Treatable traits, combination inhaler therapy and the future of asthma management

The landscape of asthma has considerably changed in the last decade. Effective medications and inhaler devices have been developed and integrated into the asthma pharmacopoeia, but unfortunately, the proportion of uncontrolled patients remains unacceptably high. This is now recognized to be mainly due to the inappropriate use of medications or inhaler devices, heterogeneity of the disease or other factors contributing to the disease. Currently, inhaled corticosteroids (ICS), with or without long‐acting beta agonists (LABA), are the cornerstone of asthma management, and recently international guidelines recognized the importance of combination inhaler therapy (ICS/LABA) even in mild asthma. In future, ultra‐long‐acting personalized medications and smart inhalers will complement combination inhaler therapy in order to effectively addresses issues such as adherence, inhaler technique and polypharmacy (both of drugs and devices). Asthma is now acknowledged as a multifaceted cluster of disorders and the treatment model has evolved from one‐size‐fits‐all to precision medicine approaches such as treatable traits (TTs, defined as measurable and treatable clinically important factors) which encourages the quality use of medications and identification and management of all underlying behavioural and biological treatable risk factors. TT requires research and validation in a clinical context and the implementation strategies and efficacy in various settings (primary/secondary/tertiary care, low‐middle income countries) and populations (mild/moderate/severe asthma) are currently evolving. Combination inhaler therapy and the TTs approach are complementary treatment approaches. This review examines the current status of personalized medicine and combination inhaler therapy, and describes futuristic views for these two strategies.


INTRODUCTION
Asthma affects over 300 million people globally and asthma medications range from bronchodilators to anti-inflammatorycorticosteroids and add-on biologics therapies. 1,2 Currently, inhaled corticosteroids (ICS) with long-acting selective β2-adrenoreceptor agonists (LABA) are the cornerstone of asthma management. They attenuate asthma symptoms and the underlying inflammation that drives the symptoms. 2 Despite the proven efficacy and safety of several inhaled ICS-LABA fixeddose combinations, many patients with asthma are not well controlled and remain at risk of exacerbations. The Global Burden of Disease Study estimated that globally, approximately 400,000 lives were lost due to asthma in 2015. 3 Targeted biologic therapies have improved asthma outcomes, but they are currently cost prohibitive for widespread use and hence restricted as an add-on therapy for severe uncontrolled asthma (a condition that affects only 3%-10% of people with asthma) in high-income countries. As a result, fixed-dose combination inhalers are the drug of choice for >90% of people with asthma and the research suggests that the efficacy of these medications is curtailed due to several factors such as poor adherence, inhaler polypharmacy and inadequate inhaler techniques leading to poor asthma control. [4][5][6] Asthma is a multifaceted cluster of disorders, and this heterogeneity is now being recognized as another reason for the failure of current asthma management strategies. 7,8 Successively, the management strategies have advanced from 'one size fits all' to personalized tailored therapies considering various inherent factors of patients such as phenotypes, endotypes, comorbidities, habitual-dissimilarities, genotypes and ethnotypes. 9 The concept of treatable traits is an emerging area which addresses the clinically important measurable and treatable inherent factors of patients, and ensures the right treatment for the right patient at the right time, 10 raising the hope for asthma remission as a therapeutic goal. 11 The therapeutic armamentarium for clinicians currently includes an encouraging array of treatments such as inhaled short-acting beta 2-agonists (SABA), ICS, LABA, long-acting muscarinic antagonists (LAMA), oral leukotriene receptor antagonists (LTRA) therapies and add-on therapies (e.g., biologics). Vigilant use of these medications is important to maximize the efficacy and minimize iatrogenic side effects. The treatable traits model of care enables clinicians to promote the quality use of medicines and tackle other patient-specific factors that contribute to the disease condition.
Visualizing the future of asthma management is fascinating, and this review focuses on the treatable traits approach, and combination inhaler therapy, including the application of treatable traits approach to tackle the issues related to combination therapy (e.g., adherence, inhaler polypharmacy/device technique). In this review, we will discuss the definition, current scenario, anticipated future developments, future applications and future research of treatable traits and combination inhaler therapies.

Treatable traits
Management approaches that address the heterogeneity of asthma in the real world and incorporate advances in knowledge are urgently needed. In order to improve patient outcomes, asthma requires individualized approaches to assessment and management. This aligns with recent calls for new personalized approaches to the assessment and management of asthma and airway disease, with 'Treatable Traits' proposed as a useful concept to implement precision or personalized medicine. The 2017 Lancet Commission on asthma specifically recommends 'A revolution in thinking about asthma, delivering precision medicine (i.e., treatable traits)'. 12 The treatable traits approach is a model of care that has been designed to address the limitations of the step-care approach to the management of obstructive airway diseases. [13][14][15] The key elements of a treatable traits strategy include the identification of traits that are clinically important, identifiable and treatable. Inherent to the approach is a multidimensional assessment to identify traits followed by individualized treatments implemented to target each trait. This article considers how treatable traits can develop to improve the future of asthma management.
What is a treatable traits approach?
Personalized and precision medicine are new treatment approaches that can address the complexity and heterogeneity of chronic disease. The future of asthma management will see the increasing use of these approaches in asthma management.
Asthma is complex, meaning that it has several different components or pathogenic pathways that can contribute to the illness. Furthermore, not all pathways operate in all people at the same time, meaning that there is heterogeneity in the manifestations of asthma. On the one hand, this complexity and heterogeneity contribute to difficult-to-manage asthma, yet it also provides opportunities for personalized management strategies that can improve patients outcomes in asthma. The future for asthma management is to realize these opportunities. Systematic and multidimensional assessment was developed to address the complexity and heterogeneity in asthma, starting initially in severe asthma and asthma in older adults, where comorbidity and overlap with chronic obstructive pulmonary disease (COPD) are particular issues. 7,16,17 The strategy has since been developed to include the identification and treatment of so-called 'Treatable Traits', and many papers that describe the concepts and potential application of treatable traits have been published, including systematic reviews and two proofof-concept clinical trials: one in severe asthma and another in COPD. 18,19 Collectively, this body of evidence supports the treatable traits strategy for the management of patients with chronic airway diseases.

What is a treatable trait?
An identifiable feature that can be assessed and targeted by treatment to improve a clinical outcome is called a treatable trait. 20 Three characteristics are present in each treatable trait 10,21,22 : (1) clinical significance (i.e., the trait is associated with a clinical outcome, for example, asthma exacerbation, quality of life [QoL] or asthma control); (2) detectable (i.e., measurable via specific and validated 'trait identification markers [TIM]', e.g., the trait of T2 inflammation is assessed by the TIM of circulating eosinophils); and, (3) treatable (an effective treatment is available).
Eosinophilic/T2 airway inflammation is an excellent example of a treatable trait in asthma. This endotype is mediated by specific cytokines such as interleukin (IL)-5. 23 The levels of eosinophilic inflammation are directly proportional to exacerbation risk indicating its clinical relevance. Moreover, it can be detected via blood eosinophil count (a TIM) and can be treated via corticosteroids (inhaled or oral) or T2-targeted biologics. Hence, eosinophilic airway inflammation meets all the criteria for a treatable trait (i.e., relevant, detectable and treatable).

The future of treatable traits
Treatable traits approach has already been described for use in tertiary care settings. The future development of treatable traits will identify how to adapt treatable traits to different settings, such as primary care; establish the key traits that need to be addressed, so-called 'super-traits'; determine how to prioritize traits; identify what are the core outcomes to assess to determine the efficacy of treatable traits interventions; determine how to engage patients in a treatable traits approach; and how to implement a treatable traits approach, for example, the composition of the multidisciplinary team (MDT).
The adaptation of a treatable traits model of care to different settings will be essential. The treatable traits approach has been described in severe asthma management in a tertiary care setting, and shown to be highly effective. 18 However, asthma is highly prevalent in primary care, being one of the most common reasons for seeing a general practitioner. It is necessary to adapt treatable traits to the very different practice parameters in primary care. Asthma in pregnancy is a life event that leads to poor asthma control in one-third of women, 24 increases the risk of attacks [25][26][27][28] and leads to adverse foetal outcomes. [25][26][27][28] This is another opportunity to implement treatable traits. Similarly, the practice model and the effectiveness of the treatable traits approach in low-and middle-income countries requires more research. 29 Each of these areas has different needs and requires a treatable traits strategy that addresses the specific priorities of each situation. In addition, there are opportunities to define new treatable traits, such as physical inactivity, vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) and excessive use of oral corticosteroid (OCS). In this area, combination inhaler therapy offers a particular opportunity, since it is an example of a single treatment modality that can effectively target multiple treatable traits.
With these developments in mind, it is useful to define the goals for treatable traits over the next 5 years. These are summarized in Table 1. Placing greater emphasis on traits over diagnostic labels is an important shift. The diagnostic label will be seen as the start of the assessment process, not the completion. For example, assessment will not only identify the presence of asthma, but also describe key traits, such as eosinophilic asthma, exacerbation-prone, or inadequate management skills. This is an example of a compound description that identifies several treatable traits that are relevant for that individual patient and where each has specific treatment implications. To achieve this shift, it will be necessary to adequately assess the patient before implementing treatment (i.e., test before treatment).
A further goal is to see asthma exacerbations as sentinel events that trigger a review of a patient's condition and identify what traits can be targeted to prevent future events. This would mean that after an exacerbation, a treatable traits assessment is performed that would review traits, including: comorbidities, smoking, adherence, inhaler technique, environmental and psychosocial factors; and would then adjust management strategies to address patient-specific traits (e.g., ICS, smoking cessation, pulmonary rehabilitation). Since these are significant practice changes, a goal for the next 5 years is to generate evidence of the effectiveness of this model of care across different settings.

Combination inhaler therapy: Targeting two key traits-Airway obstruction and eosinophilic airway inflammation
The application of combination therapy is a unique case for the future of treatable traits, since it can treat multiple traits simultaneously, such as T2 inflammation (by ICS), airflow obstruction (by LABA/LAMA) and inhaler device polypharmacy (by a single inhaler device) ( Figure 1). Future developments could add to this list by targeting adherence and poor inhaler device technique through the use of improved inhaler devices with monitoring and feedback capabilities, and strategies to manage exacerbations.

What are inhalers?
Aerosol medications have a rich history of more than 3500 years. However, the first modern pressurized metered dose inhaler (pMDI) was introduced in 1956. 30 pMDIs are pressurized canisters of medicine in a plastic holder with a mouthpiece T A B L E 1 Goals for treatable traits over 5 years.

Goals Features
Move from diagnostic labels to traits Simple diagnostic labels will evolve to compound descriptions that identify key traits.
Test before Treating Clinicians will be performing a multidimensional assessment before initiating treatment to determine which traits are present and use this to guide treatment.
Zero tolerance for attacks Acute attacks/exacerbations of airways disease will be seen as sentinel events that prompt a change in management. After a sentinel event, a treatable traits approach may recommend to: that deliver a reliable, consistent dose of medication when activated. Another form of inhaler is a breath-actuated (i.e., the medicine is released to the airways when taking a deep, fast breath from the inhaler) dry powder inhaler (DPI).

Inhaled asthma medications
SABAs have been used as inhaled bronchodilators since the 1970s. There are over 30 inhalers now approved for use in asthma, commonly referred to as controllers/preventers (used to reduce airway inflammation, control asthma symptoms and reduce the risk of exacerbations) and relievers (providing rapid relief from asthma symptoms). 31 Currently, combination inhaler therapy (largely ICS/LABA combination) is the cornerstone of asthma management. 2 Recent evidence suggests that ICS/LABA combination is also beneficial in mild asthma, and the present GINA guidelines recommend ICS/LABA fixed-dose combination as first-line therapy for mild asthma. ICS-formoterol combination is a fast-onset long-acting combination suitable for both as needed reliever and maintenance therapy. 31,32 GINA recommends a stepped increase of ICS dose for people with uncontrolled or persistent asthma. That is, for people with persistent, moderate to severe asthma, medium-or high-dose ICS and LABA combinations (dual therapy) are currently recommended. When patients' symptoms remain uncontrolled despite dual therapy, adding a LAMA (i.e., ICS, LABA and LAMA, also described as triple therapy) is recommended. 2,33 A 2021 systematic review which included 11,894 children and adults with moderate to severe asthma from 20 randomized controlled trials (RCTs) compared triple therapy versus dual therapy, and the former was significantly associated with fewer asthma exacerbations and improvement in asthma control. 34 Recently, a few triple therapy formulations in a single-inhaler device, single inhaler triple therapy (SITT), have been approved (e.g., Trimbow ® by Chiesi, Enerzair ® by Novartis, Breeztri ® by AstraZeneca and Trelegy ® by GSK) for patients with uncontrolled asthma despite dual therapy. Enerzair ® and Trelegy ® are once daily inhalers. 33,34 Challenges of inhaled asthma medications Challenges of inhaled medications include treatable traits such as poor adherence, inhaler polypharmacy and inadequate inhaler technology. Fixed-dose inhalers have the advantage of minimizing inhaler device polypharmacy and subsequently improving adherence ( Figure 1). The use of inhaler devices can be challenging for many patients and may lead to critical handling errors, and that may significantly affect the delivery of drugs into the lungs, thus increasing the risk of potential adverse effects. 4,5 Inadequate inhaler technique is a treatable trait which needs to be assessed during the multidimensional assessment of treatable traits and addressed during the treatment if present.

Anticipated future developments
There will be a surge in the use of combination inhaler therapies (ICS/LABA), especially due to the increased use for mild asthma. With growing evidence, the use of triple therapy (ICS/LABA/LAMA) also will rise. Unfortunately, some people will remain uncontrolled after trialling dual/triple inhaler therapies. This could be due to other traits causing symptoms, incorrect diagnosis, inadequate dose, disease progression, patient-related factors such as adherence or ineffective inhaler technique, or a combination of these factors. Use of the treatable traits approach and new technology may improve some of these factors which may subsequently improve the percentage of patients achieving asthma control.

Ultra-long-acting medications
Once daily administration of medications generally leads to increased convenience for patients, better adherence and overall improvement of clinical outcomes compared to multiple administrations per day. A few once-daily LABAs (e.g., abediterol, indacaterol, olodaterol and vilanterol) and combinations (dual and triple therapy) are currently available. It is also important to have a rapid onset of action if these medications are also to be used as relievers. We anticipate that more once daily medications/combinations with rapid onset of action will be available in future and the cost will be substantially reduced as more options are accessible.

Smart inhalers
The efficacy and feasibility data of smart inhalers to improve adherence and inhaler techniques are currently evolving. 35 F I G U R E 1 Combination inhaler therapy targets multiple treatable traits.
The recently approved Enerzair SITT included an optional electronic sensor which could be paired to a smartphone app. Both the sensor and app send medication reminders to patients. The sensor of the SITT will be activated by inhalation, which will transmit the date and time of the inhalation to the app and the healthcare providers' app, and the data will be recorded and stored. This data could be used to further monitor patients' adherence in relation to clinical response.
With advances in smart inhaler sensors and platforms, greater support from payers, healthcare organizations and clinicians, and a growing body of supporting evidence, substantial growth in this smart sector is expected. The future inhaler devices will be distinguished by their digital/smart features (e.g., the capability to send medication reminders, record adherence, assist inhaler technique, document patient-reported outcomes and user-friendliness for both patient and healthcare provider).

Future research: Tailoring treatment beyond treatable traits
Asthma therapies target various biologic pathways consisting of multiple candidate genes with variations that may alter the therapeutic response. For example, polymorphisms of target receptors and/or drug-metabolizing enzymes. [36][37][38][39][40] Genome-wide association studies (GWAS) may further improve the understanding of the variability of response to medications in different patients, but they are still far from being used in clinical practice in respiratory medicine. In the era of precision medicine, addressing the genetic factors that influence the therapeutic response to medication is essential, and further research in this area is warranted. 41 Ideal combination therapy inhaler for the future Imagining a single smart inhaler containing all the required medications for the patient with once daily dosing and rapid onset of action, prescribed after multidimensional treatable traits assessments to maximize the efficacy and safety (i.e., tailored to patient-specific characteristics), and promoting adherence, adequate inhaler technique and monitoring via smart technology is fascinating. Modern smart inhalers incorporating these features are currently emerging (e.g., Enerzair SITT), and implementing the treatable traits approach will further enhance its effectiveness. We anticipate that future inhalers will start incorporating the features described above.

Key data supporting treatable traits
A number of studies support treatable traits in asthma and provide direction for future research. The NOVELTY study provided data on trait prevalence, and variation by diagnosis (asthma, COPD, Asthma-COPD overlap syndrome [ACOS]), setting (primary/specialist care) and country. 42 These are useful data that allow for trait prioritization by these variables. The efficacy of treatable traits in severe asthma was examined by McDonald et al. in an RCT, in a tertiary care setting and using a nurse case manager to implement the strategy. 18 The NOVELTY study recruited 11,226 patients with asthma, COPD and ACOS from primary care clinics and specialized referral hospitals in 19 countries around the world, and evaluated the prevalence of 30 treatable traits. This study showed that while there is wide variation in the prevalence of individual traits within patients, there were no large global geographical variations. NOVELTY confirmed that patients have more than one treatable trait present at any one time. The mean treatable traits prevalence was: 4.6 (asthma), 5.4 (COPD) and 6.4 (ACOS) per person. 42 This compares with severe asthma where there is an average of 10 traits per person.
The study also gave insights into future treatable traits implementation for primary care. The prevalence of treatable traits was generally lower in primary care than in specialized clinics. There were also several traits that tended to occur together. In asthma, the traits most frequently paired included rhinosinusitis, respiratory and non-respiratory allergies, T2-high markers, obesity, occupational exposures, indoor use of biomass/coal and frequent reliever use. These data can be used to develop a prioritization of which treatable traits to target when implementing treatable traits in different settings and patient groups.
Traditionally the pulmonary domain has been the main focus of asthma treatment because the treatment targets of airway inflammation and airflow obstruction are the accepted key elements of asthma. Treatable traits approach provides an expanded, multidimensional view of asthma that includes traits in other domains, such as extrapulmonary traits (e.g., obesity, cardiac history, VCD/ILO) and risk factors and behavioural traits (e.g., smoking, poor adherence). These additional domains are given equal importance in the treatable traits model of care. When deciding to use this approach, it is necessary to understand the likely benefits of treatment. This was established by McDonald et al. in a study of treatable traits in severe asthma. Participants (n = 140) with severe asthma underwent a multidimensional assessment to characterize treatable traits. The study found a mean ± SD of 10.44 ± 3.03 traits/person, comprising 3.01 ± 1.54 pulmonary, 4.85 ± 1.86 extrapulmonary and 2.58 ± 1.31 behavioural traits. These traits were clinically relevant, since the total number of traits correlated significantly with health status when assessed by the St George Respiratory Questionnaire (r = 0.61, p < 0.001). A subgroup of participants (n = 55) were then enrolled into a 16-week parallel-group RCT to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patientreported outcome of health-related Quality of Life (HRQoL; measured by the Asthma QoL Questionnaire [AQLQ]) was the primary end-point.
The intervention group received treatment for a mean ± SD of 8.36 ± 1.92 traits, which occurred during 5.32 ± 2.53 treatment visits over the 16-week trial. Each treatable trait received a specific intervention. For example, eosinophilic inflammation (sputum eosinophils ≥3%), high dose ICS (fluticasone 500 μg twice/day) plus systemic corticosteroids (prednisone 12.5 mg/day) were used, with treatment adjusted by re-assessments of sputum cell counts. For neutrophilic inflammation (sputum neutrophils ≥61%), azithromycin 250 mg daily for 16 weeks was used. Finally, systemic inflammation was identified by measures of high-sensitivity C-reactive protein (≥3 mg/L) and treated with rosuvastatin (20 mg/day for 16 weeks).
The study established that individualized treatment targeting established traits was feasible and led to significantly improved HRQoL (0.86 units, p < 0.001), asthma control (0.73, p = 0.01) and reduced primary care visits (Figure 2).
A nurse case manager coordinated various treatments and the tasks performed include summarizing the traits identified, coordinating the case discussion with the MDT, assessing the importance of each trait from the perspective of both the physician and patient, providing education on the traits and their individual treatments, and coordinating the various visits between the MDT. Busse likened the role of the case-manager to the 'conductor of the treatable trait symphony'. 43 This study provides a roadmap for implementing treatable traits in severe asthma and indicates the likely benefits of the approach. It can serve as a basis for planning the future of treatable traits interventions in asthma.

Future of treatable traits in severe asthma
Future research will explore treatable traits approaches tailored to different settings, targeting a reduced number of traits, and the place of novel treatments or traits. Current approaches to achieve asthma control in severe disease have largely focused on the pulmonary domain. In the treatable traits RCT of McDonald et al., one of the most significant areas in which benefit occurred was improved airflow limitation. Optimal bronchodilator therapy involves LABA/ LAMA, and this can be delivered by combination inhaler therapy. Delivering this intervention represents an area of future improvement in asthma management. Similarly, biologic therapy represents an area for future development. Biologic therapy that targets T2 inflammation is highly effective in severe T2 asthma. 44 As a single therapy, this represents an example of successful treatable trait-based approach. Future work will define how to embed this approach with other treatable traits.
Down titration of medications also might be possible when a treatable traits approach has identified factors contributing to symptoms, management is initiated, and better control is achieved.
Another question is whether this approach could be more tailored to reduce the overall effort but yet capture the desired optimal control. For example, it would be helpful to know whether treatment of particular domains or specific traits provides the greatest benefit and could thus serve as principal priorities: is it pulmonary, extrapulmonary, or behavioural/risk domain?
A novel analysis by Hiles et al., combined the data of the two treatable traits RCTs of McDonald et al. and performed Bayesian Modelling Averaging regression to identify which traits were associated with baseline HRQoL, and which treatments of those traits resulted in the largest improvement in HRQoL. The treatments that lead to the greatest changes were receiving a statin for systemic inflammation and OCS for eosinophilic airway inflammation. Treatments for exercise intolerance, anxiety and obesity were associated with F I G U R E 2 Efficacy of TT in severe asthma: Improvement in QoL after usual care versus personalized intervention in severe asthma. Content has been reproduced with permission from the Centre of Excellence in Treatable Traits, originally developed as part of the Centre of Excellence in Treatable Traits (https://treatabletraits.org.au). improvements in HRQoL but with a smaller effect size. 45 While this analysis included only a small sample, it demonstrates methods for future research to determine priority targets.

Trait prioritization and super-traits
The demands and resource limitations in clinical practice mean that it is necessary to prioritize certain treatable traits for assessment and management. This prioritization can be done based on several different parameters, including outcomes, prevalence, treatability and setting ( Table 2).
Treatable traits can be prioritized into those that relate to specific outcomes, such as disease exacerbations or frequent OCS use. Using this approach focuses on high-burden outcomes and reduces the number of traits to 10 that are associated with future exacerbation risk in severe asthma. 46 These traits respond to a combination of specific pharmacotherapy and behavioural interventions.
Issues related to prevalence of treatable traits can also be used to prioritize traits. To start by targeting the most prevalent trait may be adequate in some health-care settings. For instance, a tertiary care setting offering a severe asthma service might choose to assess many traits and offer therapy, recognizing the high disease burden of their patient group. In primary care, and in low-middle income countries, a more focused approach is required, based on available resources, including time. This allows a minimum number of traits to be identified. A review of this strategy has suggested that the core traits to target may be: T2 inflammation, airflow limitation, smoking, inhaler device technique/ adherence and some key comorbidities/risk-factors, such as high BMI.
An emerging concept is that of super-traits. These are traits that are essential to identify and treat in order to effectively manage other traits, or traits that have such a large positive treatment effect that management is crucial, or traits that once identified and treated lead to improvement on other apparently unrelated traits. Examples of supertraits with each of these characteristics are: • Adherence/Inhaler device technique: this trait describes key asthma self-management skills that are essential for the pharmacological and behavioural treatment of many other traits. For example, adequate inhaler device technique is essential for successful therapy of the traits of T2 high eosinophilic inflammation (with ICS), and airflow limitation (with inhaled long-acting bronchodilators). Adherence underpins successful pharmacotherapy of all traits. Similarly, adherence is essential to the behavioural change required to improve traits such as obesity, physical inactivity or smoking. • T2 inflammation: the effect size of treating T2 inflammation with ICS (in mild-moderate asthma) or targeted biologics (in severe eosinophilic asthma) is large with number needed-to-treat (NNT) of 2-3 for ICS 47 and an average 50% reduction in severe exacerbations with biologics indicating T2 inflammation may be a super-trait in asthma. • High BMI/obesity: targeting this trait with a 5%-10% weight loss leads to improvement in other traits, such as dyspnoea, cardiovascular risk factors and comorbidities such as diabetes, hypertension and obstructive sleep apnoea. [48][49][50] • Smoking may also be a super-trait to target with smoking cessation since it will influence lung function decline, exacerbation risk, ICS treatment responsiveness, mucus hypersecretion and recurrent infective bronchitis.

Setting
The management strategies and priorities that are needed to effectively implement a treatable traits intervention are likely to be different for each health care setting. With knowledge of the different issues surrounding trait prioritization and each health care setting, it is possible to propose a future implementation model that considers these factors. This is described in Figure 3, where super-traits are targeted and treated in primary care. This then facilitates recognition of characteristics that can be used to trigger early referral to specialist care, if the patient remains with persistent symptoms despite treating super-traits. In this way, the treatable traits model avoids recurring cycles of treatment escalation that can occur in step-based care pathways, and prevents protracted referral to tertiary care. In the tertiary setting, a multidimensional assessment can be used to identify more extensive traits to target.

Connected comorbidities
Comorbidity is a key part of treatable traits, and is increasingly recognized as a complication of disease as people age.
In treatable traits, it is recognized that certain comorbidities are connected and can have wide-ranging impacts. Addressing these may lead to significant improvements in health outcomes. These are termed connected comorbidities. A connected comorbidity refers to a trait that once identified and treated, outcomes beyond the immediate trait itself are improved. There are many examples of connected comorbidities in airway disease. For example, obesity is a treatable trait recognized by an elevated BMI as a TIM and treated by T A B L E 2 Future trait prioritization strategies.

Strategies to prioritize treatable traits for intervention
• Trait prevalence • Trait impact and risk • Treatability • Connected comorbidity • Patient and clinician priority • Treatable traits approach for harm minimisation weight reduction measures. This leads to improved asthma control. 50,51 However studies of weight loss in airway disease identify other important benefits including reduced blood pressure, improved lipid markers and improved depression scores. 48,52 The future of treatable traits can be to identify connected comorbidities and use these to plan a treatable traits intervention.

Treatable traits implementation
Perhaps the most challenging part of the treatable traits approach is implementation. Not because of the complexity of the intervention but the behaviour and system change needed. Overcoming this obstacle is however achievable if we identify the barriers and facilitator to successful implementation. Some of this work has already been undertaken. In qualitative studies, patients are reporting the importance of personalized treatment, objective testing and whether their treatments are right for them as individuals. 53 Additionally, carers of people with severe asthma also highlight the need for personalized approaches. 54 While treatable traits approach is proposed as the future for asthma management, patients cannot afford to wait the estimated 17 years that is required for new knowledge to translate to practice. 55 A qualitative study by Majellano et al., sought to understand the barriers to the implementation of personalized medicine strategies for the management of severe asthma among 40 health care professionals from multidisciplinary backgrounds. From the perspective of these clinicians, personalized care in severe asthma was both desirable and challenging but the barriers for implementation were multilevel spanning patient-, system-and provider-related factors. 56 These are presented in Figure 4.
This study is important as it is a guide for implementation. From the clinicians' perspective, support and education about treatable traits approach is necessary. This can be achieved through the development of digital education platforms, like the Severe Asthma Toolkit 57 (https://toolkit. severeasthma.org.au), smart phone applications and digital control panels that can be used at the point-of-care. 13 Strategies to support individual patients and the MDT are also needed. In tertiary care, this can be achieved by case manager. 18 The role of the case manager in treatable traits studies has been described in an earlier section. This seems to be a critical role in ensuring the members of the team are communicating effectively with each other and the patient, in ensuring the priorities and goals of the patient are recognized and addressed, and in ensuring the patient is engaged, informed and an active participant in the treatment programme. Case managers are used routinely in other areas of chronic disease management and should be considered essential in the management of complex asthma. Recognition of the roles of the team members is also necessary. Some traits can be addressed by the physician, the nurse/case manager, physiotherapist, speech pathologist, psychologist or dietitian. Using this teambased approach can take the pressure off time-restricted consultations with the physician alone. 17,58,59 In a study by Majellano et al. 56 clinicians also perceived that patient knowledge was often poor and adherence was suboptimal, conversely in a study from McDonald et al. that sought to understand the patient experience of people with asthma and COPD, participants indicated that they wanted to know more about their disease and its management from their health care provider and that they frequently 'did not feel heard or recognised'. 53 If we are to effectively translate treatable traits to practice, we must address this discordance.
Addressing the health literacy of patients and clinicians about treatable traits approach is an important future goal for both research and practice, to ensure they understand the new approach, the terms used, and that they agree on the treatment programme. In another study involving patients with asthma and COPD, McDonald et al., sought to determine the concordance between patients and physicians in terms of the importance of traits that were identified through a multidimensional assessment. Not surprisingly there were important traits with poor agreement, including key super-traits of inhaler technique adequacy, airflow limitation and obesity. 60 Shared decision making (SDM) may help overcome these implementation issues. The SDM process involves patients and clinicians making decisions collaboratively, informed by the best available scientific evidence as well as considering patient's values and informed preferences. This approach has been shown to improve outcomes in asthma ( Figure 5). 61 Implementation will take a concerted effort on the part of health care providers and payers in order to structure a health care system that places that patient in the centre of the care. We have recommended a pathway to do this in order for treatable traits to become a standard model of care for people with asthma ( Figure 3).

New treatable traits
The initial list of treatable traits was developed by consensus and validated by subsequent data. 42 It is likely that there are other traits. Some examples are: physical inactivity, VCD/ILO, side effects of treatments and the social determinants of health.

Physical activity in severe asthma
In the general population, physical activity and sedentary behaviour are important modifiable risk factors that have a major impact on health and survival. 62 They are treatable and there are multiple health benefits of light-to-moderate physical activity, including a reduction in deaths. 62 Physical activity is measurable by questionnaire and objectively by activity monitors. In severe asthma, decreased physical activity is common and independently associated with HRQoL impairment. 63,64 In order to become a treatable trait, an effective intervention for physical inactivity in asthma is needed.
Consumers identify this as an urgent need. There is a negative impact of impaired participation in activity, 65 and patients with asthma rate physical activity as one of the most important outcomes they want to achieve following any asthma treatment. 66 Pilot data from a feasibility RCT of two physical activity interventions, comparing a mindfulness F I G U R E 4 Barriers to personalized severe asthma care from the health care system perspective. Content has been reproduced with permission from the Centre of Excellence in Treatable Traits, originally developed as part of the Centre of Excellence in Treatable Traits (https://treatabletraits.org.au). and yoga intervention to an activity intervention involving a Fitbit and motivational interviewing suggest that physical activity can be improved in severe asthma. 67 Vocal cord dysfunction VCD/ILO is a disorder of laryngeal function that mimics asthma but is not responsive to asthma therapy. It is frequently misdiagnosed as asthma, which leads to delayed VCD/ILO diagnosis, increased morbidity and excessive health care costs. 68 In a severe asthma registry, the clinicianreported prevalence of VCD/ILO was 6.7%, 46 but when objectively assessed using standardized criteria, the prevalence was as high as 36%. 69 Recognition of VCD/ILO as a specific trait is important, because it confounds assessment of asthma control 68 and is an independent risk factor for both severe asthma attacks and QoL impairment. 46,70 The standard of care for VCD/ILO is speech pathology intervention, but there is a limited evidence base from RCTs to support this. Funding for and access to assessment and efficacious treatments, such as speech pathology and laryngeal botulinum-toxin 71 is also limited. There is a clear need to better characterize the patient experience in VCD/ILO, standardize diagnosis, provide evidence of effective therapy, train clinicians in the recognition and management of VCD/ILO and develop and disseminate a model of care for patients with VCD/ILO.

Side-effects of treatment-OCS and antibiotic stewardship in asthma
In Australia, 25% of the adult severe asthma population are using maintenance OCS. 46 This is associated with increased risk of comorbidity and significantly higher health care costs from the treatments of these adverse effects. 72 Recent research indicates that the side effects associated with OCS begin at a cumulative lifetime dose of just 1 g (i.e., four short courses of OCS). 73 Minimizing unnecessary exposure to OCS is a major priority. 74 International guidelines now recommend oral azithromycin for management of some patients with asthma, 44,75 and long-term low-dose azithromycin reduced attacks in patients with moderate and severe asthma. 76 While effective, a major concern over long-term antibiotic therapy is the development of antimicrobial resistance. The British Thoracic Society has emphasized the need for further research on relative efficacy and safety of different macrolides and dosage regimens. 77 Future asthma management will balance the benefits and potential adverse effects of treatment.

Social determinants of health
The social determinants of health, including income, education, employment, security, working conditions, food security, housing, early childhood development, social inclusion, access to affordable healthcare and structural conflict (https://www. who.int/health-topics/social-determinants-of-health#tab=tab_ 1) are clinically important and identifiable, but as yet we cannot establish if they are treatable. So, they represent potential treatable traits.
In conclusion, the treatable traits approach is a fascinating treatment approach emerging in asthma medicine. Combination inhaler therapy will compliment this approach by tackling multiple super-traits. Together they have the potential to revolutionize future of asthma management.

CONFLICT OF INTEREST STATEMENT
Peter G. Gibson reports personal fees for lectures from AstraZeneca, GlaxoSmithKline and Novartis, grants from AstraZeneca and GlaxoSmithKline, outside the submitted work. Vanessa M. McDonald reports grants and F I G U R E 5 Shared decision-making and asthma outcomes. Content has been reproduced with permission from the Centre of Excellence in Treatable Traits, originally developed as part of the Centre of Excellence in Treatable Traits (https://treatabletraits. org.au). personal fees from GlaxoSmithKline, AstraZeneca and Menarini, outside the submitted work. Dennis Thomas has nothing to disclose. Vanessa M. McDonald is an Editorial Board member of Respirology and a co-author of this article and was excluded from all editorial decision-making related to the acceptance of this article for publication.