Publications by authors named "Parameswaran Nair"

179 Publications

Differential expression of sputum and serum autoantibodies in patients with chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 Apr 28. Epub 2021 Apr 28.

Pathology and Molecular Medicine, McMaster University, Canada.

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesised to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalised Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in COPD subjects compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in COPD subjects, asymptomatic smokers and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilisation of autoantibodies for diagnostic purposes.
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http://dx.doi.org/10.1152/ajplung.00518.2020DOI Listing
April 2021

Human antigen R promotes lung fibroblast differentiation to myofibroblasts and increases extracellular matrix production.

J Cell Physiol 2021 Apr 14. Epub 2021 Apr 14.

Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive scarring caused by excessive extracellular matrix (ECM) deposition and activation of α-SMA-expressing myofibroblasts. Human antigen R (HuR) is an RNA binding protein that promotes protein translation. Upon translocation from the nucleus to the cytoplasm, HuR functions to stabilize messenger RNA (mRNA) to increase protein levels. However, the role of HuR in promoting ECM production, myofibroblast differentiation, and lung fibrosis is unknown. Human lung fibroblasts (HLFs) treated with transforming growth factor β1 (TGF-β1) showed a significant increase in translocation of HuR from the nucleus to the cytoplasm. TGF-β-treated HLFs that were transfected with HuR small interfering RNA had a significant reduction in α-SMA protein as well as the ECM proteins COL1A1, COL3A, and FN1. HuR was also bound to mRNA for ACTA2, COL1A1, COL3A1, and FN. HuR knockdown affected the mRNA stability of ACTA2 but not that of the ECM genes COL1A1, COL3A1, or FN. In mouse models of pulmonary fibrosis, there was higher cytoplasmic HuR in lung structural cells compared to control mice. In human IPF lungs, there was also more cytoplasmic HuR. This study is the first to show that HuR in lung fibroblasts controls their differentiation to myofibroblasts and consequent ECM production. Further research on HuR could assist in establishing the basis for the development of new target therapy for fibrotic diseases, such as IPF.
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http://dx.doi.org/10.1002/jcp.30380DOI Listing
April 2021

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

FASEB J 2021 Mar;35(3):e21376

Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.
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http://dx.doi.org/10.1096/fj.202002350RDOI Listing
March 2021

Neutrophilic asthma: misconception or misnomer?

Lancet Respir Med 2021 05 9;9(5):441-443. Epub 2021 Feb 9.

Department of Pneumology and Department of Intensive Care Medicine, University of Rostock Medical Clinic, Rostock, Germany.

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http://dx.doi.org/10.1016/S2213-2600(21)00023-0DOI Listing
May 2021

There is more to severe asthma associated with obesity than inflammation.

Respirology 2021 Apr 9;26(4):288-289. Epub 2021 Feb 9.

Division of Respirology, Department of Medicine, McMaster University and St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.

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http://dx.doi.org/10.1111/resp.14012DOI Listing
April 2021

The role of eosinophils in sepsis and acute respiratory distress syndrome: a scoping review.

Can J Anaesth 2021 May 25;68(5):715-726. Epub 2021 Jan 25.

Department of Medicine, Division of Respirology, St Joseph's Healthcare and McMaster University, Hamilton, ON, Canada.

Purpose: Septic shock and acute respiratory distress syndrome (ARDS) are characterized by a dysregulated immune host response that may respond to steroid therapy. Eosinophils contribute to type 2 inflammation that often responds to steroid therapy; their role in immune dysregulation and outcomes in sepsis and ARDS is unclear.

Source: A systematic search of Cochrane Library, MEDLINE, and EMBASE was performed from inception to 9 September 2020. The search comprised the following terms: eosinophils, sepsis, septic shock, and ARDS. Two reviewers independently screened abstracts and texts and extracted data on disease severity and clinical outcomes.

Principal Findings: Thirty-nine studies were identified: 30 evaluated serum eosinophil count in sepsis, one evaluated eosinophil activity in sepsis, three assessed bronchoalveolar lavage (BAL) eosinophil count in ARDS, four assessed eosinophil activity in ARDS, and one assessed peripheral eosinophil count in ARDS. Eleven studies showed an association between eosinopenia and sepsis, and eight studies found persistent eosinopenia at > 48 hr of intensive care unit admission to predict mortality and readmission in septic patients. Three studies found BAL eosinophil count to be low in ARDS, although one found that levels rose in late-phase ARDS. Three studies found eosinophil activity markers in BAL to be high in ARDS and correlate with ARDS severity.

Conclusion: Persistent peripheral eosinopenia is a marker of bacterial sepsis and is independently associated with poor outcomes. Bronchoalveolar lavage eosinophil counts are low in early-phase ARDS, but increase in late-phase ARDS, while elevated markers of eosinophil activity correlate with ARDS severity. Further studies understanding the mechanisms leading to eosinopenia in sepsis and increased eosinophil activity in ARDS are needed.
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http://dx.doi.org/10.1007/s12630-021-01920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833890PMC
May 2021

Monitoring eosinophils to guide therapy with biologics in asthma: does the compartment matter?

Allergy 2021 04 31;76(4):1294-1297. Epub 2020 Dec 31.

Department of Medicine, Division of Respirology, McMaster University and St Joseph's Healthcare, Hamilton, ON, Canada.

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http://dx.doi.org/10.1111/all.14700DOI Listing
April 2021

Lessons of the month: A breathless severe asthmatic in the genomic era: Occam's razor or Hickam's dictum?

Clin Med (Lond) 2020 11;20(6):e264-e266

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

Breathlessness is a subjective symptom that may stem from a number of pathological and functional aetiologies. Consequently, clinicians are often faced with the challenge of navigating between the tensions of Occam's razor (parsimonious aetiology) or Hickam's dictum (multiple diagnoses). We report a case of a 36-year-old woman with a lifelong history of episodic breathlessness caused at various times by dysfunctions of lung parenchyma (emphysema) and airway smooth muscle (asthma), skeletal muscle (filamin-C fibrillary myopathy) and cardiac muscle (cardiomyopathy). We illustrate the utility of the modern diagnostic toolbox in the assessment, understanding and management of complex dyspnoea (including the use of inflammometry, inhaled-gas magnetic resonance imaging-guided bronchial thermoplasty, and genetic testing), and also demonstrate the importance of interdisciplinary data interpretation in establishing accurate aetiologic diagnoses.
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http://dx.doi.org/10.7861/clinmed.2020-0661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687324PMC
November 2020

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past, present, and future directions.

Allergy 2020 Nov 13. Epub 2020 Nov 13.

Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.
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http://dx.doi.org/10.1111/all.14658DOI Listing
November 2020

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19.

Am J Physiol Lung Cell Mol Physiol 2021 01 28;320(1):L152-L157. Epub 2020 Oct 28.

Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.
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http://dx.doi.org/10.1152/ajplung.00455.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869954PMC
January 2021

TWIST1 DNA methylation is a cell marker of airway and parenchymal lung fibroblasts that are differentially methylated in asthma.

Clin Epigenetics 2020 10 2;12(1):145. Epub 2020 Oct 2.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.

Background: Mesenchymal fibroblasts are ubiquitous cells that maintain the extracellular matrix of organs. Within the lung, airway and parenchymal fibroblasts are crucial for lung development and are altered with disease, but it has been difficult to understand their roles due to the lack of distinct molecular markers. We studied genome-wide DNA methylation and gene expression in airway and parenchymal lung fibroblasts from healthy and asthmatic donors, to identify a robust cell marker and to determine if these cells are molecularly distinct in asthma.

Results: Airway (N = 8) and parenchymal (N = 15) lung fibroblasts from healthy individuals differed in the expression of 158 genes, and DNA methylation of 3936 CpGs (Bonferroni adjusted p value < 0.05). Differential DNA methylation between cell types was associated with differential expression of 42 genes, but no single DNA methylation CpG feature (location, effect size, number) defined the interaction. Replication of gene expression and DNA methylation in a second cohort identified TWIST1 gene expression, DNA methylation and protein expression as a cell marker of airway and parenchymal lung fibroblasts, with DNA methylation having 100% predictive discriminatory power. DNA methylation was differentially altered in parenchymal (112 regions) and airway fibroblasts (17 regions) with asthmatic status, with no overlap between regions.

Conclusions: Differential methylation of TWIST1 is a robust cell marker of airway and parenchymal lung fibroblasts. Airway and parenchymal fibroblast DNA methylation are differentially altered in individuals with asthma, and the role of both cell types should be considered in the pathogenesis of asthma.
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http://dx.doi.org/10.1186/s13148-020-00931-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531162PMC
October 2020

Eosinophilia and Response to Bronchial Thermoplasty.

Am J Respir Crit Care Med 2021 01;203(1):148

Firestone Institute for Respiratory Health Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1164/rccm.202008-3221LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781137PMC
January 2021

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 2020

Asthma exacerbations on benralizumab are largely non-eosinophilic.

Allergy 2021 01 7;76(1):375-379. Epub 2020 Aug 7.

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

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http://dx.doi.org/10.1111/all.14514DOI Listing
January 2021

Predictors of response to anti-IL-5 biologics.

Respirology 2020 Nov 6;25(11):1123-1125. Epub 2020 Aug 6.

Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, ON, L8N4A6, Canada.

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http://dx.doi.org/10.1111/resp.13926DOI Listing
November 2020

Dupilumab, severe asthma airway responses, and SARS-CoV-2 serology.

Allergy 2021 03 24;76(3):957-958. Epub 2020 Aug 24.

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

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http://dx.doi.org/10.1111/all.14534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436521PMC
March 2021

Sputum Inflammometry to Manage Chronic Obstructive Pulmonary Disease Exacerbations: Beyond Guidelines.

Tuberc Respir Dis (Seoul) 2020 Jul 18;83(3):175-184. Epub 2020 Jun 18.

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

Quantitative sputum cytometry facilitates in assessing the nature of bronchitis associated with exacerbations of chronic obstructive pulmonary disease (COPD). This is not assessed in most clinical trials that evaluate the effectiveness of strategies to prevent or to treat exacerbations. While up to a quarter of exacerbations may be associated with raised eosinophil numbers, the vast majority of exacerbations are associated with neutrophilic bronchitis that may indicate airway infections. While eosinophilia may be a predictor of response to corticosteroids (oral and inhaled), the limited efficacy of anti-interleukin 5 therapies would suggest that eosinophils may not directly contribute to those exacerbations. However, they may contribute to airspace enlargement in patients with COPD through various mechanisms involving the interleukin 13 and matrix metalloprotease pathways. The absence of eosinophils may facilitate in limiting the unnecessary use of corticosteroids. The presence of neutrophiia could prompt an investigation for the specific pathogens in the airway. Additionally, sputum measurements may also provide insight into the mechanisms of susceptibility to airway infections. Iron within sputum macrophages, identified by hemosiderin staining (and by more direct quantification) may impair macrophage functions while the low levels of immunoglobulins in sputum may also contribute to airway infections. The assessment of sputum at the time of exacerbations thus would facilitate in customizing treatment and treat current exacerbations and reduce future risk of exacerbations.
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http://dx.doi.org/10.4046/trd.2020.0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362747PMC
July 2020

The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma.

Am J Respir Crit Care Med 2020 10;202(8):1105-1114

CardioRespiratory Research Group, Division of Respirology, Department of Medicine, and.

Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions. We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma. Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma. There was a significant increase in sputum DR3 ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP . Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes. The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
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http://dx.doi.org/10.1164/rccm.201909-1722OCDOI Listing
October 2020

Review of monoclonal antibody therapies in asthma and allergic diseases - a new paradigm for precision medicine.

Asian Pac J Allergy Immunol 2020 Jun;38(2):78-90

Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, UK.

Background: Elucidation of the critical immune pathways involved in allergic inflammation has identified, apart from IgE, therapeutic targets in the cytokine network suitable for intervention by biological therapies.

Objective: The drugs that target the cytokine networks pertinent to asthma and allergic diseases are reviewed and some illustrative case histories presented. The overview proposes a framework to use when deciding which monoclonal antibody (mAb) to select for treatment of severe asthma based on total IgE concentration, peripheral blood eosinophil count, induced sputum analysis and measurement of fractional exhaled nitric oxide (FENO).

Methods: Internet-based literature search including PubMed for studies on biological therapies targeting IgE and the cytokine network in allergic inflammation focusing on asthma with and without rhinosinusitis and nasal polyposis, eczema, urticaria and food allergies. Lists of pivotal trials published in the peer reviewed literature and pertaining to their own mAb products were also provided by GSK, AstraZeneca and Sanofi. Therapeutic agents licensed or in advanced stages of development (Phase 2b and 3) were selected for discussion.

Results: The survey identifies a number of mAbs with substantial potential for the future targeted treatment of asthma with and without rhinosinusitis and nasal polyposis, eczema, urticaria and food allergies uncontrolled by existing therapies. A pragmatic framework is proposed for selecting the optimal mAb for initial use in individual patients with severe asthma.

Conclusions: Launch of these new biologicals may revolutionise the treatment of allergic diseases if employed in an endotype-specific fashion, heralding an unprecedented era of personalised medicine.
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http://dx.doi.org/10.12932/AP-020220-0752DOI Listing
June 2020

Luminal Eosinophil Cell Death as a Biomarker for Loss of Asthma Control?

Chest 2020 06;157(6):1680-1681

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

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http://dx.doi.org/10.1016/j.chest.2020.01.021DOI Listing
June 2020

EAACI Biologicals Guidelines-Recommendations for severe asthma.

Allergy 2021 01 10;76(1):14-44. Epub 2020 Aug 10.

Department of Biochemistry and Molecular Biology, Chemistry School, Complutense University of Madrid, Madrid, Spain.

Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.
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http://dx.doi.org/10.1111/all.14425DOI Listing
January 2021

Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.

Eur Respir J 2020 10 8;56(4). Epub 2020 Oct 8.

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

Background: In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50-60%.

Objective: To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response.

Methods: In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.

Results: Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.

Conclusion: A significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.
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http://dx.doi.org/10.1183/13993003.00117-2020DOI Listing
October 2020

Effects of Anti-T2 Biologic Treatment on Lung Ventilation Evaluated by MRI in Adults With Prednisone-Dependent Asthma.

Chest 2020 10 16;158(4):1350-1360. Epub 2020 May 16.

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

Background: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to "anti-T2" therapy.

Research Question: Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma?

Study Design And Methods: Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%).

Results: MRI VDP was improved pre- (ΔVDP: -3% ± 4%, P = .02) and post-bronchodilator (ΔVDP: -3% ± 4%; P = .04) after additional anti-T2 therapy that controlled eosinophilic bronchitis (n = 2 mepolizumab, n = 2 reslizumab, n = 3 benralizumab, n = 1 dupilumab, n = 2 increased daily prednisone). A greater post-bronchodilator ΔVDP was observed in those patients with median or higher percentage of sputum eosinophils at baseline (≥15.8%; P = .01). In 7 of 10 patients with asthma, residual ventilation defects persisted despite bronchodilator and anti-T2 therapy.

Interpretation: Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma.
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http://dx.doi.org/10.1016/j.chest.2020.04.056DOI Listing
October 2020

Reproducibility of Hyperpolarized Xe MRI Ventilation Defect Percent in Severe Asthma to Evaluate Clinical Trial Feasibility.

Acad Radiol 2020 May 14. Epub 2020 May 14.

Robarts Research Institute, Western University, London, Canada; Department of Medical Biophysics, Western University, London, Canada; Department of Medicine, Western University, London, Canada.

Rationale And Objectives: Xe MRI has been developed to noninvasively visualize and quantify the functional consequence of airway obstruction in asthma. Its widespread application requires evidence of intersite reproducibility and agreement. Our objective was to evaluate reproducibility and agreement of Xe ventilation MRI measurements in severe asthmatics at two sites.

Materials And Methods: In seven adults with severe asthma, Xe ventilation MRI was acquired pre- and post-bronchodilator at two geographic sites within 24-hours. Xe MRI signal-to-noise ratio (SNR) was calculated and ventilation abnormalities were quantified as the whole-lung and slice-by-slice ventilation defect percent (VDP). Intraclass correlation coefficients (ICC) and Bland-Altman analysis were used to determine intersite Xe VDP reproducibility and agreement.

Results: Whole-lung and slice-by-slice Xe VDP measured at both sites were correlated and reproducible (pre-bronchodilator: whole-lung ICC = 0.90, p = 0.005, slice-by-slice ICC = 0.78, p < 0.0001; post-bronchodilator: whole-lung ICC = 0.94, p < 0.0001, slice-by-slice ICC = 0.83, p < 0.0001) notwithstanding intersite differences in the Xe-dose-equivalent-volume (101 ± 15 mL site 1, 49 ± 6 mL site 2, p < 0.0001), gas-mixture (Xe/He site 1; Xe/N site 2) and SNR (40 ± 19 site 1, 23 ± 5 site 2, p = 0.02). Qualitative Xe gas distribution differences were observed between sites and slice-by-slice Xe VDP, but not whole-lung Xe VDP, was significantly lower at site 1 (pre-bronchodilator VDP: whole-lung bias = -3%, p > 0.99, slice-by-slice bias = -3%, p = 0.0001; post-bronchodilator VDP: whole-lung bias = -2%, p = 0.59, slice-by-slice-bias = -2%, p = 0.0003).

Conclusion: Xe MRI VDP at two different sites measured within 24-hours in the same severe asthmatics were correlated. Qualitative and quantitative intersite differences in Xe regional gas distribution and VDP point to site-specific variability that may be due to differences in gas-mixture composition or SNR.
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http://dx.doi.org/10.1016/j.acra.2020.04.025DOI Listing
May 2020

Medication Regimen Complexity Index Prediction of Adverse Drug Reaction-Related Hospital Admissions.

Ann Pharmacother 2020 10 30;54(10):996-1000. Epub 2020 Apr 30.

University of Tasmania, Hobart, Tasmania, Australia.

Background: The relationship between the medication regimen complexity index (MRCI) and adverse drug reaction (ADR)-related hospital admissions has not yet specifically been investigated.

Objective: To evaluate the MRCI and compare with medication count for prediction of ADR-related hospital admissions in older patients.

Methods: This was a retrospective analysis of a prospectively collected convenience sample of 768 unplanned medical admissions of Australians aged 65 years old and older. The sample consisted of 115 (15.0%) ADR-related unplanned hospital admissions and 653 (85.0%) non-ADR-related unplanned medical admissions. The MRCI score was calculated from the medical records and analyzed to predict ADR-related hospital admissions.

Results: The cohort had a median age of 81 years, 5 comorbidities, and 11 medications, with a slight majority of women. The MRCI score was not significantly different in patients who had ADR-related admissions compared with other medical admissions-38.5 versus 34.0, respectively; Wilcoxon Rank Sum test = 33 522; = 0.067. The medication count was significantly different between the ADR-related admissions compared with other medical admissions: 12 versus 10; = 32 508; = 0.021. However, the medication count was not a strong predictor of ADR-related admissions; unadjusted odds ratio = 1.044; 95% CI = 1.006-1.084.

Conclusion And Relevance: The MRCI score did not discriminate between ADR-related admissions and other medical admissions despite taking time to calculate with potential for inconsistent application. Medication count is more readily applicable with marginally greater relevance in this cohort; however, both measures do not appear to be useful when used alone for clinicians to identify patients at risk of ADRs.
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http://dx.doi.org/10.1177/1060028020919188DOI Listing
October 2020

Sputum and serum immunoglobulins in adult asthmatics with recurrent respiratory tract infections.

Allergy 2020 08 6;75(8):2105-2108. Epub 2020 Apr 6.

Firestone Institute for Respiratory Health, St. Joseph's Healthcare, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1111/all.14283DOI Listing
August 2020

Exon 8 KIT mutation and pulmonary eosinophilia.

Allergy 2020 08 12;75(8):2094-2096. Epub 2020 May 12.

Division of Hematology, McMaster University, Hamilton, ON, Canada.

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http://dx.doi.org/10.1111/all.14272DOI Listing
August 2020

Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma.

Allergy 2020 05 1;75(5):1058-1068. Epub 2020 Apr 1.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, National Heart and Lung Institute, London, UK.

Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor α, is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluated the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. PubMed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects >12 years old and 24-52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (Incidence rate ratio 0.51; 95% CI 0.45-0.59) and the percentage use of oral corticosteroid use (mean difference (MD) -28.2 mg/d; 95% CI -40.7 to -15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/d] improved, without reaching the minimal important clinical difference: ACQ-5 MD -0.28 (95% CI -0.39 to -0.17); AQLQ MD +0.28 (95% CI 0.20-0.37); and rescue medication MD -0.35 (95% CI -0.73 to +0.02). FEV increased (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There was an increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio of dupilumab versus standard therapy was 464 000$/QALY (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.
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http://dx.doi.org/10.1111/all.14268DOI Listing
May 2020

Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma.

Allergy 2020 05;75(5):1043-1057

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair, Development, National Heart and Lung Institute, London, UK.

Allergic asthma is a frequent asthma phenotype. Both IgE and type 2 cytokines are increased, with some degree of overlap with other phenotypes. Systematic reviews assessed the efficacy and safety of benralizumab, dupilumab and omalizumab (alphabetical order) vs standard of care for patients with uncontrolled severe allergic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. All three biologicals reduced with high certainty the annualized asthma exacerbation rate: benralizumab incidence rate ratios (IRR) 0.63 (95% CI 0.50 - 0.81); dupilumab IRR 0.58 (95%CI 0.47 - 0.73); and omalizumab IRR 0.56 (95%CI 0.42 - 0.73). Benralizumab and dupilumab improved asthma control with high certainty and omalizumab with moderate certainty; however, none reached the minimal important difference (MID). Both benralizumab and omalizumab improved QoL with high certainty, but only omalizumab reached the MID. Omalizumab enabled ICS dose reduction with high certainty. Benralizumab and omalizumab showed an increase in drug-related adverse events (AEs) with low to moderate certainty. All three biologicals had moderate certainty for an ICER/QALY value above the willingness to pay threshold. There was high certainty that in children 6-12 years old omalizumab decreased the annualized exacerbation rate [IRR 0.57 (95%CI 0.45-0.72)], improved QoL [relative risk 1.43 (95%CI 1.12 -1.83)], reduced ICS [mean difference (MD) -0.45 (95% CI -0.58 to -0.32)] and rescue medication use [ MD -0.41 (95%CI -0.66 to -0.15)].
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http://dx.doi.org/10.1111/all.14235DOI Listing
May 2020

Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma.

Allergy 2020 05 24;75(5):1023-1042. Epub 2020 Feb 24.

Iberoamerican Cochrane Centre, Department of Clinical Epidemiology and Public Health, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV . More data on long-term safety are needed together with more efficacy data in the paediatric population.
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http://dx.doi.org/10.1111/all.14221DOI Listing
May 2020