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 (FENO) 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; FENO: 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 FENO 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

TraitTrait identification marker/diagnostic criteriaPossible treatmentsEvidence#Airway smooth muscle contractionBronchodilator reversibility, peak expiratory flow variability, airway hyperresponsivenessBronchodilators: maintenance (LABA/LAMA)/rescue (SABA/SAMA/rapid-acting LABA), bronchial thermoplasty, trigger avoidance (e.g. NSAID)ISystemic allergic inflammationElevated serum IgEAllergen avoidance, immunotherapy, anti-IgE monoclonal antibody therapyIDyspnoeaDyspnoea score ≥2, modified Medical Research Council scalePulmonary rehabilitation, breathing retrainingIEmphysema (loss of elastic recoil)Chest CT, plethysmography, lung complianceSmoking cessation, lung volume reduction surgery, lung transplantation, α1-antitrypsin replacement if deficientIAirway inflammation (eosinophilic)Sputum eosinophils ≥3% and/or FENO ≥30 ppb and/or blood eosinophils ≥0.3×109 L−1Corticosteroids, anti-IL-5, -13, -4 monoclonal antibody therapy, trigger avoidance (e.g. NSAID)I–IIPulmonary hypertensionDoppler echocardiography, brain natriuretic peptide, right heart catheterisationOxygen therapy, pulmonary vasodilator therapy, lung transplantI–IIBronchiectasisHigh-resolution chest CTPhysiotherapy, mucociliary clearance techniques, macrolides, pulmonary rehabilitation, vaccinationI–II¶Bacterial colonisationPresence of a recognised bacterial pathogen in sputum (sputum culture, quantitative PCR)Antibiotics and tailored antibiotic written action plan for infectionsIIAirway inflammation (neutrophilic)Sputum neutrophils ≥61%Macrolides, tetracyclines, roflumilastIICough reflex hypersensitivityCapsaicin challenge, cough counts, cough questionnaireSpeech pathology intervention, gabapentinIIMucus hypersecretionVolume ≥25 mL of mucus produced daily for the past week in the absence of an infectionMucociliary clearance techniques with a physiotherapist, inhaled hypertonic saline, macrolidesIIHypoxaemiaPaO2 ≤55 mmHg; PaO2 56–59 mmHg and evidence of complications of hypoxaemia, e.g. pulmonary hypertension, polycythaemia, right-sided heart failureDomiciliary oxygen therapyII

TABLE 2

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

TraitTrait identification marker/diagnostic criteriaPossible treatmentsEvidence¶DepressionQuestionnaires (e.g. HADS Depression domain score ≥8), psychologist/liaison psychiatrist assessmentCBT, pharmacotherapyIAnxietyQuestionnaires (e.g. HADS Anxiety domain score ≥8), psychologist/liaison psychiatrist assessmentPharmacotherapy (i.e. anxiolytics/antidepressants), breathing retraining, CBTIDysfunctional breathingNijmegen Questionnaire Total score ≥23, B-PAT score >4, breath holding time, MARMBreathing retrainingIPhysical inactivity and sedentary behaviourActigraphy, International Physical Activity QuestionnairePulmonary rehabilitation, physical activity, breaking bouts of sedentary activityIOverweight/obesityOverweight: BMI 25–29.9 kg·m−2; obesity: BMI ≥30 kg·m−2Caloric restriction, exercise, bariatric surgery, pharmacotherapyI–IIDeconditioningCardiopulmonary exercise testing, 6MWTStructured exercise programme, rehabilitationI+, IIRhinosinusitisHistory and examination, imaging (sinus CT), SNOT-22Topical corticosteroids, leukotriene receptor antagonists, antihistamines, surgery, intranasal saline lavageIIVCD/ILOQuestionnaires (e.g. Pittsburgh VCD Index ≥4), laryngoscopy, dynamic neck CT, inspiratory flow–volume curveSpeech pathology intervention, laryngeal botulinum toxin, gabapentin/pregabalin, psychology/psychiatryIISystemic inflammationLeukocyte count >9×109 L−1 or hsCRP >3 mg·L−1Statins#IIAnaemiaHb: males <140 g·L−1, females <120 g·L−1Haematinic (iron/B12) supplementationI+, IVCardiovascular diseaseDoppler echocardiography, ECG, brain natriuretic peptidePharmacotherapy (β-blockers, diuretics, angiotensin-converting enzyme inhibitors), surgeryIIGastro-oesophageal reflux diseaseQuestionnaires, gastrointestinal endoscopy, pH monitoringAnti-reflux lifestyle measures, antacids, proton pump inhibitors, fundoplication surgeryIIObstructive sleep apnoeaQuestionnaires (i.e. STOP-Bang Questionnaire), polysomnographyCPAP, mandibular advancement splint, positional therapy, weight lossIII-2

TABLE 3

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

TraitTrait identification marker/diagnostic criteriaPossible treatmentsEvidence#Suboptimal inhaler techniqueDirect observation and standardised assessment checklists, assessment via chipped inhalersEducation including demonstration, observations and regular reassessmentISuboptimal adherencePrescription refill rates, self-reported use of <80% of prescribed medication, chipped inhalers, FENO suppression test, measurement of drug concentrationsSelf-management support, education, simplification of medication regimen (i.e. reduce number of medications, frequency of doses and number of devices)ISmokingSelf-reported current smoking, elevated exhaled carbon monoxide, urinary cotinineSmoking cessation counselling ± pharmacotherapyISide-effects of treatmentsPatient report, monitored withdrawalOptimisation of treatment, alternative therapy, change deviceIAbsence of a written action planPatient does not possess a written action plan, or reports not using the prescribed plan during exacerbationsIndividualised self-management education with a written action planIExercise intolerance<350 m on 6MWTPulmonary rehabilitationIDecreased bone mineral density (osteoporosis)T-score ≤ −2.5Pharmacotherapy based on osteoporosis guidelines, vitamin D supplementation, resistance trainingI¶, IISarcopeniaAppendicular skeletal muscle mass index: males <7.26 kg·m−2, females <5.45 kg·m−2Diet (high protein), resistance trainingI¶, II

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 settingsSevere 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, FENO 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