Publications by authors named "Martin Kolb"

209 Publications

R-Scale for Pulmonary Fibrosis (PF): a simple, visual tool for the assessment of health-related quality of life.

Eur Respir J 2021 Jun 10. Epub 2021 Jun 10.

Center for Interstitial Lung Disease, University of Washington, Seattle, WA, USA

Rationale: Patients with Idiopathic Pulmonary Fibrosis (IPF) experience impaired health related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice.

Objectives: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits.

Methods: A novel and simple 5-item numerical rating scale (NRS) was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at the center for ILD, were recruited to complete the R-Scale-PF, the Kings Brief Interstitial Lung Disease Questionnaire (K-BILD), and the EuroQol 5-Dimensional 5-Level Questionnaire (EQ-5D-5 L) in addition to pulmonary function and 6-min walk tests.

Measurements And Main Results: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5 L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walk distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity.

Conclusions: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5 L. It is hoped that this novel simple NRS tool subject to validation in patients from other centers will provide the opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.
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http://dx.doi.org/10.1183/13993003.00917-2021DOI Listing
June 2021

Repeat bronchoalveolar lavage in idiopathic pulmonary fibrosis: proceed with caution?

Eur Respir J 2021 May 27;57(5). Epub 2021 May 27.

Dept of Medicine, McMaster University, Hamilton, ON, Canada.

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http://dx.doi.org/10.1183/13993003.00691-2021DOI Listing
May 2021

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

Ann Am Thorac Soc 2021 May 25. Epub 2021 May 25.

University of British Columbia, Medicine, Vancouver, British Columbia, Canada.

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.

Objective: 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 home to clinic. Travel distance was dichotomized at ≤70km (near) and >70km (far). Demographics and disease severity at initial referral, change in lung function, and risk of death or transplant were analyzed in unadjusted and adjusted models for their association with travel distance.

Results: The cohort included 1162 patients, of whom 856 lived near and 306 lived far from their ILD clinic. Patients residing farther from clinic were younger, more likely to have smoked, had greater 6-minute walk distance, and lower composite risk scores compared to patients residing closer to clinic. In models adjusted for age, sex, and baseline forced vital capacity, patients from farther away had greater risk of death or lung transplant compared to patients residing closer (HR=1.52 95%CI 1.10 to 2.11), a finding predominantly driven by patients with connective-tissue disease (CTD) associated ILD (HR=2.14 95%CI 1.16 to 3.94).

Conclusions: Patients with fibrotic ILD with a longer travel distance to their ILD clinic had better prognostic indices at baseline, but a higher risk of death or lung transplant in the total cohort and in patients with CTD-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.
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http://dx.doi.org/10.1513/AnnalsATS.202102-216OCDOI Listing
May 2021

Mouse Models of Lung Fibrosis.

Methods Mol Biol 2021 ;2299:291-321

Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hamilton, Hamilton, ON, Canada.

The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease. We also describe the benefits of conducting preliminary discovery trials, to aid in the selection of suitable primary and secondary outcomes to be further evaluated and assessed in subsequent internal and external validation studies. We outline all relevant research methodologies and protocols routinely performed by our research group and hope that these strategies and protocols will be a useful guide for biomedical and translational researchers aiming to develop safe and beneficial therapies for patients with fibrotic lung disease.
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http://dx.doi.org/10.1007/978-1-0716-1382-5_21DOI Listing
January 2021

Inhaled Treprostinil in Group 3 Pulmonary Hypertension.

N Engl J Med 2021 May;384(19):1869

University of Lyon, Lyon, France

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http://dx.doi.org/10.1056/NEJMc2103465DOI Listing
May 2021

Abrogation of mesenchyme-specific TGF-β signaling results in lung malformation with prenatal pulmonary cysts in mice.

Am J Physiol Lung Cell Mol Physiol 2021 Apr 21. Epub 2021 Apr 21.

Department of Surgery, Children's Hospital of Los Angeles, United States.

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene (Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β--β-catenin--Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.
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http://dx.doi.org/10.1152/ajplung.00299.2020DOI Listing
April 2021

Prevalence and prognostic impact of physical frailty in interstitial lung disease: A prospective cohort study.

Respirology 2021 Apr 19. Epub 2021 Apr 19.

Department of Medicine, Division of Respirology, McMaster University, Hamilton, Ontario, Canada.

Background And Objective: Physical frailty is associated with increased mortality and hospitalizations in older adults. We describe the prevalence of physical frailty and its prognostic impact in patients with a spectrum of fibrotic interstitial lung disease (ILD).

Methods: Patients with fibrotic ILD at the McMaster University ILD programme were prospectively followed up from November 2015 to March 2020. Baseline data were used to classify patients as non-frail (score = 0), pre-frail (score = 1-2) or frail (score = 3-5) based on modified Fried physical frailty criteria. The association between physical frailty and mortality was assessed using time-to-event models, adjusted for age, sex, lung function and diagnosis using the ILD Gender-Age-Physiology (ILD-GAP) score.

Results: We included 463 patients (55% male, mean [SD] age 68 [11] years); 82 (18%) were non-frail, 258 (56%) pre-frail and 123 (26%) frail. The most common ILD diagnoses were idiopathic pulmonary fibrosis (n = 183, 40%) and connective tissue disease-associated-ILD (n = 79, 17%). Mean time since diagnosis was 2.7 ± 4.6 years. There were 56 deaths within the median follow-up of 1.71 (interquartile range [IQR] 1.24, 2.31) years. Both frail and pre-frail individuals had a higher risk of death compared to those categorized as non-frail at baseline (adjusted hazard ratio [aHR] 4.14, 95% CI 1.27-13.5 for pre-frail and aHR 4.41, 95% CI 1.29-15.1 for frail).

Conclusion: Physical frailty is prevalent in patients with ILD and is independently associated with an increased risk of death. Assessment of physical frailty provides additional prognostic value to recognized risk scores such as the ILD-GAP score, and may present a modifiable target for intervention.
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http://dx.doi.org/10.1111/resp.14066DOI Listing
April 2021

Fibrotic extracellular matrix induces release of extracellular vesicles with pro-fibrotic miRNA from fibrocytes.

Thorax 2021 Apr 15. Epub 2021 Apr 15.

Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario, Canada

Rationale: Extracellular vesicles (EVs) are small lipid vesicles, and EV-coupled microRNAs (miRNAs) are important modulators of biological processes. Fibrocytes are circulating bone marrow-derived cells that migrate into the injured lungs and contribute to fibrogenesis. The question of whether EV-coupled miRNAs derived from fibrocytes are able to regulate pulmonary fibrosis has not been addressed yet.

Methods: Pulmonary fibrosis was induced in rats by intratracheal administration of an adenoviral gene vector encoding active transforming growth factor-β1 (TGF-β1) or control vector. Primary fibrocytes and fibroblasts were cultured from rat lungs and were sorted by anti-CD45 magnetic beads. Human circulating fibrocytes and fibrocytes in bronchoalveolar lavage fluid (BALF) were isolated by fibronectin-coated dishes. Fibrocytes were cultured on different stiffness plates or decellularised lung scaffolds. We also determined the effects of extracellular matrix (ECM) and recombinant TGF-β1 on the cellular and EV-coupled miRNA expression of fibrocytes.

Results: The EVs of fibrocytes derived from fibrotic lungs significantly upregulated the expression of of fibroblasts. Culturing on rigid plates or fibrotic decellularised lung scaffolds increased miR-21-5 p expression compared with soft plates or normal lung scaffolds. Dissolved ECM collected from fibrotic lungs and recombinant TGF-β1 increased miR-21-5 p expression on fibrocytes, and these effects were attenuated on soft plates. Fibrocytes from BALF collected from fibrotic interstitial pneumonia patients showed higher miR-21-5 p expression than those from other patients.

Conclusions: Our results indicate that ECM contributes to fibrogenesis through biomechanical and biochemical effects on miRNA expression in fibrocytes.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215962DOI Listing
April 2021

Delphi Consensus Recommendations on Management of Dosing, Adverse Events, and Comorbidities in the Treatment of Idiopathic Pulmonary Fibrosis with Nintedanib.

Clin Med Insights Circ Respir Pulm Med 2021 30;15:11795484211006050. Epub 2021 Mar 30.

Vanderbilt University School of Medicine, Nashville, TN, USA.

Purpose: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF), which slows disease progression. Management of patients with IPF receiving nintedanib can be complicated by tolerability issues, comorbidities, and concomitant medications. We developed consensus recommendations on the management of dosing, adverse events and comorbidities in patients with IPF treated with nintedanib.

Methods: A modified Delphi process using 3 questionnaires was used to survey 14 pulmonologists experienced in using nintedanib. Panelists rated their agreement with statements on a Likert scale from -5 (strongly disagree) to +5 (strongly agree). Consensus was predefined as a mean score of ⩽-2.5 or ⩾+2.5 with a standard deviation not crossing zero.

Results: The panelists' recommendations were largely aligned with clinical trial data, real-world evidence, and the prescribing information, and provided additional guidance regarding minimizing gastrointestinal effects, periodic monitoring for liver dysfunction, caution with respect to concomitant administration of cytochrome P450 3A4 and P-glycoprotein 1 inhibitors and inducers and anticoagulants, and management of comorbidities. The panelists unanimously agreed that adverse event management should be individualized, based on careful consideration of the risks and benefits of each possible intervention and discussion with the patient.

Conclusions: These consensus recommendations provide additional guidance on the appropriate management of IPF with nintedanib, for use alongside evidence-based literature and the prescribing information.
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http://dx.doi.org/10.1177/11795484211006050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013629PMC
March 2021

Systemic Sclerosis and Associated Interstitial Lung Disease in Ontario, Canada: An Examination of Prevalence and Survival Over 10 Years.

J Rheumatol 2021 Apr 1. Epub 2021 Apr 1.

Schulich School of Medicine and Dentistry, Western University, St. Joseph Health Care, London, Canada; Boehringer Ingelheim (Canada) Limited, Burlington, Canada; HOPE Research Centre, Sunnybrook Research Institute, Toronto, Canada; Dept of Respiratory Medicine, Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. Funding for this study was provided by Boehringer-Ingelheim (Canada) Limited. Pope JE has undertaken consultancy work for AbbVie, Actelion, Baxter, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB. Quansah K and Flavin J are employees of Boehringer Ingelheim Canada Limited. Hassan S and Seung SJ received unrestricted funding from Boehringer Ingelheim Canada Limited. Kolb M reports grants and personal fees from Roche, Boehringer Ingelheim and Prometic, personal fees from Gilead and Genoa, and grants from Actelion, Respivert, Alkermes and Pharmaxis. Address correspondence to Dr. Janet E Pope, St Joseph's Health Care, 268 Grosvenor St., Rheumatology D2, London, Ontario, Canada, N6G 2S3. E-mail:

Objective: Systemic sclerosis (SSc) is a rare autoimmune disease. Pulmonary complications of SSc are one of the leading causes of morbidity and mortality. The objective of this study was to determine prevalence and survival estimates of SSc and SSc-ILD in a Canadian province (Ontario) using administrative data over 10 years.

Methods: Using ICD-10-CA codes, adult patients diagnosed with SSc and SSc-ILD between April 1, 2008 and March 31, 2018 were identified from the National Ambulatory Care Reporting System (NACRS) and Discharge Abstract Database (DAD) administrative databases. SSc was identified first and ILD if present occurred after the SSc diagnosis. Prevalence estimates were determined for both SSc and SSc-ILD. For survival, Kaplan Meier survival curves were generated.

Results: At the start of fiscal year 2017/18 (final year of the cohort), there were 2,114 prevalent SSc cases for a cumulative prevalence of 19.1 per 100,000 persons and 257 prevalent cases of SSc-ILD, generating a prevalence of 2.32 cases per 100,000 persons. Mean age was 57 and 58 years with 84% and 80% females for SSc and SSc- ILD patients, respectively. One, 5 and 10 year survival rates respectively for the SSc group were 85.0%, 64.5% and 44.9%, and 77.1%, 44.4% and 22.0% for the SSc-ILD.

Conclusion: This study provides the first population-based estimates of SSc and SSc- ILD in Canada for prevalence and survival. Results confirm that the prevalence estimates of SSc-ILD falls within the Canadian threshold of rare disease. It also demonstrates the poor survival in SSc especially when ILD is also present.
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http://dx.doi.org/10.3899/jrheum.201049DOI Listing
April 2021

Guideline-directed management of COVID-19: Do's and Don'ts.

Eur Respir J 2021 04 15;57(4). Epub 2021 Apr 15.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1183/13993003.00753-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996221PMC
April 2021

Circulating fibrocytes are not disease-specific prognosticators in idiopathic pulmonary fibrosis.

Eur Respir J 2021 Mar 25. Epub 2021 Mar 25.

Division of Respiratory Medicine, NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK.

Objective: Circulating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis.

Methods: We tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis.

Results: In 102 participants with idiopathic pulmonary fibrosis, a previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible. An empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants with idiopathic pulmonary fibrosis (Hazard Ratio 2.49 95% CI 2.41-2.56). We found no association of fibrocytes with lung function or disease progression.

Conclusions: In a large sample of circulating fibrocytes from people with idiopathic pulmonary fibrosis, levels of 2.22% or above were associated with greater mortality, but not with disease related decline in lung function.
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http://dx.doi.org/10.1183/13993003.00172-2021DOI Listing
March 2021

Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases.

Respir Res 2021 Mar 16;22(1):84. Epub 2021 Mar 16.

McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada.

Background: In the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib.

Methods: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies.

Results: Of 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (- 206.4 [SE 20.2] vs - 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug.

Conclusions: In patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs. Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178.
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http://dx.doi.org/10.1186/s12931-021-01668-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962343PMC
March 2021

The case of methotrexate and the lung: Dr Jekyll and Mr Hyde.

Eur Respir J 2021 Feb 11;57(2). Epub 2021 Feb 11.

Dept of Respiratory Medicine, Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

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http://dx.doi.org/10.1183/13993003.00079-2021DOI Listing
February 2021

The evolution of the : weathering the publishing pandemic.

Eur Respir J 2021 Jan 28;57(1). Epub 2021 Jan 28.

Université Paris Saclay, Inserm UMR S999, Dept of Pneumology, AP-HP, Pulmonary Hypertension Reference Center, Hôpital de Bicêtre, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1183/13993003.00084-2021DOI Listing
January 2021

Treatment Initiation in Patients with Interstitial Lung Disease in Canada.

Ann Am Thorac Soc 2021 Jan 25. Epub 2021 Jan 25.

University of British Columbia, Medicine, Vancouver, British Columbia, Canada.

Rationale: Real-life pharmacological treatment patterns of patients with interstitial lung diseases (ILD) remain elusive.

Objectives: The objective of this study was to determine how often and with what medications patients with ILD are treated in Canadian tertiary care clinics.

Methods: All patients with ILD prospectively enrolled in the Canadian Registry for Pulmonary Fibrosis were included in this observational study. All first instances of medication for each patient were compiled. Time between the diagnosis of ILD and the first initiation of an ILD-related medication was compared across diagnostic categories. Cox proportional hazards models were used to identify variables associated with time-to-treatment initiation, stratified by diagnostic category.

Results: Out of 2,652 patients, a total of 1,483 (56%) were treated with an ILD-related medication during the median follow-up of 3.0 years (1.4 to 5.9), including 349/646 (54%) patients with idiopathic pulmonary fibrosis (IPF) who received an antifibrotic. Patients with IPF were treated earlier and in greater proportion compared to those with non-IPF ILD (p=0.001). Male sex and lower lung function were associated with shorter time to treatment initiation in the full cohort.

Conclusions: Overall, 56% of patients with ILD seen across seven Canadian specialized ILD clinics received pharmacological treatment over a median follow-up of 3 years. Further studies are needed to assess longitudinal patterns of treatment and their influence on key outcomes.
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http://dx.doi.org/10.1513/AnnalsATS.202009-1122OCDOI Listing
January 2021

Role of the COX2-PGE axis in -induced exacerbation of experimental fibrosis.

Am J Physiol Lung Cell Mol Physiol 2021 03 9;320(3):L377-L392. Epub 2020 Dec 9.

Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) associated with high morbidity and mortality. Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and/or bacterial infections. Prostaglandin E (PGE) is an eicosanoid released in a cyclooxygenase-2 (COX2)-dependent manner and is considered to contribute to regulation of lung fibrosis. However, its role in infection-induced exacerbation of lung fibrosis is poorly defined. We found significantly increased levels of PGE in lung tissue of patients with ILD. Increased levels of PGE were also found in lung tissue of mice with AdTGF-β1-induced lung fibrosis and even more so in exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE release during exacerbating fibrosis. Application of parecoxib to inhibit PGE synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE worsened lung fibrosis in mice. Both interventions had no effect on -exacerbated lung fibrosis. Together, we found that the COX2-PGE axis has dual roles in fibrosis that may offset each other: PGE helps resolve infection/attenuate inflammation in fibrosis exacerbation but accentuates TGF-β/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE interventions in the setting of non-exacerbating lung fibrosis.
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http://dx.doi.org/10.1152/ajplung.00024.2020DOI Listing
March 2021

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

Respir Res 2020 Dec 7;21(1):322. Epub 2020 Dec 7.

Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1186/s12931-020-01579-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720501PMC
December 2020

HSP47: a potential target for fibrotic diseases and implications for therapy.

Expert Opin Ther Targets 2021 Jan 4;25(1):49-62. Epub 2021 Jan 4.

McMaster University, Department of medicine, FIRH, 50 Charlton Avenue East, Hamilton , Ontario, Canada.

: Chronic fibrotic disorders are challenging clinical problems. The major challenge is the identification of specific targets expressed selectively in fibrotic tissues. Collagen accumulation is the hallmark fibrosis. HSP47 is a collagen-specific chaperon with critical role in collagen folding. This review discusses the anti-fibrotic potential of HSP47. : This review compiles data retrieved from the PubMed database with keywords 'HSP47+fibrosis' from 01/2005 to 06/2020. We examined 1) collagen biology and its role in fibrotic diseases, 2) HSP47 role in fibrosis, 3) HSP47 inhibition strategies and 4) clinical investigations. The identification of the HSP47-collagen binding site led to the development of methods to screen HSP47 inhibitors with anti-fibrotic potential. Specific  delivery systems of HSP47 siRNA to fibrotic tissue reduced collagen production/secretion associated with fibrosis inhibition in preclinical models. This strategy is about to be tested in clinical trials. : As a collagen-specific chaperon, HSP47 is a promising therapeutic target in fibrosis. Preclinical models have shown encouraging anti-fibrotic results. Anti-HSP47 strategies need to be further evaluated in clinical trials. The increase in circulating-HSP47 in lung fibrosis patients highlights the potential of HSP47 as a noninvasive biomarker and may represent an important step toward personalized medicine in fibrotic disorders.
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http://dx.doi.org/10.1080/14728222.2021.1861249DOI Listing
January 2021

FK506-Binding Protein 13 Expression Is Upregulated in Interstitial Lung Disease and Correlated with Clinical Severity. A Potentially Protective Role.

Am J Respir Cell Mol Biol 2021 02;64(2):235-246

Department of Medicine, Firestone Institute for Respiratory Health, and.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of idiopathic pulmonary fibrosis lung tissues and correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsy specimens of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13 mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21), and resolution (Day 50) phases. FKBP13 mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13 lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity of interstitial lung diseases and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation, and fibrosis.
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http://dx.doi.org/10.1165/rcmb.2020-0121OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017597PMC
February 2021

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

Thorax 2021 01 6;76(1):37-43. Epub 2020 Oct 6.

The University of British Columbia Department of Medicine, Vancouver, British Columbia, Canada

Rationale: The European Quality of Life 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) is a multidimensional patient-reported questionnaire that supports calculation of quality-adjusted life-years. Our objectives were to demonstrate feasibility of use and to calculate the minimum important difference (MID) of the EQ-5D-5L and its associated visual analogue scale (EQ-VAS) in patients with fibrotic interstitial lung disease (ILD).

Methods: Patients who completed the EQ-5D-5L were identified from the prospective multicentre CAnadian REgistry for Pulmonary Fibrosis. Validity, internal consistency and responsiveness of the EQ-5D-5L were assessed, followed by calculation of the MID for the EQ-5D-5L and EQ-VAS. Anchor-based methods used an unadjusted linear regression against pulmonary function tests (PFTs) and dyspnoea and other quality of life questionnaires. Distribution-based method used one-half SD and SE measurement (SEM) calculations.

Results: 1816 patients were analysed, including 472 (26%) with idiopathic pulmonary fibrosis. EQ-5D-5L scores were strongly correlated with the dyspnoea and other quality of life questionnaires and weakly associated with PFTs. The estimated MID for EQ-5D-5L ranged from 0.0050 to 0.054 and from 0.078 to 0.095 for the anchor-based and distribution-based methods, respectively. The MID for EQ-VAS ranged from 0.5 to 5.0 and from 8.0 to 9.7 for the anchor-based and distribution-based methods. Findings were similar across ILD subtypes, sex and age.

Conclusion: We used a large and diverse cohort of patients with a variety of fibrotic ILD subtypes to suggest validity and MID of both the EQ-5D-5L and EQ-VAS. These findings will assist in designing future clinical trials and supporting cost-effectiveness analyses of potential treatments for patients with fibrotic ILD.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214944DOI Listing
January 2021

Guidance production before evidence generation for critical issues: the example of COVID-19.

Eur Respir Rev 2020 Sep 5;29(157). Epub 2020 Oct 5.

Lady Davis Carmel Medical Center, Pulmonary Division, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.

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http://dx.doi.org/10.1183/16000617.0310-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537942PMC
September 2020

Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow.

Eur Respir J 2020 11 12;56(5). Epub 2020 Nov 12.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1183/13993003.03147-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530910PMC
November 2020

Sputum quantitative cytometry in patients with interstitial lung disease and chronic cough.

Respir Med 2020 Aug - Sep;170:106067. Epub 2020 Jun 17.

Firestone Institute for Respiratory Health, St. Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada; Division of Respirology, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada.

Background: Chronic cough frequently occurs in patients with diffuse interstitial lung diseases (ILDs), and can have negative effects on quality-of-life. While there are multiple possible contributors to cough in this setting, the contribution and consequences of airway inflammation have not been previously measured. We aimed to estimate the prevalence of airway cellular inflammation in patients with chronic cough and ILD, and examine the interaction between airway inflammation and changes in lung function.

Methods: We examined all patients with physician-diagnosed ILD and chronic cough who had sputum quantitative cytometry ordered between 2004 and 2018. The prevalence of airway inflammation was estimated by applying previously established criteria for bronchitis. FEV and FVC were compared between individuals based on the presence of airway inflammation. The changes in FEV and FVC were compared between individuals who had their treatment tailored to their sputum result, and those who did not.

Results: Airway inflammation was present in 50% of patients (n = 173), and was associated with lower FEV (1.87 vs 2.05 L, p = 0.043) and FVC (2.39 vs 2.71, p = 0.024). Sputum-guided management of airway eosinophilia was associated with improvements in FEV (+120 vs -205mL, p < 0.0001) and stability of FVC (+13 vs -284mL, p = 0.003).

Conclusions: Airway inflammation is common in patients with chronic cough and ILD, and its presence may negatively affect lung function. Further research is required to understand if there is a role for quantitative sputum cytometry in this population, particularly if sputum-guided management of airway inflammation could lead to improvements in cough and other ILD outcomes.
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http://dx.doi.org/10.1016/j.rmed.2020.106067DOI Listing
June 2021

Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship.

Pulm Pharmacol Ther 2020 08 1;63:101933. Epub 2020 Aug 1.

Avalyn Pharma, 701 Pike Street, Suite 1500, Seattle, WA, 98101, United States. Electronic address:

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not dose-proportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation pharmacokinetic mimic) or continuous exposure (oral pharmacokinetic mimic), nintedanib (1-100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response. Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice-daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalent-delivered lung exposure, QD short duration inhaled nintedanib (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1β) and soluble collagen). Comparatively, the increased inhaled lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited increased effect by further reducing silica-induced elastance, IL-1β and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced bronchoalveolar lavage fluid macrophage and neutrophil counts with oral achieving significance. In summary, pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.
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http://dx.doi.org/10.1016/j.pupt.2020.101933DOI Listing
August 2020

Progressive fibrosing interstitial lung disease: treatable traits and therapeutic strategies.

Curr Opin Pulm Med 2020 09;26(5):436-442

Firestone Institute for Respiratory Health, Research Institute at St Joseph's Healthcare, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Purpose Of Review: In this review, the authors describe therapeutic strategies for a disease group called progressive fibrosing interstitial lung disease (PF-ILD) and highlight the importance of the definition of progression, prognosis, and treatment response.

Recent Findings: Although it is a relatively new concept, the term PF-ILD has been increasingly applied in clinical research and practice. Three domains commonly used to detect the disease progression include clinical symptoms, rate of forced vital capacity (FVC) decline and the extent of fibrosis on imaging. Although details of the pathogenesis of PF-ILD are still unclear, it has become apparent that genetic predisposition and an abnormal tissue microenvironment and host response are involved in the nature of the disease. Antifibrotic agents recently showed their efficacy on the treatment of PF-ILD. Both nintedanib and pirfenidone can slow the disease progression, as defined by a decline of FVC from baseline, of PF-ILD whenever compared with placebo, similar to the results in idiopathic pulmonary fibrosis (IPF) trials. This effect seems consistent irrespective of the underlying ILD diagnosis.

Summary: Recent evidence supports the use of antifibrotic therapy in the management of the phenotype progressive non-IPF ILD. Ongoing studies exploring genetic and other molecular biomarkers could identify at-risk individuals or predict treatment response and prognosis (endotypes). This would support the concept of 'treatable traits' in the field of ILD.
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http://dx.doi.org/10.1097/MCP.0000000000000712DOI Listing
September 2020

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

Ann Am Thorac Soc 2020 09;17(9):1077-1084

Department of Medicine and.

Interstitial lung disease (ILD) develops in a large percentage of patients with connective tissue disease (CTD) and is associated with increased morbidity and mortality. Patients with CTD-associated ILD (CTD-ILD) often present at a young age, suggesting that ILD likely impacts workplace productivity. We aimed to determine the employment rate and workplace productivity loss, along with its associated factors and estimated costs, in patients with fibrotic CTD-ILD. Patients with fibrotic CTD-ILD from the six centers of the Canadian Registry for Pulmonary Fibrosis were eligible. Health-related productivity loss was assessed using the Work Productivity and Activity Impairment questionnaire. Proposed factors associated with low workplace productivity were forced into a multivariable regression model. Average productivity loss in hours/week was used to calculate the costs of productivity loss based on hourly wages obtained from national census data matched for age and sex. Workplace productivity loss outcomes were compared between patients with CTD-ILD and patients with a non-CTD fibrotic ILD. Of 375 eligible patients with fibrotic CTD-ILD, 113 (30%) were employed. Productivity loss was reported by 59% of employed patients, with a mean loss of 9.4 ± 1.2 hours/week, including 3.9 ± 0.9 hours/week from absenteeism and 5.5 ± 0.7 hours/week from presenteeism. Employment among patients 25-54 years of age with fibrotic CTD-ILD was 27% lower than that in the matched general Canadian population (56% vs. 83%;  < 0.001). Employment among patients ≥55 years of age with CTD-ILD was 17% lower than that in the matched population (19% vs. 36%;  < 0.001). Workplace productivity loss was not associated with respiratory symptoms or lung physiology. Annual costs of productivity loss were calculated at 13,593 Canadian dollars per employee with fibrotic CTD-ILD. Workplace productivity loss was similar in patients with fibrotic CTD-ILD and those with non-CTD fibrotic ILD. Patients with fibrotic CTD-ILD frequently report workplace productivity loss, which is unexplained by respiratory symptoms or lung physiology and is associated with significant costs.
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http://dx.doi.org/10.1513/AnnalsATS.201911-822OCDOI Listing
September 2020

Current models of pulmonary fibrosis for future drug discovery efforts.

Expert Opin Drug Discov 2020 08 12;15(8):931-941. Epub 2020 May 12.

Firestone Institute for Respiratory Health, Research Institute at St Joseph's Healthcare, Department of Medicine, McMaster University , Hamilton, ON, Canada.

Introduction: Pulmonary fibrosis includes several lung disorders characterized by progressive fibrosis, of which idiopathic pulmonary fibrosis (IPF) is a particularly severe form with a median survival time of 3-5 years after diagnosis. Although numerous compounds have shown efficacy in attenuating pulmonary fibrosis using animal models, only a few compounds have shown their beneficial effects for IPF in clinical trials. Thus, there is an emergent need to improve the preclinical development process to better identify, characterize and select clinically useful targets.

Areas Covered: In this review, the authors extensively describe current models of pulmonary fibrosis, including rodent models, models, and models.

Expert Opinion: Based upon our current understanding, improving the identification and characterization of clinically relevant molecules or pathways responsible for progressive fibrotic diseases and use of the appropriate preclinical model system to test these will likely be required to improve the drug development pipeline for pulmonary fibrosis. Combination with appropriate preclinical models with (precision-cut lung slices) or models would be beneficial for high-throughput drug discovery or validation of drug effects.
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http://dx.doi.org/10.1080/17460441.2020.1755252DOI Listing
August 2020

Practical Considerations for the Diagnosis and Treatment of Fibrotic Interstitial Lung Disease During the Coronavirus Disease 2019 Pandemic.

Chest 2020 09 22;158(3):1069-1078. Epub 2020 Apr 22.

Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has affected virtually all aspects of patient care. Health-care systems around the world are trying simultaneously to treat patients with COVID-19, prepare for its long-term impacts, and treat patients with other acute and chronic diseases. There are multiple ways that the COVID-19 pandemic will directly affect patients with fibrotic interstitial lung disease (ILD), particularly given their common risk factors for poor outcomes. Major issues for patients with ILD will include restricted access to key components of the diagnostic process, new uncertainties in the use of common ILD pharmacotherapies, limited ability to monitor both disease severity and the presence of medication adverse effects, and significantly curtailed research activities. The purpose of this review is to summarize how COVID-19 has impacted key components of the diagnosis and management of fibrotic ILD as well as to provide strategies to mitigate these challenges. We further review major obstacles for researchers and identify priority areas for future ILD research related to COVID-19. Our goals are to provide practical considerations to support the care of patients with ILD during the COVID-19 pandemic and to provide a road map for clinicians caring for these patients during future infectious disease outbreaks.
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http://dx.doi.org/10.1016/j.chest.2020.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194738PMC
September 2020