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.

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.

Assessment Of Ratio Of Peak Expiratory Flow Rate To Vital Capacity For Identifying Pulmonary Fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is associated with reduction in vital capacity (VC) and increase in expiratory flow rates, including peak expiratory flow (PEF). Full pulmonary function testing and computed tomography chest scans are limited resources in some geographic areas and a simple and sensitive screening test would be of value. We hypothesized that increase in the ratio of % predicted PEF over % predicted VC (%PEF/%VC), from spirometry alone might be sensitive to screen for pulmonary fibrosis. METHODS: The %PEF/%VC from 1,000 consecutive spirometric flow volume curves was nearly normally distributed: 7.5% (approximately 1.5 standard deviations) had a ratio ≥ 1.4. We evaluated the sensitivity and specificity of this cut point for a diagnosis of PF in a retrospective chart review of 391 patients with good quality spirometry and respirologists' confirmed diagnoses. RESULTS: Of the 391 patients analyzed, 98 had PF, 79 were normal, 70 had a combined obstructive and restrictive processes, 57 had obstructive lung disease, 61 had extra-parenchymal restriction and 26 had non-fibrotic interstitial lung disease. A %PEF/%VC ≥ 1.4 was only 54.1% sensitive in predicting PF, however it had a specificity of 94.9%. There was a 95.1% specificity for ruling in intra-parenchymal opposed to extra-parenchymal restriction. CONCLUSION: A %PEF/%VC ≥ 1.4 was not sensitive enough to screen for PF but did demonstrate high specificity and thus may be helpful in identifying intraparenchymal restriction.

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.

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.

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.

Prevalence, imaging patterns and risk factors of interstitial lung disease in connective tissue disease: a systematic review and meta-analysis.

INTRODUCTION: Interstitial lung disease (ILD) is a frequent manifestation of connective tissue disease (CTD) with substantial variability in prevalence and outcomes reported across CTD subtypes. This systematic review summarises the prevalence, risk factors and ILD patterns on chest computed tomography of CTD-ILD. METHODS: A comprehensive search was performed in Medline and Embase to identify eligible studies. Meta-analyses were completed using a random effects model to determine the pooled prevalence of CTD-ILD and ILD patterns. RESULTS: 11 582 unique citations were identified with 237 articles included. Pooled prevalence of ILD was 11% in rheumatoid arthritis (95% CI 7-15%), 47% in systemic sclerosis (44-50%), 41% in idiopathic inflammatory myositis (33-50%), 17% in primary Sjögren's syndrome (12-21%), 56% in mixed connective tissue disease (39-72%) and 6% in systemic lupus erythematosus (3-10%). Usual interstitial pneumonia was the most prevalent ILD pattern in rheumatoid arthritis (pooled prevalence of 46%), while nonspecific interstitial pneumonia was the most common ILD pattern in all other CTD subtypes (pooled prevalence range 27-76%). Across all CTDs with available data, positive serology and higher inflammatory markers were risk factors for development of ILD. DISCUSSION: We identified substantial variability in ILD across CTD subtypes suggesting that CTD-ILD is too heterogenous to be considered a single entity.

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.

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.

Prevalence of allergen sensitization in 1000 adults in Saskatchewan.

BACKGROUND: The prevalence of sensitization varies geographically based on multiple environmental factors including humidity. The aim of this study was to determine the prevalence of atopy in symptomatic adults. More importantly we aimed to obtain a regional statistic of sensitization to common allergens given Saskatchewan's dry climate. METHODS: One thousand consecutive symptomatic adults were screened for atopy via skin prick test over 10 years (2006-2016) in the Division of Respirology. An atopic screen was performed with twenty common aeroallergens by a single investigator, Dr. D. Cockcroft. A positive test was considered to be a wheal ≥3 mm and markedly positive reactions ≥8 mm were also documented. RESULTS: The prevalence of atopy by means of a positive skin test (≥3 mm) was 45.5%. The prevalence of one or more markedly positive reactions (≥8 mm) was 29.5% of the total population. The most frequent sensitization was to cat dander (58.2%), followed by mixed grass (32.1%), and birch (26.8%). Dust mite sensitization was 22.4% and mouse 6.2%. A positive epidemiology screen for cat/grass/mite would have incorporated 82.0% (n = 373) of subjects with positive skin tests. Those who failed the cat/grass/mite screen were mainly sensitized to trees (n = 34), molds (n = 22), weeds (n = 7), and animals (n = 8). CONCLUSIONS: There is a high prevalence of cat sensitization in Saskatchewan, much higher than recorded in other centers internationally. This is likely due to a high proportion of cat ownership. The prevalence of mite sensitization is lower than those mentioned at other centres likely due to Saskatchewan's dry climate. The significance of the rate of markedly positive reactions (≥8 mm wheal) when compared to humid areas with higher burden of mite is unknown. There is a low prevalence of roach also likely due to the dry climate and mouse sensitization was low but still identified as a significant indoor allergen. A cat/grass/mite screen may be useful with a 82.0% sensitivity.