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BackgroundIncreasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies.MethodsWe surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α).ResultsAgreement over diagnosis (α=0.282), ease of classification (α= −0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5–10 yearsversusversusCanada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that “Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators”.ConclusionsOur results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement.

Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.govNCT04246528. Registered on 27 January 2020

Adults with cystic fibrosis (CF) develop exuberant inflammatory responses during pulmonary exacerbations (PEx) but whether distinct systemic inflammatory profiles can be identified and whether these associate with disparate treatment outcomes are unclear. We conducted a pilot study to address this question and hypothesized that CF adults with a pauci-inflammatory phenotype might derive less clinical benefit from intravenous (IV) antibiotic treatment than patients with other systemic inflammatory phenotypes.Six proteins reflective of systemic inflammation were examined in 37 PEx from 28 unique CF subjects. We applied exploratory factor analysis and cluster analysis to identify biological clusters. Levels of blood proteins at PEx and clinical outcomes following IV antibiotic treatment were compared between clusters.Three clusters of PEx were identified. The pauci-inflammatory phenotype was characterized by lower levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, calprotectin, and C-reactive protein (CRP) (p0.05). Higher levels of IL-6 and IL-1β were observed in the other 2 inflammatory clusters, but one of them was associated with higher calprotectin levels (p = 0.001) (neutrophil-predominant phenotype); whereas the other was associated with increased TNF-α and IL-10 levels (p0.001) (pro-inflammatory phenotype). A greater proportion of events from the neutrophil-predominant phenotype presented with acute respiratory symptoms and a larger decrease in ppFEVThree distinct inflammatory phenotypes were identified at PEx admission and each presented with unique clinical characteristics.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Cystic fibrosis (CF) pulmonary exacerbations (PEx) remain underdiagnosed by CF clinicians. Serum C-reactive protein (CRP) and calprotectin are inflammatory biomarkers that have the potential to aid in the diagnosis of PEx. 19 subjects (56 stable, 46 PEx visits) from a longitudinal study were included and the diagnostic performance of absolute and fold-change CRP and calprotectin cut-offs to discriminate stable and PEx visits was assessed. Based on Youden's index, optimal absolute and fold-change thresholds to identify PEx were 9.5 mg/L (Sn 76%, Sp 73%; AUC 0.76) and 2.2-fold (Sn 50%, Sp 96%; AUC 0.78) for CRP and 8.1 mg/L (Sn 61%, Sp 79%; AUC 0.72) and 1.3-fold (Sn 57%, Sp 88%; AUC 0.74) for calprotectin. A step-wise algorithm was able to improve diagnostic performance (Sn 80%; Sp 88%). CRP and calprotectin could discriminate stable vs. PEx visits with good performance and appear promising as diagnostic biomarkers but further validation studies are required prior to implementing these diagnostic thresholds.

Sex differences in morbidity and mortality have been reported in the cystic fibrosis (CF) population worldwide. However, it is unclear why CF women have worse clinical outcomes than men. In this review, we focus on the influence of female sex hormones on CF pulmonary outcomes and summarise data from in vitro and in vivo experiments on how oestrogen and progesterone might modify mucociliary clearance, immunity and infection in the CF airways. The potential for novel sex hormone-related therapeutic interventions is also discussed., A disparity in survival has been noted between men and women with cystic fibrosis where female sex hormones may facilitate lung disease progression. There is strong evidence that implicates oestrogen in numerous aspects of CF airway pathophysiology. https://bit.ly/34ef4Cv

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 CT...

The effects of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on lung function, pulmonary exacerbations, and quality of life have been well documented. However, CF is a multiorgan disease, and therefore an evidence base is emerging on the systemic effects of CFTR modulators beyond the pulmonary system. This is of great clinical importance, as many of these studies provide proof of concept that CFTR modulators might be used one day to prevent or treat extrapulmonary manifestations stemming from CFTR dysfunction. In this concise review of the literature, we summarize the results of key publications that have evaluated the effects of CFTR modulators on weight and growth, pancreatic function, the gastrointestinal and hepatobiliary systems, sinus disease, bone disease, exercise tolerance, fertility, mental health, and immunity. Although many of these studies have reported beneficial extrapulmonary effects related to the use of ivacaftor (IVA) in patients with CF with at least one gating mutation, most of the evidence is low or very low quality, given the limited number of patients evaluated and the lack of control groups. Based on an even smaller number of studies evaluating the extrapulmonary effects of lumacaftor-IVA, the benefits are less clear. Although limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extrapulmonary manifestations of CF.

Elevated blood eosinophil counts are linked to worse outcomes in asthma and COPD, but have yet to be well characterized in CF. We hypothesized that higher stable visit blood eosinophil counts are associated with increased rates of lung function decline and pulmonary exacerbations (PEx).We performed a retrospective analysis of adult CF patients (≥19 years) enrolled from 2012 to 2018 in a prospective cohort study focused on blood biomarkers. We included individuals with at least one year of follow-up post-stable visit blood draw and compared clinical characteristics by blood eosinophil count (300 cells/µL vs. ≥300 cells/µL). We used multivariate mixed-effects linear regression to estimate annual change in ppFEVOf 109 patients, 17 (15.6%) had eosinophil counts ≥300 cells/µL. After adjustment for age, sex, BMI, and baseline ppFEVThe high eosinophil group experienced increased respiratory symptoms, but the rates of lung function decline and PEx were comparable between groups.

OBJECTIVE: Typically, migraine prevention trials focus on reducing migraine days. This narrow focus may not capture all that is important to people with migraine. Inconsistency in outcome selection across trials limits the potential for data pooling and evidence synthesis. In response, we describe the development of core outcome set for migraine (COSMIG). DESIGN: A two-stage approach sought to achieve international, multistakeholder consensus on both the core domain set and core measurement set. Following construction of a comprehensive list of outcomes, expert panellists (patients, healthcare professionals and researchers) completed a three-round electronic-Delphi study to support a reduction and prioritisation of core domains and outcomes. Participants in a consensus meeting finalised the core domains and methods of assessment. All stages were overseen by an international core team, including patient research partners. RESULTS: There was a good representation of patients (episodic migraine (n=34) and chronic migraine (n=42)) and healthcare professionals (n=33) with high response and retention rates. The initial list of domains and outcomes was reduced from >50 to 7 core domains for consideration in the consensus meeting, during which a 2-domain core outcome set was agreed. CONCLUSION: International and multistakeholder consensus emerged to describe a two-domain core outcome set for reporting research on preventive interventions for chronic and episodic migraine: migraine-specific pain and migraine-specific quality of life. Intensity of migraine pain assessed with an 11-point Numerical Rating Scale and the frequency as the number of headache/migraine days over a specified time period. Migraine-specific quality of life assessed using the Migraine Functional Impact Questionnaire.

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.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.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.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.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.

Objectives NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0–24 and C24 with time to virological failure was evaluated by Cox regression. Results Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P Conclusions Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

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.Could BMI and weight loss over time be reliable prognostic indicators in patients with fibrotic ILD?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 (BMI30). 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.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.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.

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 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.

Lumacaftor-ivacaftor (LUM-IVA) was approved for use in Canada in January 2016. Observational studies have reported a higher incidence of treatment-emergent adverse events (AEs) leading to treatment...

Previous studies have suggested that interstitial lung disease (ILD) progresses most rapidly early in the course of systemic sclerosis-associated (SSc)-ILD, and that SSc-ILD is often more stable or even "burned out" after the first 4 years following diagnosis.Our objectives were to determine whether an apparent plateau in pulmonary function decline is due to survival bias and to identify distinct prognostic phenotypes of ILD progression.Consecutive patients with SSc-ILD from a single center were included. Pulmonary function measurements were typically performed every 6 months. Study participants were categorized into long-term survivors (8 yr survival from diagnosis), and those with medium-term and short-term mortality (4-8 and4 yr survival, respectively). We excluded those censored with less than 8 years of follow-up. Subject-specific slopes for change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DlThe cohort included 171 study participants with SSc-ILD. A plateau in the progression of FVC was apparent in the full cohort analysis but disappeared with stratification into prognostic subgroups to account for survival bias. Those with short-term mortality had a higher annual rate of decline in FVC (-4.10 [95% confidence interval (CI), -7.92 to -0.28] vs. -2.14 [95% CI, -3.31 to -0.97] and -0.94 [-1.46 to -0.42]; P = 0.003) and DlAdults with SSc-ILD have distinct patterns of physiological progression that remain relatively consistent during long-term follow-up; however, recent change in FVC cannot be used to predict future change in FVC within shorter follow-up intervals. The findings of this study provide important information on the course of disease in SSc-ILD and identify specific phenotypes of progression that may improve clinical decision-making and design of future therapeutic trials.

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 f...

Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes.Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies.The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies.We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

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 ...

Summary Background Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjogren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclerodermie Quebec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

Additional file 1: Table E1. Baseline characteristics of patients with and without 6-month follow-up. Table E2. Baseline characteristics across ILD subtypes. Table E3. Change in anchors across tertiles of change in UCSDSOBQ over 12 months. Table E4. IPF and non-IPF subgroup analysis of anchor- and distribution-based estimates of MID for UCSDSOBQ. Table E5. CTD-ILD and non-CTD-ILD subgroup analysis of anchor- and distribution-based estimates of MID for UCSDSOBQ. Table E6. Female and male subgroup analysis of anchor- and distribution-based estimates of MID for the UCSDSOBQ. Table E7. Older and younger subgroup analysis of anchor- and distribution-based estimates of MID for the UCSDSOBQ.

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.

Background Cystic Fibrosis (CF) is a hereditary pulmonary and extra-pulmonary disease that occurs equally in men and women. However, a difference in morbidity and mortality rates between the sexes has been long documented. Similarly, a sex-disparity in disease severity has been reported in asthma as well. Studies done to date point to estrogen as a possible cause of this sex disparity in pulmonary outcomes in both conditions. Case presentation Here, we describe a case of a patient with CF and asthma/allergic bronchopulmonary aspergillosis (ABPA) undergoing sex reassignment therapy (male-to-female) and the negative impact it had on her lung function and frequency of pulmonary exacerbations in the context of increasing doses of exogenous estrogen. Conclusions This case raises the possibility of a link between estrogen and worsening pulmonary outcomes and the need for further studies into transgender individuals with CF and/or asthma/ABPA as well as those undergoing high dose estrogen therapy for other indications.

There remains a limited understanding of the factors influencing clinical trial participation for individuals with Cystic Fibrosis (CF). A comprehensive survey was developed to examine the interests, preferences, and barriers/facilitators to research and clinical trial participation for CF patients. A consecutive sample of 198 CF adults attending the St. Paul's Hospital CF Clinic and parents of children with CF attending the BC Children's Hospital CF Clinic from Vancouver, Canada were surveyed. Parents of pediatric patients were less comfortable with blood collection, required more safety data prior to participating, and were more concerned about potential side effects. Very few respondents (

Rationale Lumacaftor/ivacaftor (LUM/IVA) modestly improves lung function following 1 month of treatment but it is unknown if this translates into improvements in exercise endurance and exertional symptoms. Methods Adult CF participants completed a symptom-limited constant load cycling test with simultaneous assessments of dyspnea and leg discomfort ratings pre- and 1 month post-initiation of LUM/IVA. Results Endurance time, exertional dyspnea and leg discomfort ratings at submaximal exercise did not change significantly. There was a significant inverse correlation between changes in leg discomfort and endurance time (r = - 0.88; p = 0.009) following 1-month of LUM/IVA. Conclusions Overall, 1-month of LUM/IVA did not increase endurance time or modify exertional dyspnea or leg discomfort ratings. However, individuals who experienced a reduction in leg discomfort following LUM/IVA had an improvement in endurance time. Future studies with a larger sample size are needed to verify these findings and to assess the long-term effects of LUM/IVA on exercise outcomes., Respiratory Research, 21 (1), ISSN:1465-993X, ISSN:1465-9921

RationaleThe 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).MethodsPatients 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.Results1816 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.ConclusionWe 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.

Additional file 1: Table S1. Cluster composition for each ILD subtype. Table S2. Major types of connective tissue diseases in each cluster.

Background and objective It is unknown whether oesophageal disease is associated with systemic sclerosis-associated interstitial lung disease (SSc-ILD) severity, progression or mortality. Methods High-resolution computed tomography (HRCT) scans from 145 SSc-ILD patients were scored for fibrosis score, oesophageal diameter and presence of hiatal hernia. Fibrosis asymmetry was calculated as: (most affected side - least affected side)/(most affected side + least affected side). Mixed effects models were used for repeated measures analyses. Results Mean fibrosis score was 8.6%, and most patients had mild-to-moderate physiological impairment. Every 1 cm increase in oesophageal diameter was associated with 1.8% higher fibrosis score and 5.5% lower forced vital capacity (FVC; P ≤ 0.001 for unadjusted and adjusted analyses). Patients with hiatal hernia had 3.9% higher fibrosis score, with persistent differences on adjusted analysis (P = 0.001). Oesophageal diameter predicted worsening fibrosis score over the subsequent year (P = 0.02), but not when adjusting for baseline fibrosis score (P = 0.16). Oesophageal diameter was independently associated with mortality (P = 0.001). Oesophageal diameter was not associated with asymmetric disease or radiological features of gross aspiration. Conclusion Oesophageal diameter and hiatal hernia are independently associated with SSc-ILD severity and mortality, but not with ILD progression or asymmetric disease. Oesophageal disease is unlikely to be a significant driver of ILD progression in SSc.

A previously healthy 34-year-old woman from Vancouver, British Columbia was referred for a left upper lobe lung mass. Main differential diagnoses were infection and malignancy. She underwent a bron...

RATIONALE: Non-invasive energy expenditure (EE) measurement is used to monitor physical activity in chronic lung disease. Unlike widely used motion-based devices calibrated in healthy populations, ...

BACKGROUND AND OBJECTIVE Despite its clinical and prognostic significance, few studies have evaluated the severity of exertional oxygen desaturation in fibrotic interstitial lung disease (ILD). Our objectives were to identify clinical and physiological variables that predict the extent of exertional oxygen desaturation in fibrotic ILD and to quantify the severity of desaturation compared to chronic obstructive pulmonary disease (COPD). METHODS This retrospective study compared the results of 6-min walk test (6MWT) performed while breathing room air in fibrotic ILD patients and COPD patients eligible for pulmonary rehabilitation. Outcomes included the oxygen saturation (SpO2 ) nadir and the change in SpO2 from rest during a 6MWT. Predictor variables were identified on unadjusted analysis, followed by multivariate analysis to identify independent predictors of desaturation. RESULTS The study included 134 patients with fibrotic ILD and 274 patients with COPD. The ILD and COPD cohorts had similar age, sex, frequency of major comorbidities, walk distance, baseline SpO2 and baseline Borg dyspnoea scores. DLCO was the strongest predictor of desaturation in both cohorts. Compared to patients with COPD, ILD patients had significantly lower SpO2 nadir values (88.1 ± 6.4 vs 91.0 ± 4.6) and greater decrease in SpO2 from baseline (7.4 ± 5.2 vs 4.5 ± 3.7) after adjusting for demographic features and pulmonary physiology (P < 0.0005), with greater between-group differences at lower DLCO values. CONCLUSION Patients with fibrotic ILD have greater oxygen desaturation during 6MWT compared to patients with COPD when adjusting for demographic features and pulmonary physiology. These findings suggest the need for disease-specific studies to evaluate the potential utility of ambulatory oxygen in fibrotic ILD.

Background and objective The objectives of this study were to determine the prevalence and characteristics of cough in idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Methods Cough severity was measured in consecutive patients with IPF (n = 77), HP (n = 32) and SSc-ILD (n = 67) using a 10-cm visual analogue scale (VAS). Dyspnoea and quality of life were measured using established questionnaires. Cough severity was compared across ILD subtypes and predictors of cough severity were determined using multivariate analysis. Results Cough was more common in IPF and chronic HP compared to SSc-ILD (87% and 83% vs 68%, P = 0.02). The median (interquartile range) VAS score was 39 (17–65) in the IPF cohort, 29 (11–48) in HP and 18 (0–33) in SSc-ILD (P

Background The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. Methods Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. Results The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. Conclusions CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

Background: Dehydroepiandrosterone sulfate (DHEAS) has antifibrotic properties in vitro and DHEAS plasma levels in patients with idiopathic pulmonary fibrosis (IPF) are low. Objective: To determine the association of DHEAS plasma levels with pulmonary function in patients with fibrotic interstitial lung disease (ILD). Methods: Blood samples were acquired from two distinct ILD cohorts. DHEAS plasma levels were measured by ELISA and tested for their associations with forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO). The primary analysis was performed in a Canadian fibrotic ILD cohort and then validated in a male Swiss IPF cohort. Results: In the derivation cohort mean (SD) age was 68 (10) years, FVC% 76 (18), and DLCO% 50 (16). Median (IQR) DHEAS plasma levels were 0.39 (0.23-0.63) mcg/ml in 76 men and 0.41 (0.23-0.60) mcg/ml in 53 women. The validation cohort (32 men) had a mean (SD) age of 68 (9) years, FVC% 62 (15), DLCO% 44 (12), and median (IQR) DHEAS of 0.33 (0.20-0.61) mcg/ml. In the derivation cohort, DHEAS correlated with FVC% in men (r=0.43, p Conclusion: We identified an age-independent association of DHEAS with FVC and DLCO in a diverse cohort of patients with fibrotic ILD with confirmation in a well-characterized cohort of men with IPF.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Fibrotic interstitial lung diseases (ILDs) are highly morbid chronic disorders that frequently occur in working age individuals. The goal of this study was to determine workplace productivity loss, its determinants, and its estimated costs in patients with fibrotic ILD.Patients with idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, idiopathic nonspecific interstitial pneumonia, or unclassifiable ILD were identified from the six-center Canadian Registry for Pulmonary Fibrosis (CARE-PF). The Work Productivity and Activity Impairment questionnaire was used to determine health-related productivity loss. Independent predictors of low workplace productivity were identified by using multivariate regression. Patient data were compared with Canadian population census data. The average productivity loss (hours per week) and the individual's hourly wage were used to estimate the costs of productivity loss.Of 650 eligible patients, 148 (23%) were employed. Productivity loss was reported by 55% of employed patients with an average productivity loss of 7.8 ± 0.9 h per week (2.3 ± 0.6 h per week related to absenteeism and 5.5 ± 0.6 h per week related to presenteeism). Employment among patients with ILD aged 25 to 54 years was 23% lower than the age- and sex-matched general Canadian population (60% vs 83%; P .001). Employment among patients with ILD aged ≥ 55 years was 18% lower than in the age- and sex-matched population (20% vs 38%; P .001). Dyspnea and cough were independent predictors of workplace productivity loss. Estimated annual costs of productivity loss were 11,610 Canadian dollars per employee with ILD.Workplace productivity loss is common in fibrotic ILD, strongly correlated with symptom severity, and associated with significant cost.

Cystic fibrosis-related diabetes (CFRD) is a well-known comorbidity among the CF population. To investigate whether CFRD impacts health-related quality of life (HRQoL), domain scores from the Cystic Fibrosis Questionnaire-Revised for adolescents and adults over 14 years old (CFQ-R 14+) were compared between CF individuals with CFRD on insulin, CFRD not on insulin, impaired glucose tolerance, and normal blood glucose tolerance. The median score for the Treatment Burden domain was significantly worse for individuals with CFRD on insulin (p 0.001) compared to the other diagnostic groups, and this association remained significant following adjustment for confounding variables. In conclusion, the additional requirement for insulin significantly contributes to treatment burden in adults with CFRD and therefore novel strategies to reduce treatment burden for this group are urgently needed.

This chapter reviews the fundamentals in acid-base interpretation and the differential diagnosis for each acid-base pattern. We also discuss oxygen transfer physiology and pathophysiology with a final case based illustration of the topic.