PRISM :: Browsing by Author "Leigh, Richard"

Browsing by Author "Leigh, Richard"

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Open Access
A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma
(2018-06-18) Swystun, Veronica; Green, Francis H Y; Dennis, John H; Rampakakis, Emmanouil; Lalli, Gurkeet; Fadayomi, Morenike; Chiu, Andrea; Shrestha, Grishma; El Shahat, Sharif G; Nelson, David E; El Mays, Tamer Y; Pieron, Cora A; Leigh, Richard
Abstract Background This study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model. Methods This was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge. Results No significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo. Conclusions S1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated. Trial registration ClinicalTrials.gov, NCT02334553 . Registered on 12 November 2014.
Open Access
Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study
(2023-04-24) Thamboo, Andrew V.; Lee, Melissa; Bhutani, Mohit; Chan, Charles; Chan, Yvonne; Chapman, Ken R.; Chin, Christopher J.; Connors, Lori; Dorscheid, Del; Ellis, Anne K.; Gall, Richard M.; Godbout, Krystelle; Janjua, Arif; Javer, Amin; Kilty, Shaun; Kim, Harold; Kirkpatrick, Gordon; Lee, John M.; Leigh, Richard; Lemiere, Catherine; Monteiro, Eric; Neighbour, Helen; Keith, Paul K.; Philteos, George; Quirt, Jaclyn; Rotenberg, Brian; Ruiz, Juan C.; Scott, John R.; Sommer, Doron D.; Sowerby, Leigh; Tewfik, Marc; Waserman, Susan; Witterick, Ian; Wright, Erin D.; Yamashita, Cory; Desrosiers, Martin
Abstract Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. Methods A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1–9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures—kappa coefficient ( $$\kappa$$ κ ) value > 0.61. Results After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. Conclusion This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years. Graphical abstract
Open Access
Canadian Thoracic Society 2012 Guideline Update: Diagnosis and Management of Asthma in Preschoolers, Children and Adults
(2012-01-01) Lougheed, M Diane; Lemiere, Catherine; Ducharme, Francine M; Licskai, Chris; Dell, Sharon D; Rowe, Brian H; FitzGerald, Mark; Leigh, Richard; Watson, Wade; Boulet, Louis-Philippe; Canadian Thoracic Society Asthma Clinical Assembly,
BACKGROUND: In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines.METHODS: Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta2-agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations.RESULTS: The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified.CONCLUSIONS: The present clinical practice guideline is the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee’s new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence.
Open Access
Canadian Thoracic Society 2012 Guideline Update: Diagnosis and Management of Asthma in Preschoolers, Children and Adults: Executive Summary
(2012-01-01) Lougheed, M Diane; Lemiere, Catherine; Ducharme, Francine M; Licskai, Chris; Dell, Sharon D; Rowe, Brian H; FitzGerald, Mark; Leigh, Richard; Watson, Wade; Boulet, Louis-Philippe; Canadian Thoracic Society Asthma Clinical Assembly,
BACKGROUND: In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines.METHODS: Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta2-agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations.RESULTS: The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified.CONCLUSIONS: The present document is an executive summary of the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee’s new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence.
Open Access
Canadian Thoracic Society Asthma Committee Commentary on Long-Acting Beta-2 Agonist Use for Asthma in Canada
(2010-01-01) Lougheed, M Diane; Lemiere, Catherine; Dell, Sharon; Ducharme, Francine; FitzGerald, J Mark; Leigh, Richard; Licskai, Chris; Rowe, Brian H; Bowie, Dennis; Becker, Allan; Boulet, Louis-Philippe
Open Access
Canadian Thoracic Society Asthma Management Continuum – 2010 Consensus Summary for Children Six Years of Age and Over, and Adults
(2010-01-01) Lougheed, M Diane; Lemière, Catherine; Dell, Sharon D; Ducharme, Francine M; FitzGerald, J Mark; Leigh, Richard; Licskai, Chris; Rowe, Brian H; Bowie, Dennis; Becker, Allan; Boulet, Louis-Philippe
BACKGROUND/OBJECTIVE: To integrate new evidence into the Canadian Asthma Management Continuum diagram, encompassing both pediatric and adult asthma.METHODS: The Canadian Thoracic Society Asthma Committee members, comprised of experts in pediatric and adult respirology, allergy and immunology, emergency medicine, general pediatrics, family medicine, pharmacoepidemiology and evidence-based medicine, updated the continuum diagram, based primarily on the 2008 Global Initiative for Asthma guidelines, and performed a focused review of literature pertaining to key aspects of asthma diagnosis and management in children six years of age and over, and adults.RESULTS: In patients six years of age and over, management of asthma begins with establishing an accurate diagnosis, typically by supplementing medical history with objective measures of lung function. All patients and caregivers should receive self-management education, including a written action plan. Inhaled corticosteroids (ICS) remain the first-line controller therapy for all ages. When asthma is not controlled with a low dose of ICS, the literature supports the addition of long-acting beta2-agonists in adults, while the preferred approach in children is to increase the dose of ICS. Leukotriene receptor antagonists are acceptable as second-line monotherapy and as an alternative add-on therapy in both age groups. Anti-immunoglobulin E therapy may be of benefit in adults, and in children 12 years of age and over with difficult to control allergic asthma, despite high-dose ICS and at least one other controller.CONCLUSIONS: The foundation of asthma management is establishing an accurate diagnosis based on objective measures (eg, spirometry) in individuals six years of age and over. Emphasis is placed on the similarities and differences between pediatric and adult asthma management approaches to achieve asthma control.
Open Access
Cerebrovascular responses to submaximal exercise in women with COPD
(BioMed Central, 2014-06-05) Hartmann, Sara E.; Leigh, Richard; Poulin, Marc J.
Open Access
Co-infection with HRV and Pseudomonas aeruginosa Modulates Beta-Defensin-2 Expression from the Airway Epithelium
(2015-12-21) Arnason, Jason; Leigh, Richard; Proud, David; Armstrong, Glen; Chadee, Kris
Respiratory infections are the most common triggers of acute exacerbations of chronic obstructive pulmonary disease (COPD), with human rhinovirus (HRV) and Pseudomonas aeruginosa being two common pathogens detected. Human beta-defensin (HBD)-2 is an antimicrobial peptide that plays an integral role in the innate defense response to infection. Here, we sought to determine how co-infection of airway cells with HRV and P. aeruginosa modulates HBD2 expression, and whether the normal HBD2 response to co-infections are altered in COPD subjects compared to healthy non-smokers. Synergistic increases in HBD2 from the airway epithelium were seen with the combination HRV and P. aeruginosa compared to either treatment alone. This synergistic response was dependent on flagellin acting through the TLR5 pathway. Finally, a reduction in HBD2 was observed in epithelial cells obtained from patients with COPD compared to cells from non-smokers following HRV and P. aeruginosa co-infection.
Open Access
Commentaire du Comité sur l’asthme de la Société Canadienne de Thoracologie au Sujet de I’utilisation des Bêta-2 agonistes à Longue durée d’action dans le Traitement l’asthme au Canada
(2010-01-01) Lougheed, M Diane; Lemiere, Catherine; Dell, Sharon; Ducharme, Francine; FitzGerald, J Mark; Leigh, Richard; Licskai, Chris; Rowe, Brian H; Bowie, Dennis; Becker, Allan; Boulet, Louis-Philippe
Open Access
Cost Analysis of a Transition Care Bundle Compared with Usual Care for COPD Patients Being Discharged from Hospital: Evaluation of a Randomized Controlled Trial
(2023-03-11) Yan, Charles; Round, Jeff; Akpinar, Ilke; Atwood, Chantal E.; Deuchar, Lesly; Bhutani, Mohit; Leigh, Richard; Stickland, Michael K.
Abstract Background Appropriate management of chronic obstructive pulmonary disease (COPD) patients following acute exacerbations can reduce the risk of future exacerbations, improve health status, and lower care costs. While a transition care bundle (TCB) was associated with lower readmissions to hospitals than usual care (UC), it remains unclear whether the TCB was associated with cost savings. Objective The aim of this study was to evaluate how this TCB was associated with future Emergency Department (ED)/outpatient visits, hospital readmissions, and costs in Alberta, Canada. Methods Patients who were aged 35 years or older, who were admitted to hospital for a COPD exacerbation, and had not been treated with a care bundle received either TCB or UC. Those who received the TCB were then randomized to either TCB alone or TCB enhanced with a care coordinator. Data collected were ED/outpatient visits, hospital admissions and associated resources used for index admissions, and 7-, 30- and 90-day post-index discharge. A decision model with a 90-day time horizon was developed to estimate the cost. A generalized linear regression was conducted to adjust for imbalance in patient characteristics and comorbidities, and a sensitivity analysis was conducted on the proportion of patients’ combined ED/outpatient visits and inpatient admissions as well as the use of a care coordinator. Results Differences in length of stay (LOS) and costs between groups were statistically significant, although with some exceptions. Inpatient LOS and costs were 7.1 days (95% confidence interval [CI] 6.9–7.3) and Canadian dollars (CAN$) 13,131 (95% CI CAN$12,969–CAN$13,294) in UC, 6.1 days (95% CI 5.8–6.5) and CAN$7634 (95% CI CAN$7546–CAN$7722) in TCB with a coordinator, and 5.9 days (95% CI 5.6–6.2) and CAN$8080 (95% CI CAN$7975–CAN$8184) in TCB without a coordinator. Decision modelling indicated TCB was less costly than UC, with a mean (standard deviation [SD]) of CAN$10,172 (40) versus CAN$15,588 (85), and TCB with a coordinator was slightly less costly than without a coordinator (CAN$10,109 [49] versus CAN$10,244 [57]). Conclusion This study suggests that the use of the TCB, with or without a care coordinator, appears to be an economically attractive intervention compared with UC.
Open Access
Effectiveness of a standardized electronic admission order set for acute exacerbation of chronic obstructive pulmonary disease
(2018-05-30) Pendharkar, Sachin R; Ospina, Maria B; Southern, Danielle A; Hirani, Naushad; Graham, Jim; Faris, Peter; Bhutani, Mohit; Leigh, Richard; Mody, Christopher H; Stickland, Michael K
Abstract Background Variation in hospital management of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may prolong length of stay, increasing the risk of hospital-acquired complications and worsening quality of life. We sought to determine whether an evidence-based computerized AECOPD admission order set could improve quality and reduce length of stay. Methods The order set was designed by a provincial COPD working group and implemented voluntarily among three physician groups in a Canadian tertiary-care teaching hospital. The primary outcome was length of stay for patients admitted during order set implementation period, compared to the previous 12 months. Secondary outcomes included length of stay of patients admitted with and without order set after implementation, all-cause readmissions, and emergency department visits. Results There were 556 admissions prior to and 857 admissions after order set implementation, for which the order set was used in 47%. There was no difference in overall length of stay after implementation (median 6.37 days (95% confidence interval 5.94, 6.81) pre-implementation vs. 6.02 days (95% confidence interval 5.59, 6.46) post-implementation, p = 0.26). In the post-implementation period, order set use was associated with a 1.15-day reduction in length of stay (95% confidence interval − 0.5, − 1.81, p = 0.001) compared to patients admitted without the order set. There was no difference in readmissions. Conclusions Use of a computerized guidelines-based admission order set for COPD exacerbations reduced hospital length of stay without increasing readmissions. Interventions to increase order set use could lead to greater improvements in length of stay and quality of care.
Open Access
Effects of a Short Course of Inhaled Corticosteroids in Noneosinophilic Asthmatic Subjects
(2011-01-01) Lemière, Catherine; Tremblay, Caroline; FitzGerald, Mark; Aaron, Shawn D; Leigh, Richard; Boulet, Louis-Philippe; Martin, James G; Nair, Parameswaran; Olivenstein, Ronald; Chaboillez, Simone
BACKGROUND: Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS).OBJECTIVE: To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS.METHODS: A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 μg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count ≤2%. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 μg/salmeterol 50 μg, twice daily for all subjects.RESULTS: After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n=6) (decrease of 1.0±0.5) compared with the placebo group (n=6) (decrease of 0.09±0.4) (P=0.008). Forced expiratory volume in 1 s declined in the placebo group (−0.2±0.2 L) and did not change in the ICS group (0.04±0.1 L) after four weeks of treatment (P=0.02). The open-label treatment with fluticasone propionate 250 μg/salmeterol 50 μg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone.CONCLUSION: A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.
Open Access
Empowering Family Physicians to Impart Proper Inhaler Teaching to Patients with Chronic Obstructive Pulmonary Disease and Asthma
(2015-01-01) Leung, Janice M; Bhutani, Mohit; Leigh, Richard; Pelletier, Dan; Good, Cathy; Sin, Don D
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and asthma depend on inhalers for management, but critical errors committed during inhaler use can limit drug effectiveness. Outpatient education in inhaler technique remains inconsistent due to limited resources and inadequate provider knowledge.OBJECTIVE: To determine whether a simple, two-session inhaler education program can improve physician attitudes toward inhaler teaching in primary care practice.METHODS: An inhaler education program with small-group hands-on device training was instituted for family physicians (FP) in British Columbia and Alberta. Sessions were spaced one to three months apart. All critical errors were corrected in the first session. Questionnaires surveying current inhaler teaching practices and attitudes toward inhaler teaching were distributed to physicians before and after the program.RESULTS: Forty-one (60%) of a total 68 participating FPs completed both before and after program questionnaires. Before the program, only 20 (49%) reported providing some form of inhaler teaching in their practices, and only four (10%) felt fully competent to teach patients inhaler technique. After the program, 40 (98%) rated their inhaler teaching as good to excellent. Thirty-four (83%) reported providing inhaler teaching in their practices, either by themselves or by an allied health care professional they had personally trained. All stated they could teach inhaler technique within 5 min. Observation of FPs during the second session by certified respiratory educators found that none made critical errors and all had excellent technique.CONCLUSION: A physician inhaler education program can improve attitudes toward inhaler teaching and facilitate implementation in clinical practices.
Open Access
Establishing a Normal Range for Induced Sputum Cell Counts in Western Canada
(2013-01-01) Davidson, Warren J; The, Stephanie; Leigh, Richard
BACKGROUND: Induced sputum cell counts are a noninvasive, reliable method for evaluating the presence, type and degree of airway inflammation. Whether current reference values for induced sputum cell counts are applicable in other induced-sputum laboratories, particularly those in Western Canada or at elevated altitude, is not clear.OBJECTIVES: To describe the normal range of induced sputum cell counts in healthy adults in Western Canada.METHODS: A total of 105 healthy nonsmoking adults with normal bronchial responsiveness and no history of lung disease proceeded with sputum induction. Sputum samples were fixed in formalin.RESULTS: Sixty-nine subjects were included in the final analyses. The mean ± SD and median (interquartile range) of the cell counts, respectively, were: total cell count 2.453±2.108, 2.000 (2.512); neutrophils 1.212±1.491, 0.721 (1.016); eosinophils 0.034±0.069, 0.005 (0.043); macrophages 1.050±1.213, 0.696 (1.005); lymphocytes 0.057±0.161, 0.001 (0.049); and bronchial epithelial cells 0.041±0.126, 0.000 (0.027). The respective differential cell percentages were: neutrophils 50.3±23.5, 51.9 (32); eosinophils 1.4±2.3, 0.3 (2); macrophages 43±22.8, 39.3 (32); lymphocytes 2.6±5.2, 0.4 (2.5); and bronchial epithelial cells 2.2±4.8, 0.0 (2.9). Bland-Altman analysis and intraclass correlation coefficients revealed excellent interobserver agreement for measurement of sputum cell types.DISCUSSION: The range of induced sputum cell counts performed in a laboratory in Western Canada in healthy nonsmoking adult subjects was described; cellular distributions were similar to previous studies. This was also the first description of normal values for formalin-fixed induced sputum samples.CONCLUSIONS: These results confirm that current reference values for induced sputum are generalizable across different laboratories, including those in Western Canada and those at elevated altitude, and are also generalizable to formalin-fixed samples, allowing use in the broader Canadian asthma population.
Open Access
Factors influencing the implementation and uptake of a discharge care bundle for patients with acute exacerbation of chronic obstructive pulmonary disease: a qualitative focus group study
(2020-02-25) Michas, Marta; Deuchar, Lesly; Leigh, Richard; Bhutani, Mohit; Rowe, Brian H; Stickland, Michael K; Ospina, Maria B
Abstract Background Chronic obstructive pulmonary disease (COPD) is one of the most common causes of mortality and morbidity in high-income countries. In addition to the high costs of initial hospitalization, COPD patients frequently return to the emergency department (ED) and are readmitted to hospital within 30 days of discharge. A COPD acute care discharge care bundle focused on optimizing care for patients with an acute exacerbation of COPD has been shown to reduce ED revisits and hospital readmissions. The aim of this study was to explore and understand factors influencing implementation and uptake of COPD discharge care bundle items in acute care facilities from the perspective of health care providers and patients. Methods Qualitative methodology was adopted. Nine focus groups were conducted using a semi-structured guide: seven with acute and primary/community health care providers and two with patients/family members. Focus groups were audiotaped, transcribed verbatim, and coded and analyzed using a thematic approach. Results Forty-six health care providers and 14 patients/family members participated in the focus groups. Health care providers and patients identified four factors that can challenge the implementation of COPD discharge care bundles: process of care complexities, human capacity in care settings, communication and engagement, and attitudes and perceptions towards change. Both health care providers and patients recognized process of care complexity as the most important determinant of the COPD discharge bundle uptake. Processes of care complexity include patient activities in seeking and receiving care, as well as practitioner activities in making a diagnosis and recommending or implementing treatment. Important issues linked to human capacity in care settings included time constraints, high patient volume, and limited staffing. Communication during transitions in care across settings and patient engagement were also broadly discussed. Other important issues were linked to patients’, providers’, and system attitudes towards change and level of involvement in COPD discharge bundle implementation. Conclusions Complexities in the process of care were perceived as the most important determinant of COPD discharge bundle implementation. Early engagement of health providers and patients in the uptake of COPD discharge bundle items as well as clear communication between acute and post-acute settings can contribute positively to bundle uptake and implementation success.
Open Access
Glucocorticoid-driven transcriptomes in human airway epithelial cells: commonalities, differences and functional insight from cell lines and primary cells
(2019-01-31) Mostafa, Mahmoud M; Rider, Christopher F; Shah, Suharsh; Traves, Suzanne L; Gordon, Paul M K; Miller-Larsson, Anna; Leigh, Richard; Newton, Robert
Abstract Background Glucocorticoids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and, as inhaled corticosteroids (ICS), are the cornerstone of treatment for asthma. However, reduced efficacy in severe disease or exacerbations indicates a need to improve ICS actions. Methods Glucocorticoid-driven transcriptomes were compared using PrimeView microarrays between primary human bronchial epithelial (HBE) cells and the model cell lines, pulmonary type II A549 and bronchial epithelial BEAS-2B cells. Results In BEAS-2B cells, budesonide induced (≥2-fold, P ≤ 0.05) or, in a more delayed fashion, repressed (≤0.5-fold, P ≤ 0.05) the expression of 63, 133, 240, and 257 or 15, 56, 236, and 344 mRNAs at 1, 2, 6, and 18 h, respectively. Within the early-induced mRNAs were multiple transcriptional activators and repressors, thereby providing mechanisms for the subsequent modulation of gene expression. Using the above criteria, 17 (BCL6, BIRC3, CEBPD, ERRFI1, FBXL16, FKBP5, GADD45B, IRS2, KLF9, PDK4, PER1, RGCC, RGS2, SEC14L2, SLC16A12, TFCP2L1, TSC22D3) induced and 8 (ARL4C, FLRT2, IER3, IL11, PLAUR, SEMA3A, SLC4A7, SOX9) repressed mRNAs were common between A549, BEAS-2B and HBE cells at 6 h. As absolute gene expression change showed greater commonality, lowering the cut-off (≥1.25 or ≤ 0.8-fold) within these groups produced 93 induced and 82 repressed genes in common. Since large changes in few mRNAs and/or small changes in many mRNAs may drive function, gene ontology (GO)/pathway analyses were performed using both stringency criteria. Budesonide-induced genes showed GO term enrichment for positive and negative regulation of transcription, signaling, proliferation, apoptosis, and movement, as well as FOXO and PI3K-Akt signaling pathways. Repressed genes were enriched for inflammatory signaling pathways (TNF, NF-κB) and GO terms for cytokine activity, chemotaxis and cell signaling. Reduced growth factor expression and effects on proliferation and apoptosis were highlighted. Conclusions While glucocorticoids repress mRNAs associated with inflammation, prior induction of transcriptional activators and repressors may explain longer-term responses to these agents. Furthermore, positive and negative effects on signaling, proliferation, migration and apoptosis were revealed. Since many such gene expression changes occurred in human airways post-ICS inhalation, the effects observed in cell lines and primary HBE cells in vitro may be relevant to ICS in vivo.
Open Access
Human Rhinovirus Infection of Airway Epithelial Cells Modulates Airway Smooth Muscle Migration
(2015-12-22) Shariff, Sami; Leigh, Richard; Proud, David; Kubes, Paul; Giembycz, Mark
The traditional paradigm of airway remodeling in asthma has held that remodeling occurs after many years of chronic inflammation. However, studies have confirmed that remodeling changes are observed in children even before the clinical diagnosis of asthma is established. There is now robust evidence to indicate that children with recurrent human rhinovirus (HRV)-induced wheezing episodes are at significantly increased risk of developing subsequent asthma. A feature of airway remodeling is increased airway smooth muscle (ASM) mass with a greater proximity of the ASM to the subepithelial region, and we interrogated the hypothesis that HRV-induced alterations of airway epithelial cell biology might regulate ASM migration. We demonstrated that ASM chemotaxis is GPCR dependent, can be regulated by cAMP and is dependent upon CCL5 release by the epithelium post-HRV infection. These observations substantiate the growing body of evidence that links HRV infections to the subsequent development of asthma.
Open Access
Identification and Validation of Nebulized Aerosol Devices for Sputum Induction
(2014-01-01) Davidson, Warren J; Dennis, John; The, Stephanie; Litoski, Belinda; Pieron, Cora; Leigh, Richard
BACKGROUND: Induced sputum cell counts are a noninvasive and reliable method for evaluating the presence, type and degree of airway inflammation in patients with asthma. Currently, standard nebulizer devices used for sputum induction in multiple patients are labelled as single-patient devices by the manufacturer, which conflicts with infection prevention and control requirements. As such, these devices cannot feasibly be used in a clinical sputum induction program. Therefore, there is a need to identify alternative nebulizer devices that are either disposable or labelled for multi-patient use.OBJECTIVE: To apply validated rigorous, scientific testing methods to identify and validate commercially available nebulizer devices appropriate for use in a clinical sputum induction program.METHODS: Measurement of nebulized aerosol output and size for the selected nebulizer designs followed robust International Organization for Standardization methods. Sputum induction using two of these nebulizers was successfully performed on 10 healthy adult subjects. The cytotechnologist performing sputum cell counts was blinded to the type of nebulizer used.RESULTS: The studied nebulizers had variable aerosol outputs. The AeroNeb Solo (Aerogen, Ireland), Omron NE-U17 (Omron, Japan) and EASYneb II (Flaem Nuova, Italy) systems were found to have similar measurements of aerosol size. There was no significant difference in induced sputum cell results between the AeroNeb Solo and EASYneb II devices.DISCUSSION: There is a need for rigorous, scientific evaluation of nebulizer devices for clinical applications, including sputum induction, for measurement of cell counts.CONCLUSION: The present study was the most comprehensive analysis of different nebulizer devices for sputum induction to measure cell counts, and provides a framework for appropriate evaluation of nebulizer devices for induced sputum testing.
Open Access
The impact of diurnal variation on induced sputum cell counts in healthy adults
(BioMed Central, 2013-03-28) Davidson, Warren J.; Wong, Lisa E; The, Stephanie; Leigh, Richard
Open Access
Modulation Of Fibroblast Function By Human Rhinovirus Infected Airway Epithelium
(2015-12-23) Shelfoon, Christopher; Proud, David; Leigh, Richard; Kelly, Margaret; Patel, Kamala
Thickening of the lamina reticularis – a feature of airway remodeling in asthma – can be found in the airways of young children with wheeze. In association, wheezing illness due to human rhinovirus infection is an important risk factor for asthma development. We hypothesize that rhinovirus infection may be involved in the pathogenesis of lamina reticularis thickening and, by extension, airway remodeling. We show that upon infection with human rhinovirus the airway epithelium releases chemoattractants that are able to recruit human bronchial fibroblasts – the cell associated with lamina reticularis thickening. CXCL10 and CXCL8 were revealed as key players in this response, broadening their role in asthma pathogenesis. Additionally, fibroblast migration was experimentally abrogated using formoterol and other cAMP elevating agents. Taken together, the work in this thesis supports the hypothesis that rhinovirus infection is involved in the pathogenesis of airway remodeling.