Treatable Traits That Predict Health Status and Treatment Response in Airway Disease

doi:10.1016/j.jaip.2020.09.046

The Journal of Allergy and Clinical Immunology: In Practice

Volume 9, Issue 3, March 2021, Pages 1255-1264.e2

https://doi.org/10.1016/j.jaip.2020.09.046 Get rights and content

Background

A strategy based on the assessment and management of treatable traits (TTs) has been proposed as a new paradigm in airway disease. There is a potentially long list of TTs with likely different clinical impact.

Objective

To identify TTs most strongly associated with poorer health-related quality of life (HRQOL) and treatments that most substantially improved HRQOL.

Methods

We pooled data from 2 parallel-group clinical trials of multidimensional assessment and individualized management targeted to TTs versus usual care in patients with chronic obstructive pulmonary disease or severe asthma (intervention N = 45; control N = 46). Following multidimensional assessment, 22 TTs were identified and the intervention group received treatments tailored to their identified TT. We used Bayesian Model Averaging to examine associations between TTs and HRQOL (St George's Respiratory Questionnaire) at baseline, as well as between each TT treatment and the observed change in HRQOL postintervention.

Results

TTs most substantially associated with poorer baseline HRQOL were frequent chest infections, breathing pattern disorder, inadequate inhaler technique, systemic inflammation (C-reactive protein >3 mg/L), and depression. In both trials, TT treatment led to a large, significant improvement in HRQOL compared with usual care (Cohen's d = 1.19; P < .001). Receiving a statin for systemic inflammation and oral corticosteroid for eosinophilic airway inflammation was associated with the largest HRQOL improvements. Treatments for exercise intolerance, anxiety, and obesity were associated with smaller improvements in HRQOL.

Conclusions

This study contributes to identifying clinically impactful TTs by showing that TTs across pulmonary, extrapulmonary, and behavioral domains were associated with HRQOL impairment and treatment response.

Introduction

A strategy based on “treatable traits” (TTs) is proposed as a new paradigm for airway disease management, whereby certain characteristics (TTs) are systematically assessed within the pulmonary, extrapulmonary, and behavioral/risk-factor domains and treatment is targeted to these characteristics.¹^,² TTs are defined as phenotypic or endotypic characteristics that are clinically relevant, identifiable, and modifiable with treatment.¹^,² There are many potential TTs in patients with chronic airway diseases such as severe asthma and chronic obstructive pulmonary disease (COPD).¹^,² Given the heterogeneous and complex clinical presentation of these patients with frequent multimorbidity, as well as the finite time and resources available for their diagnosis and care, identifying the TTs and their treatments that provide “bang for our buck” in terms of health impact is of paramount importance.

Few studies have been conducted assessing a TT approach in the management of chronic airway disease. The first controlled clinical trial in COPD showed a large effect on health-related quality of life (HRQOL) with a 14-unit change in St George's Respiratory Questionnaire (SGRQ) score for the TT intervention group, a change 3.5 times the minimal clinically important difference.³ A randomized controlled trial (RCT) in patients with severe asthma confirmed the efficacy of targeting treatments to assessed TT, improving the SGRQ score by 13 units.⁴

Because the TT approach requires multidimensional assessment and intervention, a natural question that arises in relation to TTs, multicomponent individualized management interventions, or other similar care bundles is “which aspects lead to the effect.” Although this question could be answered with multiple RCTs that test different components individually and in combination against all other options, this is not feasible with complex models of care, such as TTs. An alternative approach is to use regression analysis to obtain indirect observational evidence of associations between components of management and change in clinically relevant outcomes. This, however, has several computational challenges in a conventional regression approach, including having more predictors than data points for model estimation and collinearity between predictors. Modeling techniques such as Bayesian Model Averaging⁵ can overcome these challenges.

To gain an understanding of which TTs and targeted treatments have the greatest impact on HRQOL in patients with chronic airway disease, this study sought to apply a novel Bayesian Model Averaging technique to analyze data from 2 trials of TTs that involved multidimensional assessment and individualized management in COPD³ and severe asthma.⁴ The specific aims were to evaluate: (1) which combination of TTs identified during multidimensional assessment were associated with worse HRQOL impairment at baseline and (2) which combination of treatments delivered during individualized management based on TTs were associated with the greatest HRQOL change over time.

Section snippets

Participants

Participants from 2 previously reported parallel-group clinical trials of multidimensional assessment and individualized management versus a usual care control group for airway diseases were pooled for this analysis: a nonrandomized controlled clinical trial in COPD (N = 17 intervention arm; N = 19 control arm)³ and an RCT in severe asthma (N = 28 intervention arm; N = 27 control arm).⁴ Participants were recruited from the respiratory ambulatory care clinic at the John Hunter Hospital

Characteristics of participants and prevalence of TTs

Compared with participants in the severe asthma trial, patients with COPD were older (mean, 70.9 years vs 52.2 years), more often males (50% vs 35%), and had more severe airflow limitation (51.2 vs 73.2 postbronchodilator FEV₁% predicted) (Table II). Baseline HRQOL was poor in both groups (SGRQ scores 53.5 in COPD and 49.1 in severe asthma). Of the 22 TTs considered in the current study (Table I), participants in the COPD trial expressed a median of 8.5 TTs (range, 4-13) and participants in the

Discussion

This study identifies what specific TTs are associated with HRQOL and treatment response in patients with chronic airway diseases (COPD and severe asthma). By applying Bayesian Model Averaging⁵ to data from 2 previously reported clinical trials,³^,⁴ our results show that (1) frequent chest infections, dysfunctional breathing/breathing pattern disorder, inadequate inhaler technique, systemic inflammation, and depression had large and reliable associations with HRQOL; (2) treating systemic

Conclusions

This study demonstrated that a combination of TTs across the pulmonary, extrapulmonary, and behavioral domains was associated with HRQOL and, when treated, was associated with HRQOL improvement. Although these findings raise questions regarding why particular TTs were associated with outcomes and not others, they also identify a list of TTs that might be worth examining further in future efficacy, effectiveness, and implementation trials. Likewise, questions remain as to how to implement a TT

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Impact of Treatable Traits on Asthma Control and Quality of Life
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Many adult patients with asthma have uncontrolled disease and impaired quality of life, despite current asthma-specific drug therapies.
This study aimed to investigate the prevalence of 9 traits in patients with asthma, their associations with disease control and quality of life, and referral rates to nonmedical health care professionals.
Retrospectively, data from patients with asthma were collected in 2 Dutch hospitals (Amphia Breda and RadboudUMC Nijmegen). Adult patients without exacerbation <3 months who were referred for a first-ever elective, outpatient, hospital-based diagnostic pathway were deemed eligible. Nine traits were assessed: dyspnea, fatigue, depression, overweight, exercise intolerance, physical inactivity, smoking, hyperventilation, and frequent exacerbations. To assess the likelihood of having poor disease control or decreased quality of life, the odds ratio (OR) was calculated per trait. Referral rates were assessed by checking patients’ files.
A total of 444 adults with asthma were studied (57% women, age: 48 ± 16 years, forced expiratory volume in 1 second: 88% ± 17% predicted). Most patients (53%) were found to have uncontrolled asthma (Asthma Control Questionnaire ≥1.5 points) and decreased quality of life (Asthma Quality of Life Questionnaire <6 points). Generally, patients had 3.0 ± 1.8 traits. Severe fatigue was most prevalent (60%) and significantly increased the likelihood of having uncontrolled asthma (OR: 3.0, 95% confidence interval [CI]: 1.9-4.7) and decreased quality of life (OR: 4.6, 95% CI: 2.7-7.9). Referrals to nonmedical health care professionals were low; most referrals were to a respiratory-specialized nurse (33%).
Adult patients with asthma with a first-ever referral to a pulmonologist frequently exhibit traits justifying the deployment of nonpharmacological interventions, especially in those with uncontrolled asthma. However, referrals to appropriate interventions appeared infrequent.
Treatable Traits in Airway Disease: From Theory to Practice
2023, Journal of Allergy and Clinical Immunology: In Practice
Chronic airway diseases such as asthma and chronic obstructive pulmonary disease are prevalent and complex conditions that often coexist in the same patient. To address this complexity in clinical practice, and to move forward toward personalized and precision medicine of airway diseases, a strategy based on the identification and treatment of so-called “treatable traits” (TTs) has been proposed. A TT is a recognizable phenotypic or endotypic characteristic that can be assessed and successfully targeted by therapy to improve a clinical outcome in a patient with airway disease. Importantly, TTs can coexist in the same patient, so they are not mutually exclusive. The TT strategy proposes to investigate in each individual patient with chronic airway disease the number and type of TTs present and to treat each of them according to guideline recommendations. This strategy is agnostic (ie, independent) to the traditional diagnostic labels (asthma, chronic obstructive pulmonary disease), so it can be applied to any patient with airway disease. Currently, there is firm evidence supporting the adequacy and validity of the TT strategy. Here, we review the current state of the art of this topic, first by presenting its theoretical background and then by discussing how to best implement it in clinical practice.
Obesity and asthma: A focused review
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In recent studies, increased physical activity and exercise led to positive measures in disease. These patients had improved measures of lung function in an observation study of 1.6 million [94], better exercise capacity [95], lower levels of systemic inflammation [95], better asthma control [59,94–96], lower levels of health care utilization [94], and decreased mood symptoms [96]. While structured programs tailored for patients may be few, a European study published in 2020 reports these short and long-term benefits in a high-intensity pulmonary rehab program [97].
Treatable Traits in Asthma and COPD
2022, Archivos de Bronconeumologia
Should we apply a treatable traits approach to asthma care?
2022, Annals of Allergy, Asthma and Immunology
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They must be linked to specific disease outcomes, and they must be treatable to qualify as a treatable trait. Since the concept of treatable traits was put forward by Agusti et al18 in 2016, the model has been further elaborated by McDonald et al,19 with a total of 24 traits identified in asthma patient cohorts.19-24 These have been grouped into the following 3 different domains: pulmonary (eg, airflow limitation and emphysema), extrapulmonary (eg, cardiovascular morbidity), and behavioral and lifestyle (eg, smoking and adherence to inhaled therapies) (Fig 2).18,19,21,25
To explore the evidence for adopting a “treatable traits” approach to asthma management.
PubMed, Medline, and Google Scholar.
The above-mentioned databases were searched for randomized, controlled phase III or IV trials of adults containing the word “asthma” in the title published in the previous 10 years and for all articles containing the title words “treatable AND trait(s),” “asthma AND biomarker(s) OR smoking OR obesity OR laryngeal OR management” published within the previous 5 years. Articles were excluded if they were not published in English. Our search identified 257 articles for consideration. We also manually searched the reference lists of studies identified and searched the websites of the British Thoracic Society, European Respiratory Society, National Institute for Health and Care Excellence, and Global Initiative for Asthma for specific guidance related to asthma management.
The “treatable traits” are described within 3 domains of pulmonary, extrapulmonary, or behavioral and lifestyle traits. We consider whether treatment should be targeted toward these traits where they are present in asthma patients, based on currently available evidence, rather than increasing treatment in response to symptoms in line with current step-up, step-down asthma management guidelines.
We advocate that a treatable traits approach should be applied more broadly to the assessment and management of inadequately controlled asthma, rather than a step-up, step-down approach based on patient symptoms. This approach should be focused on the 2 treatable pulmonary traits of T_H2 inflammation and airflow obstruction along with smoking cessation, in the first instance.
Moving towards a Treatable Traits model of care for the management of obstructive airways diseases
2021, Respiratory Medicine
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Some TTs should be prioritized based on cost, clinical utility, impact, prevalence, and patient understanding [7,9]. Traits requiring pharmacological intervention, such as type 2 inflammation [9,66] and airflow limitation [9,66], and non-pharmacological interventions, such as poor inhaler technique [66,69,70], non-adherence (intentional and non-intentional) [8,56,66], smoking [11,13,14,66], and nutritional status [66], have each been identified as key TTs [66] with a number of traits associated with an increased risk of exacerbations in asthma (Fig. 2) [71]. Identification and management of these traits may be particularly well suited to primary care and lower-resource settings [45].
Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airways diseases. Both are complex and heterogeneous. Traditionally, clinical guidelines have advocated a stepwise approach to pharmacotherapy of asthma and COPD, but there is increasing realization that both require a more personalized and precise management approach. To this end, a management strategy based on the so-called Treatable Traits has been proposed. Emerging evidence suggests that this model improves relevant outcomes in patients with chronic airway diseases but further research is needed to guide implementation. This review discusses the challenges, opportunities, and hurdles that its implementation will have to face.

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: This work was supported by a grant from GlaxoSmithKline.

: Conflicts of interest: S. A. Hiles' salary was supported by a grant from GlaxoSmithKline paid to her institution (University of Newcastle) during the conduct of the study and AstraZeneca outside the study. P. G. Gibson reports personal fees from AstraZeneca, GlaxoSmithKline, and Novartis, and grants from AstraZeneca and GlaxoSmithKline outside the submitted work. A. Agusti reports grants and personal fees from AstraZeneca, GlaxoSmithKline, and Menarini outside the submitted work and personal fees from Chiesi. V. M. McDonald reports grants from GlaxoSmithKline during the conduct of the study; grants and personal fees from GlaxoSmithKline and AstraZeneca; and personal fees from Menarini outside the submitted work. The COPD clinical trial was originally funded by a National Health and Medical Research Council PhD scholarship and the John Hunter Hospital Charitable Trust Research Scheme. The severe asthma clinical trial was originally funded by the National Health and Medical Research Council, Hunter Medical Research Institute, University of Newcastle, John Hunter Hospital Charitable Trust.

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Original ArticleTreatable Traits That Predict Health Status and Treatment Response in Airway Disease

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Participants

Characteristics of participants and prevalence of TTs

Discussion

Conclusions

J Psychosom Res

Respir Med

Treatable traits: toward precision medicine of chronic airway diseases

Eur Respir J

Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under Workshop report

Eur Respir J

Multidimensional assessment and tailored interventions for COPD: respiratory utopia or common sense?

Thorax

Targeting treatable traits in severe asthma: a randomised controlled trial

Eur Respir J

Bayesian model averaging employing fixed and flexible priors: the BMS package for R

J Stat Softw

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Eur Respir J

Standardisation of spirometry

Eur Respir J

Spirometric reference values from a sample of the general U.S. population

Am J Respir Crit Care Med

An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease

Eur Respir J

Original Article
Treatable Traits That Predict Health Status and Treatment Response in Airway Disease