largely based on older data prior to the introduction of antifibrotic drugs. We therefore aimed to identify recent trends in both patient characteristics and survival. Methods: We conducted a secondary analysis of the prospective Canadian Registry for Pulmonary Fibrosis (CARE-PF). Incident cases of IPF between 2016-2022 with a baseline pulmonary function test within 6 months of diagnosis were included. Mean age, forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) were calculated according to year of IPF diagnosis. Transplant-free survival was determined based on the time from IPF diagnosis. The 3-year survival probability of patients diagnosed in each calendar year was determined using Kaplan-Meier estimates. Monotonic trends over time were evaluated using the Mann-Kendall test. Results: The cohort included 760 patients with IPF. Mean age at diagnosis was 71 years, 75% were male, and 77% were ever-smokers with a median smoking history of 25 pack-years. The mean age at IPF diagnosis was 69 years in 2016 and rose somewhat to 72 by 2022 (p=0.003) (Figure 1A). Over the same period, the mean baseline FVC increased from 79% (95%CI 76-83%) to 85% (95%CI 80-90%) (p=0.02), while baseline DLCO did not show a trend, remaining within a range of 53-61% (p=0.37) (Figure 1B). The 3-year survival probability started at 74% (95%CI 67-82%) in 2016 and increased to 84% (95%CI 76-92%) in 2021 (Figure 1C), but this was not associated with a statistically significant upward trend (p=0.06). Conclusion: Both age and baseline FVC at time of IPF diagnosis rose over 2016-2022. The 3-year survival in IPF remained stable over 2016-2022 and was generally >70%, which is higher than previously reported. This may reflect both earlier disease detection (lead time bias), increasing uptake of antifibrotic therapy over time, and improved overall care. Figure 1

Rationale Familial pulmonary fibrosis (FPF) is defined by two or more family members within the same family being affected by interstitial lung disease (ILD). It has been found that patients with FPF may present earlier and with a more aggressive phenotype than other ILD patients. Patient-reported family history may be used as an adjunct prognostic marker, as patient-reported family history predicts reduced transplant free survival and performs well to identify at-risk individuals, even in the absence of predisposing genetic variants. The objective of this study was to characterize the prevalence, characteristics and prognosis of FPF from a large, multicenter national ILD registry. Methods The Canadian Registry for Pulmonary Fibrosis is a prospective, multicentre ILD registry. All patients with ILD (idiopathic pulmonary fibrosis (IPF), connective tissues disease ILD (CTD-ILD), hypersensitivity pneumonitis (HP), unclassifiable ILD, and other ILDs) were eligible for inclusion. Family history was ascertained by patient questionnaire or physician documentation, kinship was not recorded. In a subset, baseline CT scans were scored for radiologic patterns, blinded to clinical data. Continuous variables are presented as mean ± standard deviation (SD). Death and transplant free survival were evaluated using mixed effects Cox regression model, adjusted for age, sex, smoking, baseline lung function, and treatment. Categorical variables were analyzed using Pearson's chi-square test. Results Of 5454 eligible patients 731 (13%) had patient or physician reported FPF (Table 1). In IPF, HP and unclassifiable ILD, familial versus sporadic ILD was associated with an earlier age at diagnosis. Compared to sporadic IPF, patients with familial IPF were more likely to be female (p<0.001), never smokers (p=0.001) and be referred for lung transplant assessment (p=0.024). Physician reported FPF was associated with increased mortality in adjusted models (HR 1.33, 95%CI 1.09 to 1.62). Of the 1519 participants with radiologic data, 197 (15%) had FPF. Radiologist defined NSIP (p<0.001) and UIP (p=0.014) were more common in FPF compared to sporadic ILD. Conclusions In this multicentre registry, FPF was prevalent in 13% of registry participants and was associated with specific clinical characteristics, including sex, earlier age at diagnosis and a higher likelihood of non-smoking status, and prognosis including mortality. These findings emphasize the importance of ascertaining family history in ILD assessments, as it may offer valuable insights for identifying at-risk individuals and refining management strategies. Further research is warranted to investigate the genetic and environmental factors contributing to FPF and its varied phenotypic presentations.

Rationale: Clinical practice guidelines define radiologic pattern categories based on integration of multiple individual features; however, it is not clear how important each feature is in the eyes of expert radiologists. Methods: Consecutive patients with fibrotic ILD in the Canadian Registry for Pulmonary Fibrosis were re-evaluated in standardized multidisciplinary discussion. An experienced chest radiologist blinded to clinical data assessed disease distribution and visually quantified the percentage of lung parenchyma affected by honeycombing, reticulation, ground glass, hypoattenuating lung, consolidation, and emphysema. Additional binary features recorded included presence of asymmetric disease, costophrenic angle sparing, 3-density sign, subpleural sparing, dilated esophagus, cysts, and lymphadenopathy. The radiologist then provided a differential diagnosis of patterns with ascribed confidence, mandated to sum to 100%. Patients with confidence >50% for a usual interstitial pneumonia (UIP), fibrotic hypersensitivity pneumonitis (fHP), and non-specific interstitial pneumonia (NSIP) pattern were used in subsequent analyses, compared to cases where no single pattern was >50% (“no confident pattern”). The strength of association of individual radiologic features with radiologist-assigned patterns (UIP, fHP, NSIP) was quantified using a multinomial model, with “no confident pattern” selected as the reference category. Results: 1498 patients were included with patterns of UIP (36%), fHP (17%), NSIP (33%), and “no confident pattern” (14%). Results of the multinomial model are displayed in Figure 1. Increasing honeycombing and reticulation suggested UIP, while ground-glass, hypoattenuating lung, subpleural sparing, and a distribution other than basal and peripheral led away from UIP, including the presence of any central component of disease. Increasing hypoattenuating lung, pure ground-glass, and a 3-density sign suggested fHP, as did a mid-upper predominant distribution, sparing of the extreme costophrenic angle, and the presence of any central component of disease. Axillary lymphadenopathy, a dilated esophagus, and subpleural sparing were strongly associated with NSIP, while increasing honeycombing, reticulation, hypoattenuating lung, and emphysema as well as a non-basal distribution led away from NSIP. The most helpful features (OR≥3 or ≤0.3) were related to distribution or were particularly distinctive findings (e.g. 3-density sign, dilated esophagus, subpleural sparing). Conclusions: Expert radiologists emphasize disease distribution and a few distinctive dichotomous features when determining ILD patterns, likely because these are more reliably identifiable with lower interobserver disagreement compared to continuous variables that lack clear demarcation of clinical significance. These data will help non-experts to assign weights to the building blocks of patterns, increase reproducibility in pattern identification, and improve future clinical practice guidelines in an evidence-based manner.

Rationale:Higher peripheral blood monocyte count has been associated with disease progression and mortality in patients with fibrotic interstitial lung disease (fILD), but with uncertainty regarding the strength of this association and the potential impact of confounding. This study aimed to characterise the associations of clinically ascertained peripheral blood monocyte count with survival and lung function decline in patients with fILD. Methods:Patients with fILD enrolled in the prospective Canadian Registry for Pulmonary Fibrosis (CARE-PF) with baseline complete blood count were included. Monocyte counts were analysed continuously and dichotomised ≥0.6 versus <0.6×109 cells·L-1 and ≥0.95 versus <0.95×109 cells·L-1. Cox proportional hazards models, unadjusted and adjusted for age, sex, lung function, smoking and treatment, evaluated associations of monocytes with transplant-free survival. Survival analysis was repeated using the prospective PROFILE cohort. Unadjusted and adjusted linear mixed models evaluated association of monocyte count with annual decline in forced vital capacity (FVC) % predicted. Results:In 1489 patients with fILD, higher monocyte count was associated with reduced transplant-free survival in unadjusted models, but not after adjustment for relevant confounders (continuous model, HR 0.79, 95% CI 0.54-1.17; p=0.24; dichotomised at 0.6 cells·L-1, HR 0.89, 95% CI 0.72-1.10; p=0.29; and dichotomised at 0.95 cells·L-1, HR 0.93, 95% CI 0.68-1.26; p=0.62). Findings were consistent in the PROFILE external replication cohort. Monocyte count was not associated with FVC % decline in the full cohort or within fILD subtypes. Conclusions:Peripheral blood monocyte count was not associated with transplant-free survival or lung function decline in this multicentre cohort study, indicating that it is not a reliable biomarker in fILD.

Rationale: Higher neighborhood-level disadvantage is associated with lower baseline lung function in patients with fibrotic interstitial lung disease (fILD), but the association of disadvantage with radiologic features and patterns remains unknown. Methods: Patients with fILD enrolled in the Canadian Registry for Pulmonary Fibrosis were evaluated in standardized multi-disciplinary discussion (MDD). Expert chest radiologists blinded to clinical data evaluated baseline computed tomography scans, visually quantifying the percentage of lung parenchyma affected by honeycombing, reticulation, ground glass opacities (GGO), and hypoattenuating lung and determining the top radiologic pattern (usual interstitial pneumonia=UIP, fibrotic hypersensitivity pneumonitis=fHP, non-specific interstitial pneumonia=NSIP, “no confident pattern”). Clinical data was introduced, and a top clinical diagnosis was assigned by the radiologist and an ILD clinician. Neighborhood disadvantage was assigned to patient residential locations using the Canadian Index of Multiple Deprivation (CIMD) score and its 4 domains (residential instability, ethnocultural composition, economic dependency, situational vulnerability), with higher scores reflecting greater disadvantage. Linear models adjusted for age, sex, smoking, race, and baseline lung function evaluated associations of CIMD score with percentage of radiologic features. Multinomial models adjusting for the same covariates determined associations of CIMD score with radiologic pattern, using UIP as the reference. Results: Of 1473 patients included, the most common diagnoses were CTD-ILD (48%), IPF (29%), and fHP (16%). Higher CIMD score (range: -1.07 to 2.57) was associated with 0.62% increased honeycombing (95%CI=0.02-1.23, p=0.04, Table). Higher ethnocultural composition score (indicating neighborhoods with higher foreign-born, immigrant, minoritized, or linguistically-isolated individuals) was associated with less reticulations and increased pure GGO. Higher CIMD score was not associated with greater odds of fHP or NSIP patterns as compared with UIP, although higher ethnocultural composition score was associated with higher odds of NSIP (OR=1.18, 95%CI=1.01-1.39, p=0.04). Within patients with a top MDD diagnosis of IPF, higher total CIMD and ethnocultural scores were associated with more honeycombing. In CTD-ILD, higher residential instability was associated with more honeycombing and higher ethnocultural composition score with more hypoattenuating lung. In fHP, none of the scores were associated with worse honeycombing, reticulations, GGO, or hypoattenuating lung. Conclusions: Neighborhood disadvantage is associated with worse honeycombing, supporting prior findings that patients living in more disadvantaged areas present to tertiary ILD care with greater disease burden. Increased ethnocultural composition scores were associated with increased extent of inflammatory features in CTD-ILD and higher odds of an NSIP pattern, suggesting possible demographic, geographic, and/or genetic risk factors for this type of fILD.

BACKGROUND: BAL cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic interstitial lung disease (ILD). Despite recommendation for its use, between- center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remain sparse. RESEARCH QUESTION: In patients with fibrotic ILD, are BAL findings associated with radio- logic features, patterns, and clinical diagnoses? STUDY DESIGN AND METHODS: Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and who were enrolled in the prospective Canadian Registry for Pulmonary Fibrosis were re-reviewed in a standardized multidisciplinary discussion (MDD). BAL was categorized according to guideline-recommended thresholds, and using thresholds of lymphocytosis > 20% and neutrophils > 4.5%. High-resolution CT (HRCT) scans were scored (anonymized to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCT scans according to guideline-defined patterns for idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis; then, MDD diagnoses were assigned, considering all available data. RESULTS: Bronchoscopy with cellular analysis was performed in 209 of 1,593 patients (13%). Lymphocyte % was weakly negatively correlated with total fibrosis % (r = -0.16, P = .023) but not statistically significantly correlated with ground glass opacity % (r = 0.01, P = .94). A mixed BAL pattern was the most frequent in all radiologic patterns (range, 45%-69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fibrotic hypersensitivity pneumonitis (21%) and usual interstitial pneumonia (18%). Only 5% of patients with MDD-based fibrotic hypersensitivity pneumonitis had a guideline-defined isolated lymphocytosis > 15%. INTERPRETATION: BAL cellular analyses did not significantly correlate with radiologic features, guideline patterns, or MDD-based diagnoses. Ground glass opacities are often interpreted to represent pulmonary inflammation, but were not associated with BAL lymphocytosis in this cohort. CHEST 2025; 167(1):172-182

Rationale: Clinical measures of progressive pulmonary fibrosis (PPF) have been proposed, but their clinical utility remains unclear. Objectives: To determine performance characteristics of lung function-based PPF measures, including new guideline criteria for discriminating clinically relevant outcomes. Methods: A multicenter retrospective cohort analysis was performed to assess the performance characteristics of eight categorical measures of FVC and DlCO decline, together with PPF guideline criteria (requiring two of the following: worsening respiratory symptoms, absolute decline in FVC ⩾5% or DlCO ⩾15%, or radiological progression) for discriminating 2-year death or lung transplant among patients fibrotic interstitial lung disease from the United States, United Kingdom, and Canada (n = 2,727). The net benefit of the top-performing measures to inform treatment initiation were compared using decision curves. Measurements and Main Results: PPF classified according to relative decline in FVC of ⩾10%, relative decline in DlCO of ⩾15%, and PPF guideline criteria displayed the best overall test performance, with area under the receiver operating characteristic curves of 0.67-0.68. Specificity was higher than sensitivity for all evaluated measures, with relative measures of lung function decline outperforming absolute measures. The net benefit of standalone relative decline in FVC ⩾10% and DlCO ⩾15% was similar to PPF guideline criteria across the range of treatment probability thresholds. Conclusions: Classifying PPF by standalone measures of FVC and DlCO decline provides clinical utility similar to PPF guideline criteria. Top-performing physiology-based measures of PPF discriminate outcomes with high specificity but low sensitivity.

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: We sought to assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: In a Phase 2, randomized (1:1:1), double-blind, placebo-controlled study (ClinicalTrials.gov ID: NCT03142191), patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in the percentage of predicted FVC (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received at least one dose of study drug. The study was terminated early because of a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% confidence interval: -2.1, 4.3; P = 0.50) and 2.2% (400 mg; 95% confidence interval: -1.1, 5.4; P = 0.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 arms than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared with placebo. CC-90001 was generally well tolerated, which was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT03142191).