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.

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.

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.

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.

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.

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.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study.

Background: Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. Methods: A multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. Results: We identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. Conclusion: PAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Contexte: La stratification des risques est fondamentale dans la prise en charge de l'hypertension artérielle pulmonaire (HTAP). L'indice de pulsatilité des artères pulmonaires (iPAP), défini comme la pression différentielle dans les artères pulmonaires divisée par la pression auriculaire droite (PAD), est un indice hémodynamique qui s'est révélé prédictif d'une dysfonction ventriculaire droite (VD) aiguë dans plusieurs situations. Notre objectif était d'évaluer l'utilité pronostique de l'iPAP dans une cohorte multicentrique diversifiée de patients atteints d'HTAP. Méthodologie: Une étude de cohorte multicentrique rétrospective de patients adultes consécutifs atteints d'une HTAP nouvellement diagnostiquée par cathétérisme cardiaque droit entre janvier 2016 et décembre 2020 a été effectuée dans quatre grands centres au Canada. Les données hémodynamiques, les données cliniques et les résultats ont été recueillis. La corrélation de l'iPAP et d'autres va-riables hémodynamiques avec la mortalité a été évaluée par les courbes caractéristiques opérationnelles du receveur et des modèles à risques proportionnels de Cox. Résultats: Nous avons recensé 590 patients dont l'âge moyen était de 61,4 ± 15,5 ans; la proportion de femmes était de 66,3 %. Un faible iPAP (défini comme une valeur < 5,3) a été associé à une hausse de la mortalité à 1 an : 10,2 % contre 5,2 % (p= 0,02). Dans un modèle multivarié comprenant l'âge, le sexe, l'indice de masse corporelle et la classe fonctionnelle, un faible iPAP a été associé à la mortalité à 1 an (aire sous la courbe de 0,64 [intervalle de confiance à 95 %; de 0,55 à 0,74]). Cependant, une PAD élevée (> 8 mmHg) a aussi été un facteur prédictif de mortalité, l'aire sous la courbe étant de 0,65. Conclusions: L'iPAP a été associé à la mortalité dans une vaste cohorte de patients atteints d'une HTAP. Toutefois, la valeur discriminante de l'iPAP n'a pas été supérieure à celle de la PAD seule.

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.

Myeloid-specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.

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.

Pulmonary hypertension and associated outcomes in noncardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Some studies suggest that patients with pulmonary hypertension (PH) may be at higher risk of complications and death after noncardiac surgery. However, the magnitude of these associations is unclear. OBJECTIVES: To determine the associations between PH and adverse outcomes after noncardiac surgery. METHODS: We searched PUBMED and EMBASE for studies published from January 1970 to April 2022. We included studies that reported the association between PH and one or more outcomes of interest occurring after noncardiac surgery. Data were pooled using random-effects models and reported as summary odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Eighteen studies met eligibility criteria (n=18,214,760). PH was independently associated with mortality (adjusted odds ratio [OR] 2.09; 95% CI, 1.51-2.90; I2=98%; 8 studies). PH was associated with a higher unadjusted risk of deep venous thrombosis (OR 4.02; 95% CI, 2.14-7.54; I2=85%; 3 studies), pulmonary embolism (OR 4.16; 95% CI, 3.23-5.36; I2=69%; 7 studies), myocardial infarction (OR 1.49; 95% CI, 1.44-1.54; I2=0%; 5 studies), congestive heart failure or cardiogenic shock (OR 3.37; 95% CI, 1.73-6.60; I2=34%; 5 studies), length of hospital stay (mean difference 1.97 days; 95% CI, 0.81-3.12; I2=99%; 5 studies), and delayed extubation (OR 5.98; 95% CI, 1.70-21.02; I2=3%; 3 studies). PH was associated with lower unadjusted risk of postoperative stroke (OR 0.93; 95% CI, 0.88-0.98; I2=0%; 3 studies). CONCLUSION: PH is a predictor of morbidity and mortality after noncardiac surgery. High quality studies are needed to determine effective strategies for reducing postoperative complications in this population.

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.

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.

Infliximab therapy in refractory sarcoidosis: a multicenter real-world analysis.

BACKGROUND: Infliximab is a monoclonal antibody that binds and neutralizes circulating tumor necrosis factor-alpha, a key inflammatory cytokine in the pathophysiology of sarcoidosis. Despite the paucity of randomized clinical trials, infliximab is often considered a therapeutic option for refractory disease. Our study aimed to investigate the effectiveness of infliximab in patients with refractory sarcoidosis. METHODS: Sarcoidosis patients from three tertiary centres were retrospectively identified by pharmacy records based on treatment with infliximab. Treatment with Infliximab was initiated in patients who failed first and second line immunomodulators as determined by a multidisciplinary team of Respirologists, Dermatologists, ENT specialists, Rheumatologists, and Neurologists. Participants were characterized by the primary organ for which infliximab was initiated and the total number of organs involved. Clinical outcomes were categorized as treatment success versus failure. We defined treatment success as (A) improvement of cutaneous, upper airway, lymph node, gastrointestinal, eye, or joint manifestations; or (B) improvement or no change in central nervous system (CNS) or pulmonary manifestations. RESULTS: 33 patients with refractory sarcoidosis were identified. The proportion of treatment success was 100% (95% CI 54.1-100) in CNS, 91.7% (95% CI 61.5-99.8) in cutaneous, 78.6% (95% CI 49.2-95.3) in pulmonary and 71.5% (95% CI 29.0-96.3) in upper airway disease. The use of infliximab was associated with a reduction prednisone dose by 50%. CONCLUSION: Infliximab is possibly an effective therapy for refractory sarcoidosis, with the greatest value in neurologic and cutaneous manifestations. Across all disease presentations, infliximab facilitated a clinically relevant reduction in corticosteroid dose. Relapse is common after discontinuation of infliximab.

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.

Survival after inpatient or outpatient pulmonary rehabilitation in patients with fibrotic interstitial lung disease: a multicentre retrospective cohort study.

BACKGROUND: The impact of pulmonary rehabilitation (PR) on survival in patients with fibrotic interstitial lung disease (ILD) is unknown. Given the challenges conducting a large randomised controlled trial, we aimed to determine whether improvement in 6-minute walk distance (6MWD) was associated with better survival. METHODS: This retrospective, international cohort study included patients with fibrotic ILD participating in either inpatient or outpatient PR at 12 sites in 5 countries. Multivariable models were used to estimate the association between change in 6MWD and time to death or lung transplantation accounting for clustering by centre and other confounders. RESULTS: 701 participants (445 men and 256 women) with fibrotic ILD were included. The mean±SD ages of the 196 inpatients and 505 outpatients were 70±11 and 69±12 years, respectively. Baseline/changes in 6MWD were 262±128/55±83 m for inpatients and 358±125/34±65 m for outpatients. Improvement in 6MWD during PR was associated with lower hazard rates for death or lung transplant on adjusted analysis for both inpatient (HR per 10 m 0.94, 95% CI 0.91 to 0.97, p<0.001) and outpatient PR (HR 0.97, 95% CI 0.95 to 1.00, p=0.042). Participation in ≥80% of planned outpatient PR sessions was associated with a 33% lower risk of death (95% CI 0.49% to 0.92%). CONCLUSIONS: Patients with fibrotic ILD who improved physical performance during PR had better survival compared with those who did not improve performance. Confirmation of these hypothesis-generating findings in a randomised controlled trial would be required to definitely change clinical practice, and would further support efforts to improve availability of PR for patients with fibrotic ILD.