Epidemiology and Prognostic Significance of Cough in Fibrotic Interstitial Lung Disease.

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objective: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100mm-Cough Severity Visual Analog Scale (VAS) from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF (n=1061) had higher median baseline cough severity than those with non-IPF fibrotic ILD (n=2825) [24 vs 20mm, p<0.001], with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in DLCO, development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2mm, 95% CI 1.6-2.9mm) had larger annualized increments in cough severity compared to the non-IPF fibrotic ILD cohort (1.1mm, 95% CI 0.8-1.4mm; p=0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusion: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

Impact of surgical lung biopsy on lung function and survival in patients with idiopathic pulmonary fibrosis in a multi-centre registry cohort.

BACKGROUND AND OBJECTIVE: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis. METHODS: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB. RESULTS: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both). CONCLUSION: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF.

Eligibility criteria from pharmaceutical randomised controlled trials of idiopathic pulmonary fibrosis: a registry-based study.

BACKGROUND: Little is known about generalisability of randomised controlled trials (RCTs) for idiopathic pulmonary fibrosis (IPF). We evaluated eligibility criteria for phase III IPF RCTs to determine their representativeness in clinical registries, and calculated forced vital capacity (FVC) changes according to eligibility criteria. METHODS: Common eligibility criteria used in >60% of IPF RCTs were identified from a literature search and applied to patients with IPF from prospective Australian and Canadian registries. Additional pre-specified criteria of 6-min walk distance (6MWD) and different measures of preceding disease progression were also evaluated. Joint longitudinal-survival modelling was used to compare FVC decline according to eligibility for individual and composite criteria. RESULTS: Out of 990 patients with IPF, 527 (53%) met all common RCT eligibility criteria at the first clinic visit, including 343 with definite IPF and 184 with radiological probable usual interstitial pneumonia pattern without histological confirmation (i.e. provisional IPF). The percentages of eligible patients for landmark RCTs of nintedanib and pirfenidone were 19-50%. Adding 6MWD ≥150 m and different measures of preceding disease progression to the composite common criteria reduced the percentages of patients meeting eligibility to 52% (n=516) and 4-18% (n=12-61), respectively. Patients meeting the composite common criteria had less-rapid 1-year FVC decline than those who did not (-90 versus -103 mL, p=0.01). Definite IPF generally had more-rapid 1-year FVC decline compared to provisional IPF. CONCLUSIONS: Eligibility criteria of previous IPF RCTs have limited generalisability to clinical IPF populations, with FVC decline differing between eligible and ineligible populations.

Neighborhood-Level Disadvantage Impacts on Patients with Fibrotic Interstitial Lung Disease.

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

Prevalence and characteristics of progressive fibrosing interstitial lung disease in a prospective registry.

BACKGROUND: Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiological, symptomatic and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain. METHODS: Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015 and 2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation or any two of: relative FVC decline ≥5% and <10%, worsening respiratory symptoms or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression. RESULTS: Of 2746 patients with fibrotic ILD (mean±sd age 65±12 years; 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD) and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared with IPF, time to progression was similar in patients with HP (hazard ratio (HR) 0.96, 95% CI 0.79-1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71-0.96) and CTD-ILD (HR 0.65, 95% CI 0.56-0.74). Background treatment varied across diagnostic subtypes, with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61% and 37% of patients with CHP, CTD-ILD and U-ILD, respectively. Increasing age, male sex, gastro-oesophageal reflux disease and lower baseline pulmonary function were independently associated with progression. CONCLUSIONS: Progression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.

Clinical relevance of rheumatoid factor and anti-citrullinated peptides in fibrotic interstitial lung disease.

BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is a frequent cause of interstitial lung disease (ILD); however, the impact of rheumatoid factor and anti-citrullinated peptide antibody seropositivity in ILD without connective tissue disease (CTD) is unclear. We examined the association of seropositivity with ILD progression, mortality and response to immunosuppression in non-CTD ILD. METHODS: A total of 1570 non-CTD patients (with idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, interstitial pneumonia with autoimmune features or unclassifiable ILD) and 181 RA-ILD patients were included from a prospective registry. Longitudinal forced vital capacity (FVC), transplant-free survival and incidence of progressive fibrosing-ILD (PF-ILD) were compared between seronegative non-CTD ILD (reference group), seropositive non-CTD ILD and RA-ILD using linear mixed-effect and Cox proportional hazards models adjusted for age, sex, smoking pack-years and baseline FVC. Interaction between seropositivity and immunosuppression on FVC decline was assessed in patients with ≥6 months of follow-up before and after the treatment. RESULTS: Two hundred and seventeen (13.8%) patients with seropositive non-CTD ILD had similar rates of FVC decline and transplant-free survival compared to seronegative non-CTD ILD, but more frequently met the criteria for PF-ILD (hazard ratio [HR] = 1.35, p = 0.004). RA-ILD had slower FVC decline (p = 0.03), less PF-ILD (HR = 0.75, p = 0.03) and lower likelihood of lung transplant or death (HR = 0.66, p = 0.01) compared to seronegative non-CTD ILD. No interaction was found between seropositivity and treatment on FVC decline in non-CTD ILD. CONCLUSION: Seropositivity in non-CTD ILD was not associated with improved outcomes or treatment response, highlighting the importance of other disease features in determining prognosis and predicting response to immunosuppression.

Inhalational exposures in patients with fibrotic interstitial lung disease: Presentation, pulmonary function and survival in the Canadian Registry for Pulmonary Fibrosis.

BACKGROUND AND OBJECTIVE: Inhalational exposures are a known cause of interstitial lung disease (ILD), but little is understood about their prevalence across ILD subtypes and their relationship with pulmonary function and survival. METHODS: Patients with fibrotic ILD were identified from the multicentre Canadian Registry for Pulmonary Fibrosis. Patients completed questionnaires regarding ILD-related occupational and environmental exposures. The relationship between exposures and the outcomes of baseline age, gender, family history, pulmonary function and survival was analysed using linear and logistic regression models, linear mixed-effect regression models and survival analysis using multivariable Cox proportional hazards along with the log-rank test. RESULTS: There were 3820 patients included in this study, with 2385 (62%) having ILD-related inhalational exposure. Exposed patients were younger, particularly in the idiopathic pulmonary fibrosis subgroup. Inhalational exposure was associated with male gender (adjusted OR 1.46, 95% CI 1.28-1.68, p < 0.001) and family history of pulmonary fibrosis (adjusted OR 1.73, 95% CI 1.40-2.15, p < 0.001). Patients with any inhalational exposure had improved transplant-free survival (hazard ratio 0.81, 95% CI 0.71-0.92, p = 0.001); this effect persisted across diagnostic subtypes. The relationship between exposures and annual change in forced vital capacity varied by ILD subtype. CONCLUSION: Patients with fibrotic ILD report high prevalence of inhalational exposures across ILD subtypes. These exposures were associated with younger age at diagnosis, male gender and family history of pulmonary fibrosis. Identification of an inhalational exposure was associated with a survival benefit. These findings suggest that inhaled exposures may impact clinical outcomes in patients with ILD, and future work should characterize the mechanisms underlying these relationships.

A cluster-based analysis evaluating the impact of comorbidities in fibrotic interstitial lung disease.

BACKGROUND: Comorbidities are frequent and have been associated with poor quality of life, increased hospitalizations, and mortality in patients with interstitial lung disease (ILD). However, it is unclear how comorbidities lead to these negative outcomes and whether they could influence ILD disease progression. The goal of this study was to identify clusters of patients based on similar comorbidity profiles and to determine whether these clusters were associated with rate of lung function decline and/or mortality. METHODS: Patients with a major fibrotic ILD (idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, connective tissue disease-associated ILD, and unclassifiable ILD) from the CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) were included. Hierarchical agglomerative clustering of comorbidities, age, sex, and smoking pack-years was conducted for each ILD subtype to identify combinations of these features that frequently occurred together in patients. The association between clusters and change in lung function over time was determined using linear mixed effects modeling, with adjustment for age, sex, and smoking pack-years. Kaplan Meier curves were used to assess differences in survival between the clusters. RESULTS: Discrete clusters were identified within each fibrotic ILD. In IPF, males with obstructive sleep apnea (OSA) had more rapid decline in FVC %-predicted (- 11.9% per year [95% CI - 15.3, - 8.5]) compared to females without any comorbidities (- 8.1% per year [95% CI - 13.6, - 2.7]; p = 0.03). Females without comorbidities also had significantly longer survival compared to all other IPF clusters. There were no significant differences in rate of lung function decline or survival between clusters in the other fibrotic ILD subtypes. CONCLUSIONS: The combination of male sex and OSA may portend worse outcomes in IPF. Further research is required to elucidate the interplay between sex and comorbidities in ILD, as well as the role of OSA in ILD disease progression.

Characteristics of pulse oximetry and arterial blood gas in patients with fibrotic interstitial lung disease.

BACKGROUND: Fibrotic interstitial lung disease (ILD) is frequently associated with abnormal oxygenation; however, little is known about the accuracy of oxygen saturation by pulse oximetry (SpO2) compared with arterial blood gas (ABG) saturation (SaO2), the factors that influence the partial pressure of carbon dioxide (PaCO2) and the impact of PaCO2 on outcomes in patients with fibrotic ILD. STUDY DESIGN AND METHODS: Patients with fibrotic ILD enrolled in a large prospective registry with a room air ABG were included. Prespecified analyses included testing the correlation between SaO2 and SpO2, the difference between SaO2 and SpO2, the association of baseline characteristics with both the difference between SaO2 and SpO2 and the PaCO2, the association of baseline characteristics with acid-base category, and the association of PaCO2 and acid-base category with time to death or transplant. RESULTS: A total of 532 patients with fibrotic ILD were included. Mean resting SaO2 was 92±4% and SpO2 was 95±3%. Mean PaCO2 was 38±6 mmHg, with 135 patients having PaCO2 <35 mmHg and 62 having PaCO2 >45 mmHg. Correlation between SaO2 and SpO2 was mild to moderate (r=0.39), with SpO2 on average 3.0% higher than SaO2. No baseline characteristics were associated with the difference in SaO2 and SpO2. Variables associated with either elevated or abnormal (elevated or low) PaCO2 included higher smoking pack-years and lower baseline forced vital capacity (FVC). Lower baseline lung function was associated with an increased risk of chronic respiratory acidosis. PaCO2 and acid-base status were not associated with time to death or transplant. INTERPRETATION: SaO2 and SpO2 are weakly-to-moderately correlated in fibrotic ILD, with limited ability to accurately predict this difference. Abnormal PaCO2 was associated with baseline FVC but was not associated with outcomes.

Validation of a Dyspnea Visual Analog Scale in Fibrotic Interstitial Lung Disease.

Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (|r| ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (|r| = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (|r| = 0.44) and weakly correlated with the European Quality of Life VAS (|r| = 0.19), forced vital capacity percent predicted (|r| = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (|r| = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm.

Impact of Antigen Exposure on Outcomes and Treatment Response in Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Patients with fibrotic hypersensitivity pneumonitis (fHP) are frequently treated with immunosuppression to slow lung function decline; however, the impact of this treatment has not been studied across different types of antigen exposure. RESEARCH QUESTION: In patients with fHP, do disease outcomes and response to treatment vary by antigen type? STUDY DESIGN AND METHODS: A multicenter interstitial lung disease database (Canadian Registry for Pulmonary Fibrosis) was used to identify patients with fHP. The causative antigen was categorized as avian, mold, unknown, or other. Treatment was defined as mycophenolate ≥ 1,000 mg/d or azathioprine ≥ 75 mg/d for ≥ 30 days. Statistical analysis included t tests, χ2 tests, and one-way analysis of variance. Unadjusted and adjusted competing risks and Cox proportional hazards models were used to assess survival. RESULTS: A total of 344 patients were identified with the following causative antigens: avian (n = 93; 27%), mold (n = 88; 26%), other (n = 15; 4%), and unknown (n = 148; 43%). Patient characteristics and lung function were similar among antigen groups with a mean FVC % predicted of 75 ± 20. The percent of patients treated with immunosuppression was similar between antigens with 58% of patients treated. There was no change in lung function or symptom scores with the initiation of immunosuppression in the full cohort. Immunosuppression was not associated with a change in survival for patients with avian or mold antigen (avian: hazard ratio, 0.41; 95% CI, 0.11-1.59; P = .20; mold: hazard ratio, 1.13; 95% CI, 0.26-4.97; P = .88). For patients with unknown causative antigen, survival was worse when treated with immunosuppression (hazard ratio, 2.65; 95% CI, 1.01-6.92; P = .047). INTERPRETATION: Response to immunosuppression varies by antigen type in patients with fHP. Additional studies are needed to test the role of immunosuppression in fHP, and particularly in those with an unknown antigen.

Characteristics and risk factors of interstitial pneumonia with autoimmune features.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD. METHODS: Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models. RESULTS: Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD. CONCLUSION: Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup.

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease.

BACKGROUND: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models. RESULTS: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02). INTERPRETATION: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice.

Trajectories and Prognostic Significance of 6-Minute Walk Test Parameters in Fibrotic Interstitial Lung Disease: A Multicenter Study.

BACKGROUND: Functional capacity, as measured by the 6-min walk test (6MWT), is often reduced in fibrotic interstitial lung disease (ILD). This study evaluated longitudinal changes and the prognostic significance of 6MWT parameters, and explored change in oxygenation status as a physiological criterion to define disease progression in patients with fibrotic ILD. RESEARCH QUESTIONS: What are the trajectories and prognostic value of 6MWT parameters in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Using prospective registries in Australia and Canada, patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD were stratified by the presence of criteria for progressive pulmonary fibrosis (PPF). The cumulative incidence of exertional and resting hypoxemia and changes in 6-min walk distance (6MWD) and composite indices (distance-saturation product and distance-saturation-oxygen product) were determined, with prognostic significance evaluated at the time of meeting criteria for PPF. New-onset exertional or resting hypoxemia was evaluated as another potential criterion for PPF. RESULTS: Patients with IPF/PPF (n = 126) and non-IPF/PPF (n = 227) had a similar cumulative incidence of exertional hypoxemia and annualized decline in 6MWD and composite indices, which varied across each PPF criterion. Patients with IPF/non-PPF (n = 231) and non-IPF/non-PPF (n = 531) had a significantly lower incidence of hypoxemia than those with IPF/PPF, with an annualized increase in 6MWD and composite indices in the non-IPF/non-PPF group. Exertional or resting hypoxemia at the time of meeting criteria for PPF was independently associated with reduced transplant-free survival in IPF and non-IPF, adjusting for patient demographics and lung function. Adding new-onset exertional or resting hypoxemia as a physiological criterion reduced the median time to development of PPF from 11.2 to 6.7 months in IPF and from 11.7 to 5.6 months in non-IPF in patients who eventually met both definitions (P < .001 for both). INTERPRETATION: Patients with IPF/PPF and non-IPF/PPF have comparable deterioration in functional capacity. Oxygenation status provides prognostic information in PPF and may assist in defining disease progression in fibrotic ILD.

Treatment of rheumatoid arthritis-associated interstitial lung disease in a multi-center registry cohort.

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is challenging to manage, with a paucity of robust data to guide treatment. Our aim was to characterize the pharmacologic treatment of RA-ILD utilizing a retrospective design in a national multi-center prospective cohort, and to identify associations between treatment and change in lung function and survival. Methods: Patients with RA-ILD and a radiological pattern of non-specific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) were included. Unadjusted and adjusted linear mixed models and Cox proportional hazards models were used to compare lung function change and risk of death or lung transplant by radiologic patterns and treatment. Results: Of 161 patients with RA-ILD, UIP pattern was more common than NSIP (55.9% vs. 44.1%). Only 44/161 (27%) patients were treated over median follow-up of 4 years with medication choice appearing unrelated to patient-specific variables. Decline in forced vital capacity (FVC) was not associated with treatment. Patients with NSIP had lower risk of death or transplant, compared to UIP (P=0.0042). In patients with NSIP, there was no difference in time to death or transplant comparing treated to untreated in adjusted models [hazard ratio (HR) =0.73; 95% confidence interval (CI): 0.15-3.62; P=0.70]. Similarly, in patients with UIP, there was no difference in time to death or lung transplant between treated and untreated in adjusted models (HR =1.06; 95% CI: 0.49-2.28; P=0.89). Conclusions: Treatment of RA-ILD is heterogeneous, with most patients in this cohort not receiving treatment. Patients with UIP had worse outcomes compared to NSIP, similar to other cohorts. Randomized clinical trials are needed to inform pharmacologic therapy in this patient population.

Sex- and Race-Based Differences in the Treatment of Interstitial Lung Diseases in North America and Australasia.

BACKGROUND: Biological sex, gender, and race are important considerations in patients with interstitial lung diseases (ILDs). RESEARCH QUESTION: Does a patient's sex assigned at birth, and race, influence ILD treatment initiation? STUDY DESIGN AND METHODS: Patients with ILD from three longitudinal prospective registries were compared in this observational study. ILD-related medications included antifibrotics and immunomodulating medications. Race was dichotomized as "White" vs "non-White." Time to treatment initiation was determined from the date of the initial ILD registry visit to the date of first medication initiation. Proportions of treated patients were compared between groups by χ2 test. Cox proportional analysis was used to determine how sex and race were associated with time to treatment initiation stratified by ILD diagnosis. RESULTS: A total of 4,572 patients were included across all cohorts. The proportion of men who received treatment was higher than for women in the Canadian cohort (47% vs 40%; P < .001), and the proportion of White patients who received treatment was also higher compared with non-White patients (46% vs 36%; P < .001). In contrast, the proportion of treated men in the Chicago cohort was lower compared with women (56% vs 64%; P = .005), and that of White patients was lower compared with non-White patients (56% vs 69%; P < .001). No sex- or race-based differences in proportions of patients treated were found in the Australasian cohort. White race was significantly associated with earlier treatment initiation compared with non-White race across diagnoses in the Canadian cohort, whereas the opposite association was found in the Australasian cohort. INTERPRETATION: Sex- and race-based differences exist in the initiation of ILD treatment, with variability across different cohorts in different countries. Reasons for these differences need to be further explored in future studies.

Predicting New-onset Exertional and Resting Hypoxemia in Fibrotic Interstitial Lung Disease.

Rationale: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic ILD. Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen. Objectives: We derived and externally validated a risk prediction tool for both new-onset exertional and new-onset resting hypoxemia. Methods: This study used ILD registries from Canada for the derivation cohort and from Australia and the United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir oxyhemoglobin saturation < 88% during 6-minute-walk tests, resting oxyhemoglobin saturation < 88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top-performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed. Results: The best-performing prediction model for both new-onset exertional and new-onset resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index, 0.70; GoF, P = 0.85) and resting hypoxemia (C-index, 0.77; GoF, P = 0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF, P = 0.001). Conclusions: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at 6 months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed because of underestimation of hypoxemia.

Mapping EQ5D utilities from forced vital capacity and diffusing capacity in fibrotic interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) includes a large group of conditions that lead to scarring of the lungs. The lack of available 5-level EuroQol 5D (EQ5D) data has limited the ability to conduct economic evaluations in ILD. The purpose of this study was to develop and validate a mapping algorithm that predicts EQ5D utilities from commonly collected pulmonary function measurements (forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]) in fibrotic ILDs. METHODS: EQ5D utility and pulmonary function measurements from the Canadian Registry for Pulmonary Fibrosis were included. Ordinary least squares (OLS), beta regression, two-part, and tobit models were used to map EQ5D utilities from FVC or DLCO. Model performance was assessed by comparing the predicted and observed utilities. Subgroup analyses were also conducted to test how well models performed across different patient characteristics. The models were then externally validated in the Australian Idiopathic Pulmonary Fibrosis Registry. RESULTS: The OLS model performed as well as other more complex models (root mean squared error: 0.17 for FVC and 0.16 for DLCO). As with the other models, the OLS algorithm performed well across the different subgroups (except for EQ5D utilities < 0.5) and in the external validation cohort. CONCLUSION: We developed a mapping algorithm that predicts EQ5D utilities from FVC and DLCO, with the intent that this algorithm can be applied to clinical trial populations and real-world cohorts that have not prioritized collection of health-related utilities. The mapping algorithm can be used in future economic evaluations of potential ILD therapies.

Integration and Application of Radiologic Patterns From Clinical Practice Guidelines on Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient. RESEARCH QUESTION: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines? STUDY DESIGN AND METHODS: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan features were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis. RESULTS: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91). INTERPRETATION: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific.