Integrating hot topics and implementation of treatable traits in asthma

Abstract

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.

Shareable abstract

The treatable traits approach is a useful model of care that addresses the complexity and heterogeneity of asthma https://bit.ly/3ZcvF6r

Introduction

Asthma is a common and recognisable chronic inflammatory disease of the airways. Despite major therapeutic advances and advanced understanding of the self-management behaviours that are required for optimal asthma care, the disease continues to impose a significant burden on individuals and society. People with asthma continue to experience dyspnoea and wheezing, as well as asthma attacks, which limits participation in activities. While these episodes are generally believed to be preventable and treatable, there remains a significant mortality from asthma that has not reduced in recent years [1, 2].

What these worrying facts tell us is that while we can specify how to treat asthma, there is a failure to fully implement these treatment approaches. A potential solution is a clearly defined and implemented model of care for asthma. “Treatable traits” has been developed as a model of care to address this need in asthma [3, 4]. In parallel with this is the need to lift our expectations of asthma outcomes, and the move to seek asthma remission is an important development. Treatable traits is also applicable to other airway diseases such as COPD and bronchiectasis [5], and potentially to other conditions [6–9].

A key aspect of asthma, in fact a defining characteristic, is its inherent variability [10, 11]. This results in asthma being both a complex and heterogenous condition. “Complexity” refers to the fact that many different issues, or traits, can exist in a single person with asthma. For example, a patient with asthma may have several concurrent active problems such as T2 airway inflammation (i.e. inflammation driven by a Type 2 response resulting in allergic and eosinophilic disease manifestations, and recognised by biomarkers such as blood and sputum eosinophils, fractional exhaled nitric oxide (F_ENO) and IgE levels), airflow limitation, impaired mucociliary clearance, chronic rhinosinusitis and non-adherence. “Heterogeneity” refers to the fact that not all traits are present in all people at any one time. For example, one person with asthma may have a high body mass index (BMI) and chronic breathlessness as dominant problems, while another may have active smoking and frequent exacerbations, and a third may have suboptimal asthma management skills and T2 inflammation. These examples all describe people with asthma, yet each person has different problems, and each will require a different management plan. This shows the limitation of a simple diagnostic label, since labelling each of these three people as “asthma” does not highlight the different treatable problems that they have. It also shows the limitations when trying to apply a “one size fits all” management approach to people with asthma, since treating each of these people in the same way is not adequate to define the different treatment plans that each person needs. These simple descriptions of the complexity and heterogeneity of asthma are not uncommon. Our patients recognise and express this when they say “my asthma is different” [12]. Because of the inherent complexity and heterogeneity of asthma, many people now believe it is more useful to refer to “the asthmas” and use the term “asthma” as an umbrella term that encompasses many different types of illness than can impact a person [13]. A key question for clinicians is how to usefully respond to the complexity and heterogeneity that is inherent in asthma. Treatable traits provides an answer to this question, and we will describe the treatable traits approach to asthma in this state-of-the-art review.

What is “treatable traits”?

Treatable traits is a precision medicine approach [14] that can be considered as a model of care [15]. With this approach, a patient undergoes a multidimensional assessment to identify clinically important and treatable problems, called traits. A personalised management plan is then developed to address the agreed traits. Each specific treatable trait is defined as a “therapeutic target identified by phenotypes or endotypes through a validated biomarker” and that has three key features. A treatable trait is 1) clinically important (e.g. associated with adverse health outcomes such as asthma attacks), 2) recognisable and measurable using specific trait identification markers (TIMs), and 3) responsive to treatment (treatable) [16]. Treatable traits can be identified in three key domains, as pulmonary issues, as comorbidities (extrapulmonary domain) and as risk factors/behavioural traits that contribute to the disease burden in asthma.

Trait prioritisation and super-traits

When implementing the treatable traits model of care, it is useful to prioritise which traits will be targeted. This can be done by considering the outcomes of treating a specific trait (and targeting those traits with large treatment effects), by considering the prevalence of specific traits (and targeting highly prevalent traits), by considering the setting in which the patient and clinician operate (and using the available tools to manage specific traits), and by targeting super-traits [17, 18]. When the outcome of therapy is used to prioritise traits, such as traits that when treated reduce disease exacerbations or frequent oral corticosteroid (OCS) use, it is possible to reduce the number of total traits from 33 traits (tabulated in the following “Clinical evidence” section) to 11 treatable traits. In a primary care setting these could be reduced even further by targeting super-traits with flags to refer the patient to tertiary care if traits are refractory to treatment [17]. Super-traits are defined as traits that are essential to identify and treat in order to manage other traits (figure 1), or traits that have such a large positive treatment effect that treatment is crucial, and that once identified and treated will lead to improvement on other apparently unrelated traits. The converse is that failure to address super-traits may lead to progressive accumulation of additional problems and a “chaotic trait cascade” as described in figure 2 and the “New concepts” section.

FIGURE 1.

Super-traits, their trait identification markers and their targeted treatments. FEV₁: forced expiratory volume in 1 s; LABA: long-acting β₂-agonist; LAMA: long-acting muscarinic antagonist; SABA: short-acting β₂-agonist; SAMA: short-acting muscarinic antagonist; T2: Type 2; F_ENO: fractional exhaled nitric oxide; IL: interleukin; BMI: body mass index.

FIGURE 2.

The “chaotic trait cascade”. The figure demonstrates the flow-on effects that occur when key super-traits are not effectively managed. Patients with uncontrolled asthma develop frequent asthma attacks, leading to a range of other effects such as increased oral corticosteroid (OCS) use, airway remodelling, anxiety, breathlessness and social impacts. These flow-on effects in turn cause other complications such as the side-effects of OCS use. This in turn worsens social impacts of asthma, and contributes to panic, anxiety, depression and physical inactivity. A person suffering from this “chaotic trait cascade” experiences symptom distress from their asthma as well as other complications of uncontrolled asthma and its treatment. BMI: body mass index; CVD: cardiovascular disease; BPD: breathing pattern disorder; ILO: inducible laryngeal obstruction; VCD: vocal cord dysfunction.

Practically this allows for a more focused approach that is based on available resources, including time, and trait prevalence patterns. It allows a minimum number of traits to be assessed and managed. This model of care is better suited to primary care or solo physician practice. Examples of super-traits with these characteristics are (figure 1):

• Inhaler device technique and adherence. These traits are essential for successful pharmacological treatment of many other traits. It is necessary to have adequate inhaler device technique in order to treat the traits of T2-high eosinophilic inflammation (with inhaled corticosteroid (ICS)) and airflow limitation (with inhaled long-acting bronchodilators). Adherence also underpins successful therapy of all traits.

• T2 inflammation. The effect size in exacerbation reduction that results from treating T2 inflammation with ICS (in mild-to-moderate asthma) or targeted monoclonal antibodies (in severe eosinophilic/allergic asthma) is large with numbers needed to treat of 2–3 for ICS [19] and an average 50% reduction in severe exacerbations with T2 biologics in severe asthma.

• Airflow limitation. This super-trait underpins symptoms in asthma, typically wheeze, dyspnoea and chest tightness. It is recognised by the TIMs forced expiratory volume in 1 s (FEV₁), forced expiratory volume/vital capacity ratio and bronchodilator responsiveness (BDR). Highly effective treatment is provided by inhaled bronchodilators, as long-acting β₂-agonists and long-acting antimuscarinic agents.

• High BMI/obesity. Targeting this trait with a 7–10% weight loss intervention leads to improvement in other traits, e.g. dyspnoea, cardiovascular risk factors and comorbidities such as diabetes, hypertension and obstructive sleep apnoea (OSA) [20].

• Smoking is a super-trait to target with smoking cessation since it can influence lung function decline, exacerbation risk, ICS treatment responsiveness, mucus hypersecretion and recurrent infective bronchitis.

Clinical evidence and treatable traits

There is firm evidence that treating each individual treatable trait (pulmonary (table 1), extrapulmonary (table 2) and behaviour/risk factor (table 3)) is clinically relevant, as described in guidelines and detailed reviews [21, 22]. For instance, individual traits have been associated with severe asthma exacerbations [23], impaired quality of life [24] and lung function decline in COPD [21, 25]. There is also evidence supporting treatable traits as a model of care. Clinical trials in both severe asthma and COPD have tested a model of care that used multidimensional assessment with TIMs to detect the traits, and then applied targeted pharmacological and non-pharmacological therapy to treat the evident traits, with implementation of the treatment via a multidisciplinary team supported by a nursing case manager. These trials resulted in significant improvements in health-related quality of life and biological outcomes in both conditions [26, 27]. A systematic review and meta-analysis assessed the benefits of treatable traits interventions that comprised multidimensional assessment and targeting of at least one trait within each of the pulmonary, extrapulmonary and behavioural/risk factor domains. The review demonstrated that treatable trait interventions improve health-related quality of life (mean difference −6.96, 95% CI −9.92– −4.01), dyspnoea, anxiety and depression. Sensitivity analysis also shows reduced hospitalisations (OR 0.52, 95% CI 0.39–0.69) and reduced all-cause mortality (OR 0.65, 95% CI 0.45–0.95) [28]. The studies in this review evaluated models of treatable traits that target multiple traits. Other studies have also demonstrated superiority when targeting one or two traits. Targeting the trait of eosinophilic inflammation measured by induced sputum or F_ENO has demonstrated superiority in exacerbation reduction over symptom-based management in both asthma [29, 30] and COPD populations [31]. Collectively, these studies support the treatable traits approach, by demonstrating a range of improved outcomes following identification of a trait and management with a targeted therapy.

TABLE 1.

List of potential treatable traits within the pulmonary domain to consider in patients with chronic airway disease

Trait	Trait identification marker/diagnostic criteria	Possible treatments	Evidence#
Airway smooth muscle contraction	Bronchodilator reversibility, peak expiratory flow variability, airway hyperresponsiveness	Bronchodilators: maintenance (LABA/LAMA)/rescue (SABA/SAMA/rapid-acting LABA), bronchial thermoplasty, trigger avoidance (e.g. NSAID)	I
Systemic allergic inflammation	Elevated serum IgE	Allergen avoidance, immunotherapy, anti-IgE monoclonal antibody therapy	I
Dyspnoea	Dyspnoea score ≥2, modified Medical Research Council scale	Pulmonary rehabilitation, breathing retraining	I
Emphysema (loss of elastic recoil)	Chest CT, plethysmography, lung compliance	Smoking cessation, lung volume reduction surgery, lung transplantation, α1-antitrypsin replacement if deficient	I
Airway inflammation (eosinophilic)	Sputum eosinophils ≥3% and/or FENO ≥30 ppb and/or blood eosinophils ≥0.3×109 L−1	Corticosteroids, anti-IL-5, -13, -4 monoclonal antibody therapy, trigger avoidance (e.g. NSAID)	I–II
Pulmonary hypertension	Doppler echocardiography, brain natriuretic peptide, right heart catheterisation	Oxygen therapy, pulmonary vasodilator therapy, lung transplant	I–II
Bronchiectasis	High-resolution chest CT	Physiotherapy, mucociliary clearance techniques, macrolides, pulmonary rehabilitation, vaccination	I–II¶
Bacterial colonisation	Presence of a recognised bacterial pathogen in sputum (sputum culture, quantitative PCR)	Antibiotics and tailored antibiotic written action plan for infections	II
Airway inflammation (neutrophilic)	Sputum neutrophils ≥61%	Macrolides, tetracyclines, roflumilast	II
Cough reflex hypersensitivity	Capsaicin challenge, cough counts, cough questionnaire	Speech pathology intervention, gabapentin	II
Mucus hypersecretion	Volume ≥25 mL of mucus produced daily for the past week in the absence of an infection	Mucociliary clearance techniques with a physiotherapist, inhaled hypertonic saline, macrolides	II
Hypoxaemia	PaO2 ≤55 mmHg; PaO2 56–59 mmHg and evidence of complications of hypoxaemia, e.g. pulmonary hypertension, polycythaemia, right-sided heart failure	Domiciliary oxygen therapy	II

LABA: long-acting β₂-agonist; LAMA: long-acting muscarinic antagonist; SABA: short-acting β₂-agonist; SAMA: short-acting muscarinic antagonist; NSAID: non-steroidal anti-inflammatory drug; CT: computed tomography; F_ENO: exhaled nitric oxide fraction; IL: interleukin; P_aO2: partial pressure of oxygen. ^#: National Health and Medical Research Council level of evidence currently available for the management/treatment of each trait; ^¶: evidence from the general population.

TABLE 2.

List of potential treatable traits within the extrapulmonary domain to consider in patients with chronic airway disease

Trait	Trait identification marker/diagnostic criteria	Possible treatments	Evidence¶
Depression	Questionnaires (e.g. HADS Depression domain score ≥8), psychologist/liaison psychiatrist assessment	CBT, pharmacotherapy	I
Anxiety	Questionnaires (e.g. HADS Anxiety domain score ≥8), psychologist/liaison psychiatrist assessment	Pharmacotherapy (i.e. anxiolytics/antidepressants), breathing retraining, CBT	I
Dysfunctional breathing	Nijmegen Questionnaire Total score ≥23, B-PAT score >4, breath holding time, MARM	Breathing retraining	I
Physical inactivity and sedentary behaviour	Actigraphy, International Physical Activity Questionnaire	Pulmonary rehabilitation, physical activity, breaking bouts of sedentary activity	I
Overweight/obesity	Overweight: BMI 25–29.9 kg·m−2; obesity: BMI ≥30 kg·m−2	Caloric restriction, exercise, bariatric surgery, pharmacotherapy	I–II
Deconditioning	Cardiopulmonary exercise testing, 6MWT	Structured exercise programme, rehabilitation	I+, II
Rhinosinusitis	History and examination, imaging (sinus CT), SNOT-22	Topical corticosteroids, leukotriene receptor antagonists, antihistamines, surgery, intranasal saline lavage	II
VCD/ILO	Questionnaires (e.g. Pittsburgh VCD Index ≥4), laryngoscopy, dynamic neck CT, inspiratory flow–volume curve	Speech pathology intervention, laryngeal botulinum toxin, gabapentin/pregabalin, psychology/psychiatry	II
Systemic inflammation	Leukocyte count >9×109 L−1 or hsCRP >3 mg·L−1	Statins#	II
Anaemia	Hb: males <140 g·L−1, females <120 g·L−1	Haematinic (iron/B12) supplementation	I+, IV
Cardiovascular disease	Doppler echocardiography, ECG, brain natriuretic peptide	Pharmacotherapy (β-blockers, diuretics, angiotensin-converting enzyme inhibitors), surgery	II
Gastro-oesophageal reflux disease	Questionnaires, gastrointestinal endoscopy, pH monitoring	Anti-reflux lifestyle measures, antacids, proton pump inhibitors, fundoplication surgery	II
Obstructive sleep apnoea	Questionnaires (i.e. STOP-Bang Questionnaire), polysomnography	CPAP, mandibular advancement splint, positional therapy, weight loss	III-2

HADS: Hospital Anxiety and Depression Scale; CBT: cognitive behavioural therapy; B-PAT: Breathing Pattern Assessment Tool; MARM: Manual Assessment of Respiratory Motion; BMI: body mass index; 6MWT: 6-min walk test; CT: computed tomography; SNOT: Sino-Nasal Outcome Test; VCD: vocal cord dysfunction; ILO: inducible laryngeal obstruction; hsCRP: high-sensitivity C-reactive protein; Hb: haemoglobin; CPAP: continuous positive airway pressure. ^#: currently research only; ^¶: National Health and Medical Research Council level of evidence currently available for the management/treatment of each trait. ⁺: evidence from the general population.

TABLE 3.

List of potential treatable traits within the behaviour/risk factor domain to consider in patients with chronic airway disease

Trait	Trait identification marker/diagnostic criteria	Possible treatments	Evidence#
Suboptimal inhaler technique	Direct observation and standardised assessment checklists, assessment via chipped inhalers	Education including demonstration, observations and regular reassessment	I
Suboptimal adherence	Prescription refill rates, self-reported use of <80% of prescribed medication, chipped inhalers, FENO suppression test, measurement of drug concentrations	Self-management support, education, simplification of medication regimen (i.e. reduce number of medications, frequency of doses and number of devices)	I
Smoking	Self-reported current smoking, elevated exhaled carbon monoxide, urinary cotinine	Smoking cessation counselling ± pharmacotherapy	I
Side-effects of treatments	Patient report, monitored withdrawal	Optimisation of treatment, alternative therapy, change device	I
Absence of a written action plan	Patient does not possess a written action plan, or reports not using the prescribed plan during exacerbations	Individualised self-management education with a written action plan	I
Exercise intolerance	<350 m on 6MWT	Pulmonary rehabilitation	I
Decreased bone mineral density (osteoporosis)	T-score ≤ −2.5	Pharmacotherapy based on osteoporosis guidelines, vitamin D supplementation, resistance training	I¶, II
Sarcopenia	Appendicular skeletal muscle mass index: males <7.26 kg·m−2, females <5.45 kg·m−2	Diet (high protein), resistance training	I¶, II

F_ENO: exhaled nitric oxide fraction; 6MWT: 6-min walk test. ^#: National Health and Medical Research Council level of evidence currently available for the management/treatment of each trait; ^¶: evidence from the general population.

We propose that we are ready to implement the treatable traits model of care, and rather than conducting large-scale efficacy randomised controlled trials we ought to focus on real-world implementation. This aligns with the current status for the implementation of guideline-based management in asthma that uses National Health and Medical Research Council (NHMRC) Level I evidence to recommend treatments in a stepped care model. At no stage has the stepped care model of management for asthma been evaluated in a randomised controlled trial, but there is nonetheless confidence for the implementation of this approach because the specific treatments are supported by high-level evidence. Similarly, the treatable traits approach offers evidence-based treatment recommendations that can be implemented via this model of care. Tables 1–3 give examples of the traits, their treatments and the associated NHMRC evidence level. There remain traits that are not yet treatable or modifiable and where further efficacy research is necessary to advance treatment, and this is discussed in the “Future directions” section. Examples of these traits include neutrophilic inflammation and systemic inflammation.

Diagnosis and treatable traits

The treatable traits model of care is well suited to the complexities of clinical practice. Asthma and COPD are common diseases and frequently overlap, meaning that a patient may have features of both conditions. Guidelines have had difficulty in successfully advising on the best approach in this situation. Asthma and COPD guidelines are separate, and each promote a different stepped care approach to treatment. There is also a movement toward more personalised guideline-based approaches, such as recommended for severe asthma and in the Global Initiative for Chronic Obstructive Lung Disease COPD guidelines [32, 33]. These issues need to be reconciled with the need for both patients and clinicians to have a handy short-hand label to use when communicating about their condition(s). This label, or disease diagnosis, ideally can be selected so that it aids communication and does not cause confusion, as in the case of diagnosis overlap. Treatable traits aids this by using the dominant traits in the diagnostic label. Examples include using a compound diagnostic label, such as “severe eosinophilic asthma”, “COPD with T2 inflammation” or “non-eosinophilic asthma” [34]. Treatable traits also offers a management solution to these clinical conundrums by identifying the traits that exist in each patient irrespective of diagnosis, and personalising treatments accordingly.

A recent compelling example of this situation relates to BDR. The measurement of a significant improvement in lung function after inhalation of fast-acting bronchodilators has been accepted as a defining characteristic and diagnostic criterion for asthma, and is often used as a requirement to enter patients into key clinical trials that evaluate the efficacy of new asthma drugs. The value of this test has recently been questioned [35]. In the study by Beasley et al. [35], the authors examined 3519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma and COPD (asthma–COPD overlap), and 2436 with a diagnosis of COPD. BDR was assessed using both traditional and newly recommended European Respiratory Society/American Thoracic Society criteria. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma+COPD) and 24.7% (COPD) using the 2005 criteria and 18.1%, 23.3% and 18.0%, respectively, using the 2021 criteria. These data show the very limited diagnostic utility of BDR for asthma. Most patients with asthma (82%) did not exhibit the disease-defining characteristic of BDR. Almost one in five patients with a competing diagnosis of COPD had BDR. If a clinician were to use this test to direct therapy, it would result in significant management problems. However, treatable traits offers a solution to this conundrum, and identifies a place for what is considered an important test. BDR is seen as a TIM for BDR airflow limitation (table 1), and is associated with the degree of airflow limitation and symptom burden, irrespective of diagnosis. The authors appropriately recommend that BDR be used as a TIM (or theranostic) for the treatable trait of chronic airway disease, and when identified, treatment with long-acting bronchodilators be applied.

Trait profiles in different settings

Severe and difficult-to-treat asthma

Patients with severe asthma have a high disease burden. When assessed by multidimensional assessment, they are found to have a mean±sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary traits, 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors [27]. This contrasts to mild-to-moderate asthma where there is a median of 4.6 traits per person with asthma [36].

The NOVELTY study showed that there was little variation in traits by geography, but large variation exists between mild and more severe asthma, and between primary care and specialist care settings. The number of traits was significantly less in primary care settings and in mild asthma [36]. These observations justify the need for severe asthma clinics to be set up that can address and treat many different traits [37, 38]. Such an approach significantly improves patient outcomes [27, 39].

Primary care

The implementation of treatable traits has been predominantly done in specialist centres, and questions have been raised about the applicability of treatable traits in primary care. This is a crucially important question because most patients with asthma have mild-to-moderate disease and are cared for in primary care. The practice model for primary care aligns well with treatable traits, because both approaches favour person-centred holistic care [40]. In addition, many aspects of the treatable traits approach could be rapidly implemented in primary care. For example, blood eosinophil counts, as a biomarker of the treatable trait of eosinophilia, are already included in routine haematology tests and could be used in primary care to guide titration of ICS [41]. A recent national study by Konradsen et al. [42] in Sweden involving 17 318 patients assessed treatable traits in primary care patients with asthma. There was a high prevalence of uncontrolled asthma, and in these patients, several of the super-traits described earlier were commonly present. Smoking, obesity, depression/anxiety and cardiovascular disease were associated with future exacerbation risk, and were potentially treatable. The authors advocated for assessing and treating these super-traits in a primary care setting. We recommend the identification of the super-traits as a feasible way to implement treatable traits in primary care. Each of the super-traits (figure 1) is appropriate to target in a primary care setting, and if there is incomplete response, then this can be used to trigger a referral for further care.

Older people

Treatable traits is of relevance in older populations, where multiple comorbidities dominate the clinical presentation [43, 44]. In a survey of treatable traits in older people with asthma, a total of 38 traits were assessed and the older population with asthma, when compared to a younger group, was found to have more chronic metabolic diseases, fixed airflow limitation, emphysema and neutrophilic inflammation. In contrast, in younger adults with asthma there were more allergic and psychiatric diseases. Future exacerbation risk was increased in older people with traits of exacerbation prone, upper respiratory infection-induced asthma attack, cardiovascular disease, diabetes and depression [45].

Specific traits

Some specific traits require careful assessment because of their impact on management. These include chronic cough, vocal cord dysfunction (VCD)/inducible laryngeal obstruction (ILO) and dysfunctional breathing/breathing pattern disorder. Older patients who have chronic cough as a trait have an increased exacerbation frequency [46, 47]. Cough hypersensitivity presents with features of laryngeal paraesthesia, allotussia and hypertussia due to sensory nerve excitability of upper airway vagal sensory nerves. The treatment of this trait in adults with asthma and cough hypersensitivity involves speech and language therapy and neuromodulators (e.g. gabapentin) [8]. In asthma, cough is also associated with the traits of bronchoconstriction and T2 inflammation, and responds to treatment of these traits with ICS and long-acting β-adrenoceptor agonist therapy, noting that ICS must be added to long-acting β₂-agonist therapy in asthma to avoid adverse effects. The relevant TIMs (table 1) can be used to identify which traits are contributing to chronic cough in asthma.

Dysfunctional breathing is a common trait in asthma [48, 49]. A cross-sectional survey of 157 patients with difficult-to-treat asthma found that 73 (47%) had dysfunctional breathing. There was greater disease impact in asthma with dysfunctional breathing, with patients experiencing poorer asthma symptom control, quality of life and increased exacerbation rates, as well as more unemployment. Dysfunctional breathing was associated with sino-nasal symptoms, anxiety, depression, sleep apnoea and gastro-oesophageal reflux [48].

VCD/ILO is a form of laryngeal dysfunction that commonly coexists with asthma [49, 50]. It can also masquerade as asthma [51]. In a systematic review, the pooled prevalence of laryngeal dysfunction in adults with asthma was 25% (95% CI 15–37%) [52]. Studies that used optimal diagnostic methods found a higher prevalence of VCD/ILO. When these conditions were identified by laryngoscopy utilising an external trigger such as exercise the prevalence increased to 38%, and when a computed tomography-based diagnostic protocol was used the prevalence was 36% [52].

These conditions can coexist and form a distinct cluster in difficult-to-treat asthma which comprises a dominance of comorbidities including obesity, VCD and dysfunctional breathing [53].

Treatable traits and key asthma issues

There are several hot topics of current importance in asthma, including single-inhaler combination therapy (SICT), asthma remission, biological therapy, T2-low asthma, T2-high asthma, OCS stewardship and excessive symptom burden. It is useful to look at how the treatable traits model of care can impact and be integrated with these issues.

Treatable traits and SICT

A major change to inhaled asthma therapy has been the use of combination inhalers, where a single inhaler contains a β₂-agonist and an ICS, or the addition of a long-acting muscarinic antagonist as a third agent. SICT targets two traits simultaneously, i.e. the trait of T2 inflammation with ICS and the trait of airflow limitation with long-acting bronchodilators (table 1). These are dominant and prevalent airway traits, and are considered “super-traits” (figure 1), making SICT an effective and pragmatic approach.

Symptom assessment is recommended for the initiation, selection and dose adjustment of single-inhaler therapy. This assumes that symptoms are concordant with the traits being targeted, which may not always be the case. Although SICT has not directly been compared with treatable traits, it has received widespread support in guidelines. It is recognised that this approach may not fully achieve treatment goals. This is especially the case in patients whose symptoms and airway inflammation are discordant. Persisting with a symptom-based dose escalation ladder can be harmful and lead to extrapulmonary treatable traits being overlooked [41, 42]. In this situation it is recommended that a treatable traits approach be adopted. The rationale for this approach is described in detail by Shaw et al. [54]. Initial therapy is commenced using a combination inhaler, and when the treatment decision needs to be reviewed because of incomplete response or adverse effects, a new combined approach is recommended, in which treatment decisions are driven by objective assessment of key treatable traits.

T2-high asthma

There has been great success in targeting the airway trait of T2 inflammation with ICS, biological therapy and allergen avoidance. Applying a treatable traits model of care has allowed regulatory approval and implementation of T2-directed biological therapy in severe asthma. With this approach, a person with severe asthma is assessed using T2 TIMs, such as blood eosinophil counts, F_ENO and blood IgE levels [55]. The appropriate targeted biological therapy is then prescribed with anticipated outcomes of reduced asthma attacks, reduced OCS requirements and improved health status.

T2-low asthma

While many people with asthma have T2 disease, it is recognised that at least 30% do not exhibit this airway trait. This endotype is termed T2-low asthma. It is important to consider treatment options in T2-low asthma [56, 57]. Patients with T2-low asthma who undergo a treatable traits assessment are identified to be heterogeneous and have a variety of airway traits, such as neutrophilic inflammation, bacterial bronchitis and impaired mucociliary clearance/mucus hypersecretion (table 1). In addition, they may also have predominant behavioural/risk factor traits that are driving their disease, such as smoking, occupational exposure, depression and high BMI (table 3) [58]. It is also recognised that long-standing asthma can lead to fixed airway obstruction and COPD [59, 60].

It is possible that other biological pathways may be active in T2-low asthma, such as tumour necrosis factor, interleukin (IL)-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells.

Treatment at present is directed at those traits which are identified. Long-term azithromycin has been shown to be effective for T2-low asthma [61], as well as asthma with impaired mucociliary clearance and recurrent bacterial bronchitis (table 1). Future work is needed to address other important aspects of asthma, such as remodelling, irreversible airflow limitation and poor symptom perception.

OCS stewardship

OCS remain the cornerstone of management for acute attacks of asthma, and for some people with severe asthma maintenance OCS continue to be used. Data published from the Australasian Severe Asthma Web-Based Database in 2019 indicated that 25% of people with severe asthma were OCS dependent at a median dose of 10 mg [23]. These prevalence data of OCS use are similar to those reported in the UK and the USA [62], and longitudinal studies of OCS use demonstrate an ongoing need to address OCS use in airway diseases [63].

While OCS are a lifesaving treatment for acute asthma they also cause significant serious adverse consequences. Cumulative lifetime doses as low as 500 mg of prednisolone are associated with comorbidities, with additional risk occurring in those exposed to ≥1000 mg. These risks include osteoporosis/fracture (hazard ratio 3.11), pneumonia (hazard ratio 2.68), cardio/cerebrovascular disease (hazard ratio 1.53), cataracts (hazard ratio 1.50), sleep apnoea (hazard ratio 1.40) and renal impairment (hazard ratio 1.36) [64].

Moreover, there is evidence of overuse in mild-to-moderate asthma. We analysed a 10% sample of the Australian Pharmaceutical Benefits Scheme dispensing data from 2014 to 2018 and assessed the proportion of people dispensed OCS for asthma, and the proportion who were dispensed a cumulative dose ≥1000 mg prednisolone-equivalent within 5 years. Over 50% were prescribed OCS in the study period, and more than a quarter (28%) were dispensed a cumulative dose ≥1000 mg prednisolone-equivalent. Of those dispensed ≥1000 mg prednisolone-equivalent during 2018, 4633 people with asthma also using high-dose ICS were dispensed ≥1000 mg prednisolone-equivalent; however, 50% of patients had poor adherence with treatment, based on evidence of infrequent dispensing of preventer medications [65].

Given the overuse of OCS in primary care and in mild-to-moderate asthma [65], minimising OCS exposure is an important therapeutic goal in asthma, and OCS stewardship initiatives have emerged to address this [66, 67]. A further concern is the overuse of OCS to erroneously treat symptoms that mimic asthma, e.g. VCD, dysfunctional breathing, anxiety and depression [67, 68]. The treatable traits approach can address this.

Data from the Australian Mepolizumab Registry demonstrated effective ways of reducing OCS in severe asthma, using treatable traits methods. Anti-IL-5 monoclonal antibody therapy in people with severe eosinophilic asthma significantly reduced OCS use. At baseline, 48% of patients were using maintenance OCS, 96% had ≥1 OCS burst and 68% had received ≥1000 mg OCS in the previous year. After commencing anti-IL-5 monoclonal antibody treatment, almost half ceased maintenance OCS at 12 months, and maintenance OCS dose reduced from a median (interquartile range) of 10 (5.0–12.5) mg·day⁻¹ at baseline to 2 (0–7.0) mg·day⁻¹ at 12 months (p<0.001) [69]. Longitudinal studies also demonstrate a reduction in OCS use after the introduction of biologics [63]. Denton et al. [39] also demonstrated that a systematic assessment of asthma in a specialist severe asthma clinic, which is part of the treatable traits intervention, can lead to a 50% reduction in OCS use. These data demonstrate that in severe disease, it is possible to reduce the OCS burden using a treatable traits approach.

Excessive symptom burden

Similarly, the treatable traits approach addresses another area of immense importance to patients, i.e. the burden of symptoms. While novel monoclonal antibody biological treatments have had life-changing impacts on people with severe asthma [69, 70], the symptom burden experienced by patients with asthma persists, and in fact has even worsened over recent decades. Two global surveys conducted prior to and after monoclonal antibody implementation (2005 and 2016) revealed people with severe asthma still have poor quality of life and experience symptoms that impact their daily lives [71]. The detrimental impact of symptoms on social, occupational and educational activities has increased over this time, with 89% of people with severe asthma now reporting disruption to daily life activities [71]. With only ∼50% of people with severe asthma being eligible for monoclonal antibodies, and of those, only 15–37% of those treated achieving symptom remission [72, 73], approaches that address the residual symptom burden need to be prioritised. Treatable traits enables the identification of symptom traits and offers personalised interventions beyond standard asthma pharmacotherapy to target these traits [3, 16, 17, 21, 74, 75].

These symptom burden impacts do not only relate to people with severe asthma. A qualitative study involving people with mild-to-moderate asthma and those with severe disease reported that the most burdensome symptoms of breathlessness and cough were evident in both groups [76]. Furthermore, in a study that rated the most important outcomes people with asthma want to achieve, the top five responses were wanting to improve quality of life, have fewer attacks, use less OCS, and experience less breathlessness and more physical activity [77]. These patient priorities highlight the importance of traits beyond those in the pulmonary domain [78].

Using a treatable traits approach, symptoms can be minimised by targeting the residual traits once asthma pharmacotherapy is optimised (tables 2 and 3).

Asthma remission

Clinical remission on treatment has emerged as a significant outcome for ∼25% of patients with severe T2 eosinophilic asthma treated with biological therapy [70, 72]. Remission can also be observed with other treatment modalities; however, a key question is what can be done for patients who do not achieve remission? In this case certain treatable traits can be identified that suggest a treatment approach for patients not in remission, and raise the possibility that treatable traits may be a path to remission in asthma. For example, asthma remission with T2 biologics was less likely when patients had coexisting treatable traits in the extrapulmonary domain, such as obesity, depression and osteoporosis. These are non-T2 comorbidities that require additional management [72]. Remission requires the absence or minimisation of symptoms. It can be hard to disentangle the symptoms caused by airflow limitation from those caused by other comorbid conditions, such as VCD, and this may lead to inappropriate asthma assessment or symptom misattribution. A treatable traits assessment will identify these other conditions, and identify and treat symptom misattribution, potentially leading to a more accurate assessment of remission.

Although asthma is a pulmonary condition, the extrapulmonary and behavioural/risk factor treatable traits are highly relevant in patients with asthma since they impact current health status and future outcomes (tables 2 and 3) [78–81]. This has been demonstrated in a study of 434 people with severe asthma and 102 people with non-severe asthma [23]. Traits were characterised using data collected in a severe asthma real-world evidence registry and predictors of future asthma attacks were determined from a 2-year longitudinal assessment. There were 10 traits that predicted future asthma attacks, and among these seven were extrapulmonary traits; in order of the greatest risk these were depression, VCD, OSA, systemic inflammation, anxiety, upper airway disease and being underweight [23]. Extrapulmonary traits in severe asthma can therefore predict patients at risk of future asthma exacerbations and, importantly, this may be modifiable by targeted treatment [27]. These data highlight the importance of identifying and targeting extrapulmonary traits in conjunction with pulmonary and behavioural/lifestyle treatable traits and offer a path to remission in asthma [82].

Novel concepts for the application of treatable traits

It has been suggested that early and effective treatment of T2 inflammation in mild-to-moderate asthma might yield long-term benefits before permanent damage to the airway from exacerbations and airway inflammation occurs [83]. This concept is supported by studies of lung function trajectory [60], and is analogous with other inflammatory and autoimmune diseases including rheumatoid arthritis and inflammatory bowel disease. In these diseases the early introduction of biologics has successfully modified the disease leading to remission. While currently there are no data supporting this approach in asthma, this may be an innovative strategy to limit the irreversible airway remodelling associated with severe asthma [83]. Furthermore, early treatment could provide a preventive solution to reduce the large social and economic impacts of severe asthma [83]. Other inflammatory conditions use a so-called proactive “treat to target” strategy, whereby disease activity is frequently and systematically assessed using a validated measure, which is then compared with a prespecified treatment target (consistent with the treatable traits approach) [84]. If the target is not reached within a particular time frame, treatment is intensified accordingly [84].

In asthma, particularly in severe disease, there are consequences of not effectivity treating the dominant traits of airway inflammation and airflow limitation. Perhaps most obviously those consequences relate to poorly controlled or poorly managed dominant traits leading to acute attacks, airway remodelling and frequent use of OCS [67, 83]. This begins a “chaotic trait cascade” of pulmonary traits, and extrapulmonary traits, and behavioural/risk factors (figure 2).

Often by the time a patient is referred to a severe asthma clinic they will have a mean of 10 treatable traits [27], despite optimal pharmacotherapy. From the patient perspective they lose “all facets of their life” [85]. Common traits include depression, anxiety, obesity, sleep disturbance, physical inactivity, VCD/ILO, social isolation, osteoporosis and cardiovascular disease [23, 27, 86]. Many of these traits may be a direct result of poorly controlled severe asthma (the “chaotic trait cascade”). By now patients feel overwhelmed by their disease, its impacts and its treatments [85–87]. If an early intervention “treat to target treatable traits” approach were to be implemented many of the traits within this cascade, that potentially develop as a result of poor asthma control, toxic OCS doses and frequent asthma attacks, could be possibly prevented.

This cascade also highlights common issues in the management of asthma that can be addressed using a treatable traits approach. Some common traits, such as VCD/ILO, dysfunctional breathing, anxiety and breathlessness, cause symptoms that mimic asthma, or are misattributed to be asthma symptoms. These prevalent asthma treatable traits interact with each other, increasing the symptom burden and often leading to erroneous treatments, e.g. the excessive use of OCS to treat VCD symptoms misattributed as asthma [68]. Treatable traits can manage this symptom misattribution and offer trait-specific treatments. This reduces the symptom burden and reduces toxicity from inappropriate overtreatment with corticosteroids.

Furthermore, traits such as dysfunctional breathing, anxiety, dyspnoea and obesity frequently co-occur in people with severe asthma, and lead to poorer outcomes [53, 78, 88]. Physical inactivity in asthma clusters together with anxiety, depression and obesity, and the clustering of these traits results in poorer asthma outcomes [80, 89, 90].

Useful concepts that can be applied in the treatment of this “chaotic trait cascade” are the concepts of “connected comorbidities” and the theory of “marginal gains” [78]. Connected comorbidities in asthma describes conditions that: 1) commonly coexist with asthma, 2) have a clinical impact on asthma itself and 3) share pathophysiological mechanisms with asthma. Importantly, when a connected comorbidity is effectively treated this will lead to improvements in asthma outcomes as well as the comorbidity-related outcomes [78].

This is also where the theory of marginal gains applies to the treatable traits concept. Marginal gains states small incremental improvements in any process amount to a significant improvement when they are all added together [91]. For example, improvements in adherence behaviours lead to less airflow limitation, less airway inflammation, fewer acute attacks, less OCS requirements, more activity and better overall health status.

Implementation of treatable traits

The implementation of treatable traits in clinical practice requires a process that will depend on the setting in which clinicians are working. Implementation approaches for treatable traits have been reviewed [15, 17, 18, 37]. In a specialist severe clinic there is Level I evidence to support an approach that is multidisciplinary and supported by case management [27]. This involves multidimensional assessment of individuals, an multidisciplinary case management meeting, development of a personalised care plan, shared decision making with the patient and implementation of the plan by the multidisciplinary team with the case manager as a care navigator (figure 3) [15]. The plan not only includes the written articulation of the traits and the targeted treatment for each trait, but it also includes important aspects of shared decision making and patient–clinician partnership. The traits are ranked in terms of importance by both the patient and the clinician [92, 93]. Where discordance exists, this invites discussion with the patient for the team to understand the traits that matter most to the patient, and the patient to understand what the physician sees as most important and why. With this discussion the team and the patient can aim to reach concordance in terms of the traits to target first and the rationale for this. Another important inclusion in this plan is the articulation of what the patient will get out of each treatment intervention from the perspective of what matters to them. For example, by engaging in a home exercise programme they will improve their exercise capacity and thereby increase their participation in the activities they enjoy.

FIGURE 3.

A schema for the process of implementing a treatable traits approach using a case manager in a tertiary care clinic.

These aspects of delivery for treatable traits interventions are important in terms of improving patient engagement in complex interventions, demystifying the complexity and ensuring the delivery of a personalised person-centred care model, which is inherent to the treatable traits model of care [15]. While this approach is best suited for tertiary care, similar models that involve the general practitioner and a practice or community nurse could be implemented in primary care [94]. The optimal treatable traits model for use in primary care needs further study. We have evolved the super-traits concept as a way to prioritise which traits to target, and it is likely this will be applicable in primary care.

Future directions

The treatable traits approach has been successful in asthma and COPD, and is now being applied in other conditions.

• Bronchiectasis. Airway infection, inflammation and mucociliary clearance dysfunction are key treatable traits in bronchiectasis. Applying the treatable traits concept to bronchiectasis complements the traditional approach that focuses on aetiology, and allows for a comprehensive management plan to be developed [17, 95–97].

• Interstitial lung disease. A framework is proposed for treatable traits in interstitial lung diseases that identifies aetiological, pulmonary, extrapulmonary and behavioural/lifestyle treatable traits which are relevant to clinical care and patient outcomes [6].

• Acute respiratory distress syndrome (ARDS). ARDS is a serious condition causing respiratory failure. It is heterogeneous with pathophysiological features differing between patients. This has allowed recognition of several subphenotypes of ARDS based on radiographic patterns, protein biomarkers, transcriptomics and/or different methods of clustering clinical and biological variables. This treatable traits approach is being tested in the management of ARDS [98–100].

• Sleep disordered breathing (SDB). Studies have recognised the limitations of current approaches to SDB, due to the complexity of the condition and the heterogeneity of mechanisms causing SDB. This has led to calls for a treatable traits approach to be developed for SDB. This approach was tested in a small trial where additional targeted therapies were used based on assessment of the underlying endotype [101]. OSA was controlled in 95% of participants with this approach.

• Long COVID. The treatable traits approach has also been proposed as a way to address the management of long COVID. In a structured analysis of 22 systematic reviews, Lewthwaite et al. [7] identified 34 symptoms and complications that were common in long COVID. These could be grouped into eight long COVID treatable trait clusters: neurological, chest, psychological, pain, fatigue, sleep impairment, functional impairment and other issues. The evidence base for treatment is at present limited; however, these clusters provide a structure for clinicians to analyse the many different aspects of persistent symptoms after coronavirus 2019 disease.

• Chronic cough. Chronic cough is a common and disabling problem. The treatable traits approach can be applied to manage chronic cough. Key traits include cough hypersensitivity, cough with T2 inflammation and bronchoconstriction, as well as relevant comorbidities such as gastro-oesophageal reflux and sino-nasal disease [47].

• Chronic sinusitis with nasal polyposis. Chronic sinusitis with nasal polyposis is a heterogeneous condition of the upper airway. Several authors have proposed a treatable traits approach to address the complexity and heterogeneity of this problem [9, 37, 102–104].

Treatable traits could also be used to direct future research. It is likely that improved phenotyping of patients would identify new mechanisms and direct trials of treatments for airways disease, and then establish new endotypes of airway disease. This approach is being tested in the Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) study in the USA [105] where patients with severe asthma will receive one of several treatments that is targeted to a predefined subgroup using biomarkers. The adaptive design allows assessment of multiple interventions, where the specific intervention is mapped to a specific patient phenotype.

Conclusions

Treatable traits is a simple and effective model of care that can be used to deliver personalised asthma management. This approach effectively addresses the inherent complexity and heterogeneity of asthma, aspects which have confounded clinicians and patients alike for many years. The approach can be adapted for different settings and resource availability, leading to a flexible treatment programme. Several tools have been developed to aid in the delivery of this model of care. Treatable traits acknowledges the clearly articulated request from patients for individualised and effective asthma care.

Shareable PDF

This PDF extract can be shared freely online.

Shareable PDF ERJ-00861-2024.Shareable ^{(324.3KB, pdf)}