The diagnostic pathway for patients with interstitial lung disease: a mixed-methods study of patients and physicians.

OBJECTIVES: The diagnostic process for patients with interstitial lung diseases (ILD) remains complex. The aim of this study was to characterise the diagnostic care pathway and identify barriers and potential solutions to access a timely and accurate ILD diagnosis. DESIGN: This mixed-method study was comprised of a quantitative chart review, patient and physician surveys and focus groups. RESULTS: Chart review was completed for 97 patients. Median time from symptom onset to ILD diagnosis was 12.0 (IQR 20.5) months, with 46% diagnosed within 1 year. Time from first computed tomography (CT) scan to respirology referral was 2.4 (IQR 21.2) months. Referrals with a prior CT were triaged sooner than referrals without (1.7±1.6 months vs 3.9±3.3 months, p=0.013, 95% CI 0.48 to 2.94). On patient surveys (n=70), 51% felt that their lung disease was not recognised early enough. Commonly reported challenges to timely diagnosis included delayed presentation to primary care, initial misdiagnoses and long wait-times for specialists. Forty-five per cent of physicians (n=20) identified diagnostic delays, attributed to delayed presentations to primary care (58%), initial misdiagnoses (67%) and delayed chest imaging (75%). Themes from patient and respirologist focus groups included patient-related, healthcare provider-related and system-related factors leading to delays in diagnosis. CONCLUSIONS: This mixed-methods study identified patient and system-related factors that contribute to diagnostic delays for patients with ILD, with most delays occurring prior to respirology referral. ILD awareness and education, earlier presentation to primary care, expedited access to chest imaging and earlier referral to respirology may expedite diagnosis.

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.

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.

Patient and Physician Assessments of Clinical Status: A Mixed-methods Study of Interstitial Lung Disease.

Background: The SARS-CoV-2 pandemic necessitated novel health care delivery for patients with interstitial lung disease (ILD), including reduced in-person appointments and physiologic testing to minimize transmission. Clinicians often have been required to rely on patients' subjective assessments of their clinical status during phone follow-up appointments. It is unknown how accurate a patient's self-assessment is compared with that of their physician during an in-person evaluation. Research Question: Are patients' self-assessments of their clinical status in agreement with their physicians' assessments, and are telemedicine vs in-person visits acceptable? Study Design and Methods: Patients were enrolled prospectively from the University of Calgary ILD clinic. Participants were asked by phone before the in-person appointment and after the appointment to rate their clinical status on a five-point Likert scale. Physicians then rated the patient's clinical status after the appointment on a similar five-point Likert scale, masked to patient responses. Patients and physicians were asked if an in-person appointment was necessary or if telemedicine would have sufficed. Clinical variables associated with physician assessments were assessed. Results: Fifty patients with mean age of 67 ± 11.8 years participated. Mean time since last follow-up was 5.0 ± 3.0 months. No correlation was found between the preclinical patient self-assessment and postclinical physician assessment (P = .18; κ = 0.28). Correlation of postclinical assessment was statistically significant (P < .001), with moderate agreement (κ = 0.49). Physicians thought telephone visits were acceptable for 58% of appointments, whereas only 12% of patients preferred telephone visits. Physician's assessment of clinical status seemed to be driven by change in diffusion capacity of the lungs for carbon monoxide (P = .039). Interpretation: Telemedicine may improve access to care for patients during pandemic management, in rural communities, and for those with impaired mobility. Despite these benefits, our data support that patients and physicians may not agree on determination of clinical status and that patients generally prefer in-person patient-physician interactions.

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.

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.

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.

Perceptions of Genetic Testing: A Mixed-Methods Study of Patients with Pulmonary Fibrosis and Their First-Degree Relatives.

Rationale: Genetic testing is an emerging tool in interstitial lung disease (ILD) as several ILD subtypes have potential genetic causes or predispositions with resultant clinical implications. There is a need to understand the perceptions of patients and their first-degree relatives of genetic testing for ILD. Objectives: The objective of this study was to investigate patients with ILD and their first-degree family members' understanding of the genetic risks associated with ILD and their interest and/or concerns about genetic testing. Methods: This mixed-methods study included patients with ILD and their first-degree relatives. Data were obtained from an online survey and three focus groups. Categorical data were reported with descriptive frequencies. Chi-square analyses were used to measure associations. Focus group discussions were transcribed, coded, and analyzed according to the grounded theory principle. Results: A total of 188 respondents completed the survey; 119 patients, 52 first-degree relatives, and 17 who were both patients and who also reported being a first-degree relative to someone with ILD. Most (79%) patients had idiopathic pulmonary fibrosis. The majority of patients and first-degree relatives were unsure if there was a genetic cause, whereas 71% of those who were both patient and first-degree relative thought there could be a genetic cause to their ILD. Fifty-nine percent of respondents worried their family members could be affected, and 72% of respondents were interested in genetic testing. Interest in genetic testing was associated with sex (P = 0.03), post-secondary education (P = 0.047), and having a family member with ILD (P = 0.02). The primary motivators were understanding risk to family members and contributing to research. First-degree relatives were concerned about insurance issues (60%) and personal stress (60%) more often than patients (40% and 28%, respectively); 29% of first-degree relatives anticipated changing their health behavior based on results. Focus group themes included disease knowledge, understanding the role of genetics in ILD, testing concerns, and how to use genetic testing information. Conclusions: This study provides insight into the perceptions of patients and first-degree relatives of ILD-related genetic testing. These findings inform the need for additional patient resources, yet a better understanding of the clinical applications of ILD genetic testing and how testing may impact diagnostics, therapeutics, and prognostication.

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.

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.

Association of BMI and Change in Weight With Mortality in Patients With Fibrotic Interstitial Lung Disease.

BACKGROUND: Mortality risk assessment in interstitial lung disease (ILD) is challenging. Our objective was to determine the prognostic significance of BMI and change in weight in the most common fibrotic ILD subtypes. RESEARCH QUESTION: Could BMI and weight loss over time be reliable prognostic indicators in patients with fibrotic ILD? STUDY DESIGN AND METHODS: This observational retrospective multicenter cohort study enrolled patients with fibrotic ILD from the six-center CAnadian REgistry for Pulmonary Fibrosis (CARE-PF, derivation) and the ILD registry at the University of California, San Francisco (UCSF, validation). Patients were subcategorized as underweight (BMI < 18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), or obese (BMI > 30). Annual change in weight was calculated for all years of follow-up as the slope of best fit using the least square method based on every available measurement. Separate multivariable analyses evaluated the associations of BMI and change in weight with mortality, adjusting for common prognostic variables. RESULTS: The derivation and validation cohorts included 1,786 and 1,779 patients, respectively. Compared with patients with normal BMI, mortality was highest in patients who were underweight (hazard ratio [HR], 3.19; 95% CI, 1.88-5.43; P < .001) and was lowest in those who were overweight (HR, 0.52; 95% CI, 0.36-0.75; P < .001) or obese (HR, 0.55; 95%CI, 0.37-0.83; P < .001) in the analysis adjusted for the ILD-GAP (gender, age, physiology) Index. Patients who had a weight loss of at least 2 kg within 1 year had increased risk of death in the subsequent year (HR, 1.41; 95% CI, 1.01-1.97; P = .04) after adjustment for the ILD-GAP Index and baseline BMI category, with a plateau in risk for patients with greater weight loss. Consistent results were observed in the validation cohort. INTERPRETATION: Both BMI and weight loss are independently associated with 1-year mortality in fibrotic ILD. BMI and weight loss may be clinically useful prognostic indicators in fibrotic ILD.

Travel Distance to Subspecialty Clinic and Outcomes in Patients with Fibrotic Interstitial Lung Disease.

Rationale: Early access to subspecialty care is associated with improved outcomes for patients with fibrotic interstitial lung disease (ILD). Access to ILD care may be limited for patients living far from subspecialty clinics. Objectives: To test the hypothesis that greater travel distance to access ILD clinical care would be associated with more severe disease at time of referral and worse clinical outcomes. Methods: Patients with fibrotic ILD were recruited from a multicenter national pulmonary fibrosis registry. Residential postal codes were geocoded to estimate travel distance from the home to the clinic. Travel distance was dichotomized at ⩽70 km (near) and >70 km (far). Demographics and disease severity at the initial referral, changes in lung function, and the risk of death or lung transplant were analyzed in unadjusted and adjusted models for their association with travel distance. Results: The cohort included 1,162 patients, of whom 856 lived near to their ILD clinic and 306 lived far from their ILD clinic. Patients residing farther from their clinic were younger, more likely to have smoked, had a greater 6-minute-walk distance, and had lower composite risk scores than patients residing closer to their clinic. In models adjusted for age, sex, and baseline forced vital capacity, patients from farther away had a greater risk of death or lung transplant than patients residing closer (hazard ratio, 1.52; 95% confidence interval [CI], 1.10-2.11), a finding predominantly driven by patients with connective tissue disease-related ILD (hazard ratio, 2.14; 95% CI, 1.16-3.94). Conclusions: Patients with fibrotic ILD with a longer travel distance to their ILD clinic had better prognostic indices at baseline but had a higher risk of death or lung transplant in the total cohort and in patients with connective tissue disease-related ILD. Assuming that disease epidemiology and severity are distributed evenly across geographic regions, these findings raise important questions about equitable access to patient care in large healthcare regions with centralized subspecialty programs.

Effect of continued antifibrotic therapy after forced vital capacity decline in patients with idiopathic pulmonary fibrosis; a real world multicenter cohort study.

RATIONALE: Longitudinal data on the impact of continued, switched or discontinued antifibrotic therapy in patients with idiopathic pulmonary fibrosis (IPF) who have disease progression is needed. OBJECTIVE: We hypothesized that ongoing antifibrotic use (versus discontinuation) in the setting of forced vital capacity (FVC) decline would be associated with less future decline and lower likelihood of a composite outcome of FVC decline, lung transplant, or death. METHODS: We performed a multicenter cohort study using data from the Canadian Registry for Pulmonary Fibrosis in patients with IPF with FVC decline ≥10% over 6 months on antifibrotic therapy. The association of continued, switched or discontinued therapy with (1) further change in FVC and (2) a composite of FVC decline ≥10%, transplant, or death, in the subsequent 6 months, was assessed using adjusted linear and logistic regression modelling, respectively. Generalized estimating equations accounted for repeated observations per patient. RESULTS: 165 patients had a decline in FVC ≥10% over 6 months while receiving antifibrotic therapy. Compared to continued use, antifibrotic discontinuation after FVC decline was associated with greater additional FVC decline (-207 mL 95%CI -353 to -62, p = 0.005) and higher odds of FVC decline ≥10%, transplant, or death (odds ratio 12.2 95%CI 1.2 to 130.5, p = 0.04). There was no difference between continued versus switched antifibrotic therapy. CONCLUSIONS: Ongoing antifibrotic therapy in the setting of FVC decline is associated with less future FVC decline and lower odds of FVC decline ≥10%, transplant, or death in a real-world cohort of IPF.

Validation and minimum important difference of the UCSD Shortness of Breath Questionnaire in fibrotic interstitial lung disease.

RATIONALE: The University of California, San Diego Shortness of Breath Questionnaire (UCSDSOBQ) is a frequently used domain-specific dyspnea questionnaire; however, there is little information available regarding its use and minimum important difference (MID) in fibrotic interstitial lung disease (ILD). We aimed to describe the key performance characteristics of the UCSDSOBQ in this population. METHODS: UCSDSOBQ scores and selected anchors were measured in 1933 patients from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Anchors included the St. George's Respiratory Questionnaire (SGRQ), European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) and EQ visual analogue scale (EQ-VAS), percent-predicted forced vital capacity (FVC%), diffusing capacity of the lung for carbon monoxide (DLCO%), and 6-min walk distance (6MWD). Concurrent validity, internal consistency, ceiling and floor effects, and responsiveness were assessed, followed by estimation of the MID by anchor-based (linear regression) and distribution-based methods (standard error of measurement). RESULTS: The UCSDSOBQ had a high level of internal consistency (Cronbach's alpha = 0.97), no obvious floor or ceiling effect, strong correlations with SGRQ, EQ-5D-5L, and EQ-VAS (|r| > 0.5), and moderate correlations with FVC%, DLCO%, and 6MWD (0.3 < |r| < 0.5). The MID estimate for UCSDSOBQ was 5 points (1-8) for the anchor-based method, and 4.5 points for the distribution-based method. CONCLUSION: This study demonstrates the validity of UCSDSOBQ in a large and heterogeneous population of patients with fibrotic ILD, and provides a robust MID estimate of 5-8 points.

Treatment Initiation in Patients with Interstitial Lung Disease in Canada.

Rationale: Real-life pharmacological treatment patterns of patients with interstitial lung diseases (ILD) remain elusive. Objectives: To determine how often and with what medications patients with ILD are treated in Canadian tertiary care clinics. Methods: All patients with ILD prospectively enrolled in the Canadian Registry for Pulmonary Fibrosis were included in this observational study. All first instances of medication for each patient were compiled. The time between the diagnosis of ILD and the first initiation of an ILD-related medication was compared across diagnostic categories. Cox proportional hazards models were used to identify variables associated with time-to-treatment initiation, stratified by diagnostic category. Results: Out of 2,652 patients, a total of 1,483 (56%) were treated with an ILD-related medication during the median follow up of 3.0 years (1.4-5.9), including 349/646 (54%) patients with idiopathic pulmonary fibrosis (IPF) who received an antifibrotic. Patients with IPF were treated earlier and in greater proportion than those with non-IPF ILD (P = 0.001). Male sex and lower lung function were associated with shorter time-to-treatment initiation in the full cohort. Conclusions: Overall, 56% of patients with ILD seen across seven Canadian specialized ILD clinics received pharmacological treatment over a median follow up of 3 years. Further studies are needed to assess longitudinal patterns of treatment and their influence on key outcomes.

Minimum important difference of the EQ-5D-5L and EQ-VAS in fibrotic interstitial lung disease.

RATIONALE: The European Quality of Life 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) is a multidimensional patient-reported questionnaire that supports calculation of quality-adjusted life-years. Our objectives were to demonstrate feasibility of use and to calculate the minimum important difference (MID) of the EQ-5D-5L and its associated visual analogue scale (EQ-VAS) in patients with fibrotic interstitial lung disease (ILD). METHODS: Patients who completed the EQ-5D-5L were identified from the prospective multicentre CAnadian REgistry for Pulmonary Fibrosis. Validity, internal consistency and responsiveness of the EQ-5D-5L were assessed, followed by calculation of the MID for the EQ-5D-5L and EQ-VAS. Anchor-based methods used an unadjusted linear regression against pulmonary function tests (PFTs) and dyspnoea and other quality of life questionnaires. Distribution-based method used one-half SD and SE measurement (SEM) calculations. RESULTS: 1816 patients were analysed, including 472 (26%) with idiopathic pulmonary fibrosis. EQ-5D-5L scores were strongly correlated with the dyspnoea and other quality of life questionnaires and weakly associated with PFTs. The estimated MID for EQ-5D-5L ranged from 0.0050 to 0.054 and from 0.078 to 0.095 for the anchor-based and distribution-based methods, respectively. The MID for EQ-VAS ranged from 0.5 to 5.0 and from 8.0 to 9.7 for the anchor-based and distribution-based methods. Findings were similar across ILD subtypes, sex and age. CONCLUSION: We used a large and diverse cohort of patients with a variety of fibrotic ILD subtypes to suggest validity and MID of both the EQ-5D-5L and EQ-VAS. These findings will assist in designing future clinical trials and supporting cost-effectiveness analyses of potential treatments for patients with fibrotic ILD.

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.

Costs of Workplace Productivity Loss in Patients with Connective Tissue Disease-associated Interstitial Lung Disease.

Rationale: Interstitial lung disease (ILD) develops in a large percentage of patients with connective tissue disease (CTD) and is associated with increased morbidity and mortality. Patients with CTD-associated ILD (CTD-ILD) often present at a young age, suggesting that ILD likely impacts workplace productivity.Objectives: We aimed to determine the employment rate and workplace productivity loss, along with its associated factors and estimated costs, in patients with fibrotic CTD-ILD.Methods: Patients with fibrotic CTD-ILD from the six centers of the Canadian Registry for Pulmonary Fibrosis were eligible. Health-related productivity loss was assessed using the Work Productivity and Activity Impairment questionnaire. Proposed factors associated with low workplace productivity were forced into a multivariable regression model. Average productivity loss in hours/week was used to calculate the costs of productivity loss based on hourly wages obtained from national census data matched for age and sex. Workplace productivity loss outcomes were compared between patients with CTD-ILD and patients with a non-CTD fibrotic ILD.Results: Of 375 eligible patients with fibrotic CTD-ILD, 113 (30%) were employed. Productivity loss was reported by 59% of employed patients, with a mean loss of 9.4 ± 1.2 hours/week, including 3.9 ± 0.9 hours/week from absenteeism and 5.5 ± 0.7 hours/week from presenteeism. Employment among patients 25-54 years of age with fibrotic CTD-ILD was 27% lower than that in the matched general Canadian population (56% vs. 83%; P < 0.001). Employment among patients ≥55 years of age with CTD-ILD was 17% lower than that in the matched population (19% vs. 36%; P < 0.001). Workplace productivity loss was not associated with respiratory symptoms or lung physiology. Annual costs of productivity loss were calculated at 13,593 Canadian dollars per employee with fibrotic CTD-ILD. Workplace productivity loss was similar in patients with fibrotic CTD-ILD and those with non-CTD fibrotic ILD.Conclusions: Patients with fibrotic CTD-ILD frequently report workplace productivity loss, which is unexplained by respiratory symptoms or lung physiology and is associated with significant costs.

Autoantibody status is not associated with change in lung function or survival in patients with idiopathic pulmonary fibrosis.

INTRODUCTION: A proportion of patients with idiopathic pulmonary fibrosis (IPF) have autoantibodies directed against intracellular targets. This study aimed to determine the relationship between serologic status, lung function decline and survival. METHODS: IPF patients assessed for antinuclear antibody (ANA) and related antigen-specific serology detected by addressable laser bead immunoassay (ALBIA) were included. Demographics, serial pulmonary function tests and survival were compared between patients with and without autoantibodies. Linear mixed models were used to estimate changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Cox-proportional hazards models were used to compare survival, adjusted for a composite score including age, sex and baseline lung function. RESULTS: Of 61 included patients, the mean baseline age was 70 years (SD = 9), 77% were male, and 87% were Caucasian. Either ANA or antigen-specific serology by ALBIA was positive in 25 (41%) during follow-up. ANA was detected in 23 (38%), and specific autoantibodies by ALBIA in 6 (10%). There was no difference in age, sex, race, smoking status, anti-fibrotic use or baseline FVC or DLCO in patients with and without autoantibodies. There was no association between autoantibody status and survival (HR = 1.18, 95% CI 0.61, 2.29), rate of decline in FVC or DLCO (difference in FVC = 4.2 mL/year, p = 0.82; difference in DLCO = 4.6*10-4 mL/min/mmHg/year, p = 0.20). CONCLUSION: These data suggest that autoantibodies are common in IPF and that patients with a subset of autoantibodies, but without features of autoimmunity, demonstrate similar disease behaviour to those without autoantibodies.