Asthma Traits Research Articles

Clinical Benefits of Targeting Treatable Traits in Asthma and Chronic Obstructive Pulmonary Disease

Asthma and chronic obstructive pulmonary disease (COPD) have long been debated regarding their similarities and differences in clinical presentation and pathology. There has also been a discussion about how common therapeutics should be used differently for each disease. Traditionally, a "one size fits all" stepwise treatment has been chosen based on the severity of each case after categorizing the diseases, such as asthma or COPD. However, recently, the need for a precise approach for the treatment of individual patients beyond the disease category has been emphasized, especially in severe cases. To achieve precise personalized therapy, it has become necessary to focus on the individual phenotypes and underlying causal molecular mechanisms (endotypes) and to identify key therapeutic targets, which are called treatable traits. This review discusses the evidence for the importance of identifying treatable traits and therapeutic strategies based on the broader perspective of chronic obstructive airway disease rather than on individual diseases such as asthma or COPD.

Ascertainment of Small Airways Dysfunction Using Oscillometry to Better Define Asthma Control and Future Risk: Are We Ready to Implement It in Clinical Practice?

The small airways comprise generations 8 to 23 of the bronchial tree, consist of airways with an internal diameter< 2mm, and are classically difficult to assess and treat in persistent asthma. Small airways dysfunction (SAD) is integral to the asthma management paradigm because it is associated with poorer symptom control and greater levels of type 2 inflammation, and it has been proposed as a potentially treatable asthma trait. Although identification of SAD based on oscillometry has been found to be clinically useful in managing asthma, very few physicians, including specialists, use this technique as part of standard or adjunct evaluation of lung function to diagnose asthma, grade severity of airway obstruction, ascertain disease control or the risk for future exacerbations, or to make management decisions. To rectify the unrecognized value of oscillometry in the asthma community, a consortium of authors who are investigators with knowledge and experience of oscillometry wished to address the most important clinical questions raised by our colleagues who are considering using this technique, including its clinical utility. In this article, we discuss integral concepts, including applicability of oscillometry as a predictive tool for asthma exacerbations and disease control, adequacy of spirometry and oscillometry in assessing SAD, potential limitations of oscillometry, and treatment options for SAD.

Integrating hot topics and implementation of treatable traits in asthma.

People with asthma experience many different problems related to their illness. The number and type of problems differ between patients. This results in asthma being a complex and heterogeneous disorder which mandates a personalised approach to management. These features pose very significant challenges for the effective implementation of evidence-based management. "Treatable traits" is a model of care that has been specifically designed to address these issues. Traits are identified in the pulmonary, extrapulmonary (comorbidity) and behavioural/risk factor domains. Traits are clinically relevant, recognisable with validated trait identification markers and treatable using evidence-based therapies. The clinician and patient agree on a personalised management plan that addresses the relevant traits, and trials show superiority of this approach with significant improvements in asthma control and quality of life. A number of tools have now been developed to assist the clinician in the implementation of this approach. The success of the treatable traits model of care is now being realised in other disease areas.

Treatable Traits in Asthma: The Importance of Extrapulmonary Traits—GERD, CRSwNP, Atopic Dermatitis, and Depression/Anxiety

Treatable Traits in Asthma: The Importance of Extrapulmonary Traits—GERD, CRSwNP, Atopic Dermatitis, and Depression/Anxiety

The treatable traits of asthma in pregnancy: a clinical audit.

Poor asthma control in pregnancy is associated with adverse perinatal outcomes. Treatable traits improve patient outcomes but the pattern and prevalence of treatable traits in pregnant women with asthma is unknown. Whether treatable traits in pregnant women with asthma can be identified via a virtual care consult is also unknown. The objective of the present study was to assess the prevalence of treatable traits in pregnant women with asthma using a virtual model of care. Pregnant women with asthma (n=196) underwent an assessment by an asthma nurse educator and a respiratory physician via telehealth. In this clinical audit, 16 treatable traits were assessed including two traits in the pulmonary domain, five traits in the behavioural/risk factors domain and nine traits in the extrapulmonary domain. Pregnant women with asthma had a mean±sd of 7.5±2.0 treatable traits per person including 1.0±0.7 treatable traits per person in the pulmonary domain, 3.5±1.56 in the extrapulmonary domain and 2±0.9 in the risk factor/behavioural domain. Treatable traits in the behavioural/risk factor domain were most prevalent and these included limited asthma knowledge (96%), inadequate inhaler technique (84%) and no written asthma action plan (80%). On average 3.8±1.24 interventions per person were delivered for a mean±sd of 7.5±2.0 treatable traits per person. Virtual antenatal asthma care is a feasible approach for assessing treatable traits in pregnant women with mild asthma. Pregnant women with asthma exhibit multiple management issues. Virtual models of care might increase asthma in pregnancy service uptake and acceptability.

Treatable Traits in Asthma: The Importance of Extrapulmonary Traits—GERD, CRSwNP, Atopic Dermatitis, and Depression/Anxiety

Treatable traits is a personalized medicine approach to the management of airway disease. Assessing traits within the 3 domains of pulmonary, extrapulmonary, and behavioral/lifestyle/risk factor traits, and applying targeted treatments to effectively manage these traits, enables a holistic and personalized approach to care. Asthma is a heterogeneous and complex airway disease that is frequently complicated by several extrapulmonary traits that impact asthma outcomes and predict future outcomes. We propose that the identification of extrapulmonary and behavioral risk factor traits and the implementation of targeted therapy will lead to improved management of people with asthma. Furthermore, many extrapulmonary traits present as "connected comorbidities"; that is, they coexist with asthma, have an impact on asthma, and effective treatment improves both asthma and the comorbidity or the comorbidities may share a similar mechanism. In this review, we explore this concept and look at atopic dermatitis, chronic rhinosinusitis with nasal polyps, gastroesophageal reflux disease, anxiety, and depression as treatable traits of asthma and how these can be managed using this approach.

Treatable traits in asthma during pregnancy: a call for a shift towards a precision-based management approach.

Asthma is the most common chronic medical condition in pregnancy. Asthma exacerbations in pregnancy are unpredictable, and are associated with adverse maternal and fetal perinatal outcomes such as preterm birth and low birthweight. Goals of asthma management in pregnancy are to establish effective asthma control and prevent exacerbations. Optimising the management of asthma in pregnancy is an important goal of practice and future research.Treatable traits is a precision medicine paradigm proposed for the management of airways diseases, which holistically addresses the complexity and heterogeneity of airways disease. It is an individualised treatment approach that aims to improve outcomes. This makes treatable traits well suited for pregnant women with asthma, who have a high prevalence of obesity, mental health conditions, poor symptom perception and suboptimal asthma management skills including low treatment adherence. These traits are measurable and treatable. In this review, we explore current knowledge on the burden of asthma, maternal and perinatal consequences of asthma during pregnancy, the treatable traits paradigm, the prevalence of treatable traits in pregnant women with asthma, and consider how the treatable traits paradigm can be integrated into the management of asthma in pregnancy.

Chronic rhinosinusitis with nasal polyps and allergic rhinitis as different multimorbid treatable traits in asthma.

Respiratory multimorbidities are linked to asthma, such as allergic rhinitis (AR) with early allergic asthma and chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) with late nonallergic asthma. Our aim was to investigate the association of asthma severity and control with specific upper airway phenotypes. Patients with asthma were prospectively recruited from 23 pulmonology and ear, nose, and throat clinics. Asthma severity and control, as well as upper airway comorbidities (AR and non-AR [NAR], CRSwNP, and CRS without nasal polyps [CRSsNP]) were assessed according to international consensus guidelines definitions. A total of 492 asthmatic patients were included. Half of the asthmatic patients (49.6%) had associated rhinitis (37.0% had AR and 12.6% had NAR) and 36.2% had CRS (16.7% had CRSsNP and 19.5% had CRSwNP), whereas 14.2% had no sinonasal symptoms. Most cases of AR (78%) and NAR (84%) were present in patients with mild-to-moderate asthma, whereas CRSwNP was more frequent in patients with severe asthma (35% [P< .001]), mainly nonatopic asthma (44% [P< .001]). Patients with severe asthma with CRSwNP had worse asthma control, which was correlated (r= 0.249 [P= .034]) with sinus occupancy. Multiple logistic regression analysis showed that late-onset asthma, intolerance of aspirin and/or nonsteroidal anti-inflammatory drugs, and CRSwNP were independently associated with severe asthma. Severe asthma is associated with CRSwNP, with sinus occupancy affecting asthma control. This study has identified 2 main different upper airway treatable traits, AR and CRSwNP, which need further evaluation to improve management and control of patients with asthma.

The treatable traits approach to adults with obstructive airways disease in primary and secondary care.

The treatable traits approach is based on the recognition that the different clinical phenotypes of asthma and chronic obstructive airways disease (COPD) are a heterogeneous group of conditions with different underlying mechanisms and clinical manifestations, and that the identification and treatment of the specific clinical features or traits facilitates a personalised approach to management. Fundamentally, it recognises two important concepts. Firstly, that treatment for obstructive lung disease can achieve better outcomes if guided by specific clinical characteristics. Secondly, that in patients with a diagnosis of asthma, and/or COPD, poor respiratory health may also be due to numerous overlapping disorders that can present with symptoms that may be indistinguishable from asthma and/or COPD, comorbidities that might require treatment in their own right, and lifestyle or environmental factors that, if addressed, might lead to better control rather than simply increasing airways directed treatment. While these concepts are well accepted, how best to implement this personalised medicine approach in primary and secondary care within existing resource constraints remains uncertain. In this review, we consider the evidence base for this management approach and propose that the priority now is to assess different prototype templates for the identification and management of treatable traits in both asthma and COPD, in primary, secondary and tertiary care, to provide the evidence that will guide their use in clinical practice in different health care systems.

Genomics of Treatable Traits in Asthma.

The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational genomics. Moving asthma diagnosis from a nonspecific umbrella term to specific phenotypes/endotypes and related traits may provide insights into features that may be prevented or alleviated by therapeutical intervention. This review provides an overview of the different asthma endotypes and phenotypes and the genomic findings from asthma studies using patient stratification strategies and asthma-related traits. Asthma genomic research for treatable traits has uncovered novel and previously reported asthma loci, primarily through studies in Europeans. Novel genomic findings for asthma phenotypes and related traits may arise from multi-trait and specific phenotyping strategies in diverse populations.

Influence of sex, cigarette smoking and airway inflammation on treatable traits in CBIOPRED severe asthma.

Influence of sex, cigarette smoking and airway inflammation on treatable traits in CBIOPRED severe asthma.

Using a knowledge translation framework to identify health care professionals' perceived barriers and enablers for personalised severe asthma care.

BackgroundWhilst multidimensional assessment enables the detection of treatable traits in severe asthma and has the potential to improve patient outcomes, healthcare disparities exist, and little is known about the factors influencing optimal management in severe asthma. This study aimed to explore perceived barriers, and enablers to implementing personalised care in severe asthma, from the healthcare professionals’ perspective.MethodsA descriptive, qualitative study involving a single focus group (n = 7) and semi-structured interviews (n = 33) with multidisciplinary healthcare professionals involved in severe asthma care was conducted. A hybrid thematic and content analysis was undertaken to identify themes, which were then deductively mapped to the Theoretical Domains Framework (TDF).ResultsOverall, three emergent themes were identified: (1) Barriers- (2) Enablers- to optimal management; (3) Desired model of care. Across all TDF domains, 6 constructs influenced development and implementation of optimal care: (1) belief about consequences, (2) environmental context and resources, (3) belief about capabilities, (4) social/professional role and identity, (5) goals and (6) knowledge.ConclusionImplementation of personalised care in severe asthma is complex and non-linear. The use of a theory-based approach effectively demonstrated how a variety of behaviours could be targeted to optimise and promote personalised care in different clinical setting.

KCa3.1 differentially regulates trachea and bronchi epithelial gene expression in a chronic-asthma mouse model.

Ion channels are potentially exploitable as pharmacological targets to treat asthma. This study evaluated the role of KCa3.1 channels, encoded by Kcnn4, in regulating the gene expression of mouse airway epithelium and the development of asthma traits. We used the ovalbumin (OVA) challenge as an asthma model in wild-type and Kcnn4-/- mice, performed histological analysis, and measured serum IgE to evaluate asthma traits. We analyzed gene expression of isolated epithelial cells of trachea or bronchi using mRNA sequencing and gene ontology and performed Ussing chamber experiments in mouse trachea to evaluate anion secretion. Gene expression of epithelial cells from mouse airways differed between trachea and bronchi, indicating regional differences in the inflammatory and transepithelial transport properties of proximal and distal airways. We found that Kcnn4 silencing reduced mast cell numbers, mucus, and collagen in the airways, and reduced the amount of epithelial anion secretion in the OVA-challenged animals. In addition, gene expression was differentially modified in the trachea and bronchi, with Kcnn4 genetic silencing significantly altering the expression of genes involved in the TNF pathway, supporting the potential of KCa3.1 as a therapeutic target for asthma.

Novel potential treatable traits in asthma: Where is the research taking us?

Asthma is a complex, heterogeneous disease in which the underlying mechanisms are not fully understood. Patients are often grouped into phenotypes (based on clinical, biologic, and physiologic characteristics) and endotypes (based on distinct genetic or molecular mechanisms). Recently, patients with asthma have been broadly split into 2 phenotypes based on their levels of type 2 inflammation: type 2 and non-type 2 asthma. However, this approach is likely oversimplified, and our understanding of the non-type 2 mechanisms in asthma remains extremely limited. Abetter understanding of asthma phenotypes and endotypes may assist in development of drugs for new therapeutic targets in asthma. One approach is to identify "treatable traits," which are specific patient characteristics related to phenotypes and endotypes that can be targeted by therapies. This review will focus on emerging treatable traits in asthma and aim to describe novel patient subgroups and endotypes that may represent the next step in the search for new therapeutic approaches.

Genetic Associations and Architecture of Asthma-COPD Overlap

BackgroundSome people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research QuestionWhat is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and MethodsWe conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).ResultsWe selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.InterpretationWe identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Temperament, Character Traits and Alexithymia in Patients with Asthma; A University Hospital Sample

Background: The relationship between psychological factors and asthma has received attention since very early times. However, there’s a lack of knowledge about the temperament and character features of asthma patients. We aimed to assess if there are specific personality traits in asthma patients.Methods: Thirty-eight patients with asthma and thirty-five healthy individuals were enrolled in the study. The sociodemographic data form and Temperament and Character Inventory (TCI) and Toronto Alexithymia Scale (TAS) were applied to all participants. Results: The mean age was 40.9 ± 15.9 in the asthma group (52.1%) and 37.3 ± 14.3 in the control group (47.9%). There were 29 females and 9 males in asthma group, 19 females and 16 males in control group. In analysis of temperament and character subscales, the scores of harm avoidance, frugality, sentimentality and transpersonal identification were higher in asthma patients than the control group; the differences were statistically significant (p&amp;lt;0.05). There were no significant differences between the groups for alexithymia (p&amp;gt;0.05).Conclusions: Our study showed that there were character and temperament differences between asthma patients and healthy group. There were no differences for alexithymia between the groups. Further studies are needed to evaluate the causes of differences and the impacts of traits on disease course.

Agreement of parent‐ and child‐reported wheeze and its association with measurable asthma traits

ObjectivesIn epidemiological studies, childhood asthma is usually assessed with questionnaires directed at parents or children, and these may give different answers. We studied how well parents and children agreed when asked to report symptoms of wheeze and investigated whose answers were closer to measurable traits of asthma.MethodsLuftiBus in the school is a cross‐sectional survey of respiratory health among Swiss schoolchildren aged 6–17 years. We applied questionnaires to parents and children asking about wheeze and exertional wheeze in the past year. We assessed agreement between parent–child answers with Cohen's kappa (k), and associations of answers from children and parents with fractional exhaled nitric oxide (FeNO) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC), using quantile regression.ResultsWe received questionnaires from 3079 children and their parents. Agreement was poor for reported wheeze (k = 0.37) and exertional wheeze (k = 0.36). Median FeNO varied when wheeze was reported by children (19 ppb, interquartile range [IQR]: 9–44), parents (22 ppb, IQR: 12–46), both (31 ppb, IQR: 16–55), or neither (11 ppb, IQR: 7–19). Median absolute FEV1/FVC was the same when wheeze was reported by children (84%, IQR: 78–89) and by parents (84%, IQR: 78–89), lower when reported by both (82%, IQR: 78–87), and higher when reported by neither (87%, IQR: 82–91). For exertional wheeze findings were similar. Results did not differ by age or sex.ConclusionOur findings suggest that surveying both parents and children and combining their responses can help us to better identify children with measurable asthma traits.

Step-up and step-down approaches in the treatment of asthma

Introduction: Significant intraindividual and temporal variability in symptom control is a feature of asthma that requires careful monitoring and the need to periodically review and adjust therapy. Both NHLBI/NAEPP and GINA offer helpful algorithms for a stepping approach to asthma. Areas covered: The problems arisen in applying the stepwise approach to the treatment of asthma proposed by NHLBI/NAEPP and GINA algorithms and their possible alternatives. Expert opinion: The current therapeutic stepping approach to asthma, which takes into account lung function, symptoms and quality of life, is certainly useful, but it does not consider the underlying mechanisms. Furthermore, patient’s overestimation or underestimation of the severity of the disease and differences in the opinions on the level of asthma control required between patients and physicians and also between physicians in both primary care and specialist settings are common and may negatively affect asthma control and future risks. A reassessment of the conventional stepping approach to management of asthma is now needed. A pragmatic approach that sets therapeutic goals for each individual and associates them with the treatable traits of asthma which, when therapeutically targeted, will in many cases help to achieve the goals, seems more reasonable than the present stepping approach.

ADAMTS4 promotes chronic airway inflammation and hyperresponsiveness in HDM-based mouse model of asthma: A potential therapeutic target for asthma traits

Abstract Asthma is a chronic airway inflammation characterized by combination of immune responses and structural remodeling that involves both large and small airways. The global prevalence of asthma is on the rise with a sizable portion of asthmatics not responding to existing medication, thus posing a substantial health and economic burden. Matrix proteases including A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) contribute to lung damage and repair responses. Our lab has recently reported a critical role for ADAMTS4 in the immunopathology of IAV infection-induced acute lung inflammation through exuberant activity of lung fibroblasts and remodeling of the extracellular matrix. Given the divergent nature of immune responses in chronic airway inflammation compared to infection, we sought to investigate the sustaining role of ADAMTS4 upon persistent exposure to aeroallergen. Using HDM-based asthma model, ADAMTS4 knockout mice exhibited a robust reduction in lung eosinophils, mucus production, and airway resistance compared to their wildtype counterparts. This was associated with a marked decrease in IL-4, IL-5, and IL-13 cytokine production and IgE secretion. Interestingly, ADAMTS4 gene deletion differentially blocked the myeloid cell recruitment to the lungs without affecting their development. Such effects were also associated with significant reduction in alveolar macrophages and peribranchial inflammation. These results suggest that the modulating immune responses by ADAMTS-4 is sustainable beyond the acute phase of inflammation and may be extensively contributing to the immunopathology of chronic airway inflammation, thus harboring a therapeutic potential for the treatment of asthma traits.

Molecular markers of type 2 airway inflammation are similar between eosinophilic severe asthma and eosinophilic chronic obstructive pulmonary disease

Airway and systemic eosinophilia are important treatable traits in both severe asthma and COPD. The molecular basis of eosinophilia in COPD is poorly understood but could involve type 2 cytokines (IL5, IL13) and prostaglandin D2 (PGD2 ). This study included non-obstructive airways disease (OAD) controls (n=19), a COPD cohort (n=96) and a severe asthma cohort (n=84). Demographics, exacerbation history, disease impact (SGRQ) and spirometry were assessed. Participants were categorized as eosinophilic using either sputum eosinophil proportion (≥3%) or blood eosinophil count (≥300/μL). Sputum type 2 inflammatory measures included PGD2 by ELISA and gene expression (qPCR) of IL5, IL13 and the haematopoietic PGD2 synthase (HPGDS). Type 2 markers did not differ across groups except HPGDS mRNA which was highest in non-OAD controls and lowest in COPD. IL5 and IL13 mRNA and PGD2 levels were significantly increased in eosinophilic vs non-eosinophilic severe asthma but did not differ between eosinophilic COPD and eosinophilic severe asthma or non-eosinophilic COPD. HPGDS expression was higher in eosinophilic severe asthma compared with eosinophilic COPD. Results were similar using sputum or blood eosinophil cut-offs. Sputum IL5 and IL13 were highly intercorrelated in severe asthma (r=0.907, p<0.001) and COPD (r=0.824, p<0.001), were moderately correlated with sputum eosinophils in severe asthma (IL5 r=0.440, p<0.001; IL13 r=0.428, p<0.001) and were weakly correlated in COPD (IL5 r=0.245, p<0.05; IL13 r=0.317, p<0.05). Molecular markers of type 2 airway inflammation do not differ between eosinophilic asthma and eosinophilic COPD; however, the relationship between eosinophilia and type 2 airway markers appears weaker in COPD than in severe asthma.