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

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


INTRODUCTION
In recent years, there has been growing interest in the treatable traits approach to the management of obstructive airways disease in adults.The treatable traits approach is based on the knowledge that obstructive airways disease is a heterogeneous group of conditions with different underlying mechanisms and clinical manifestations, and that identification and treatment of the specific clinical features or traits facilitates a personalized approach to management. 1,2Fundamentally, it recognizes two important concepts.Firstly, that treatment for obstructive lung disease can achieve better outcomes if guided by specific clinical characteristics.2][3][4][5] While these concepts are well accepted, the translation of the treatable traits approach to clinical practice has been limited by uncertainty as to how best to implement this system in primary and secondary care, recognising both the paucity of evidence on which to guide such multidimensional approaches, and the restrictions in resourcing within health systems.We will consider the implications of adopting a treatable traits approach in primary and secondary care.

PRIMARY CARE Traditional guideline management of airways disease in primary care
Asthma and COPD are very common chronic conditions in primary care, with other airways diseases such as bronchiectasis and cystic fibrosis less common but still encountered regularly.The diagnosis and management of airways diseases is a central part of general practice.As long term incurable conditions, asthma and COPD result in a major personal impact for sufferers, and a major workload and heath resource use in the community.In most health care systems, the initial presentation, diagnosis and the majority of routine and acute management is delivered by generalist primary health care teams in all but the most severe disease.This management has for many years been informed and driven by guidelines, including international 6,7 and national [8][9][10][11][12] asthma and COPD guidelines.Remarkable improvements in diagnosis, management and outcomes were driven by these guidelines and the resultant structured proactive care. 13espite increasing asthma global prevalence, 14 improvements included reduced hospitalization and mortality rates, and improved symptom control and quality of life.The diagnosis and management for most asthma patients became part of routine general practice, with specialist care reserved for those with severe, therapy resistant disease.In COPD, evidence from large randomized controlled trials demonstrated the effectiveness of pharmacological (including inhaled long acting bronchodilators and corticosteroids) and non-pharmacological (including smoking cessation, vaccination and pulmonary rehabilitation) interventions, and has mitigated against a former therapeutic nihilism.The importance of spirometry in the diagnosis and key treatment decisions was recognized, and the burden of underdiagnosis and misdiagnosis highlighted.In many primary care systems spirometry and structured proactive COPD care became standard, encouraging better diagnosis and management, again reflected in better outcomes.So a relevant question is why do we now see a need for new, more refined and targeted strategies, such as the 'treatable traits' approach?
Unfortunately, improvements in asthma mortality have stalled in most countries and COPD remains the third leading cause of death worldwide, causing 3.2 million deaths in 2019. 15,16With hindsight, it seems that a misplaced sense of complacency occurred.In the United Kingdom, confidential mortality enquiries have revealed potentially avoidable factors in the majority of asthma deaths, 17 with mortality and hospitalization rates stalling 18 and most patients still reporting significant and regular symptoms and quality of life impairment. 19Their consequent impaired ability to lead a full, productive life results in significant direct and indirect costs. 20This has occurred despite a continual stream of new licensed products, and ongoing attempts at improved training and motivation of primary healthcare teams.A considerable gap is apparent between the levels of possible control achieved in tightly structured clinical trial settings, and in the 'real world' of everyday primary care. 21

Reasons for lack of progress in the community management of airways disease
From the primary care clinician perspective, the current 'stepped' pharmacotherapy approach of guidelines may encourage the belief that 'stronger' medication is needed when control is found to be poor or when an exacerbation occurs.Although guidelines do include sections on the importance of behavioural factors (such as adherence and inhaler technique) and on the importance of co-morbidities in assessment and management, in practice it is the pharmacological management diagram that appears most vividly to the busy time-pressurized clinician, and is taped to the consulting room wall.It is often easier to reach for the prescription pad than to make a more detailed individualized assessment, and the 'bottom-line' presentation of traditional guidelines encourage this.Undoubtedly some patients have intrinsically more severe, therapy-resistant disease, requiring higher doses or new medication classes.However, even in this group, good quality holistic management (including self-management education and effective attention to behaviours and comorbidities) can often improve outcomes. 22irways diseases display both complexity (the presence of several components that interact with each-other, including genetic, physiological and behavioural factors) and heterogeneity (the variability of these factors and their interactions both between patients and within a single patient over time).Even in the milder cases that present in primary care, patients with airways disease display a variety of phenotypes (observable clinical characteristics) and endotypes (underlying pathways driving disease manifestation), 23 and two patients with apparently similar levels of control impairment may have very different underlying driving factors.The symptoms of airways disease are relatively few with wheezing, breathlessness, cough and chest tightness being prominent.However, these symptoms can result from a wide range of underlying processes, ranging from structural damage to inflammation to bronchoconstriction to psychological factors.5][26] Complexity and heterogeneity are likely to be as relevant and prominent in primary care as in in specialist clinics, although the manifestations and consequences generally less overt or dramatic.
There has been a growing disillusionment and 'fatigue' with guidelines in recent years. 27This is partly due to information overload-there are now innumerable guidelines, as well as clinician concerns of being audited negatively or being viewed as an outlier.Primary care clinicians may question guideline relevance to the patients they treat-the core recommendations are driven by large randomized controlled trials (often industry conducted) with atypical patient populations, typically excellent compliers, neither young nor old, without comorbidities, having good inhaler technique, regularly attending consultations and not smoking.This allows for potential confounders to be well controlled, but reduces the ability to extrapolate the findings to more typical patients.9][30] An increasing recognition of the need for more 'real-world' populations and settings, 31 has driven the appearance of more 'pragmatic' trials, 32 although these are not easy to design, are expensive to deliver and have so far had little impact on guideline recommendations.
However, even pragmatic trials will only ever inform on a 'group mean' rather than on an 'individual patient' frame of reference; they will tell which option is most likely to be successful for the 'average' patient rather than for an individual.In all trials there is heterogeneity of outcomes-some patients do better with one treatment and some with the comparator, 33 so although group mean data will give the best likelihood for a successful treatment option, an individual patient may be better served by the 'other' treatment option.Clinical markers for the differential response to treatments are important in individualising treatment, and extensive baseline characterization in these large trials that we invest so much effort into are vital to characterize 'responder' and 'non-responder' groups in sub-group analyses.An example of such an approach is in the detailed post-hoc analyses of COPD trial databases incorporating blood eosinophil levels, which have provided compelling evidence that biomarker evidence of eosinophilic airways inflammation is a good guide to inhaled corticosteroid (ICS) responsiveness. 34Similarly, in severe asthma, the initial rejection of mepolizumab as a treatment option based on unselected severe cases was overturned by subsequent evidence showing that when given to a targeted population with biomarker evidence of Th2 inflammation it was a highly effective intervention. 35atients also report a desire to be seen and treated as individuals, and may not be convinced by the recommended treatment, resulting in the non-adherence that remains an important cause of poor control in some patients. 36enerally, patients seem to like the underlying concepts driving personalized medicine approaches and the treatable traits approach.
Beyond the pharmacological key drivers of poor control in primary care airways disease A number of considerations beyond pharmacological treatment of airways disease are particularly relevant to the understanding of poor control and personalising management in primary care.These can be broadly divided into two categories: comorbidities and behaviours.

Comorbidities
With aging populations, more patients have multiple long term conditions. 37Some comorbidities may have a clinically relevant association with asthma and COPD, with shared symptoms and impacts on outcomes. 38Some comorbidities (e.g., ischaemic heart disease) may be associated with increased risk of death or severe exacerbations from airways disease, and other common comorbidities may produce symptoms that may be misattributed to airways disease (e.g., heart failure, dysfunctional breathing, upper airways disease and cough syndromes) or may affect symptom perception and behaviours (e.g., anxiety and/or depression).All of these comorbidities have effective treatments when recognized.
Of particular importance is psychological dysfunction, which is common in people with both asthma 39 and COPD, 40 often unreported and unrecognized, and associated with worse outcomes of many types. 41The underlying mechanisms are complex and may relate to a variety of overlapping biological and behavioural factors.Neuroimaging reveals that brain structures mediating breathlessness are closely related anatomically and functionally to those processing emotions, 42 and emotional state may influence immunological responses. 43Anxiety is associated with impaired self-management. 41Hyperventilation and dysfunctional breathing are associated with anxiety 44 and may trigger bronchoconstriction and respiratory symptoms, with simple breathing control exercises improving symptoms and quality of life in asthma. 45,46Breathing control exercises are helpful in both asthma and COPD and are part of pulmonary rehabilitation programmes.
While some anxiety is normal and inevitable with an unpleasant symptom such as dyspnoea, and can stimulate appropriate responses such as seeking help or using necessary medication, excessive anxiety can trigger inappropriate actions and can result in a 'negative feedback' situation of worsening symptoms leading to further emotional and cognitive distress.The recurrent and unpredictable experience of having breathlessness is frightening and disturbing, and can undermine wellbeing and stability.More vulnerable patients with other stressors, such as co-morbidity, psychosocial disadvantage or with genetic or environmentally driven lack of resilience, may be disproportionately affected by their condition, and cope poorly even with relatively mild disease.All clinicians recognize this variability, with some patients coping well with objectively severe disease, with others experiencing marked symptoms and poor outcomes despite apparently mild disease.Symptom and quality of life scores correlate poorly with objective physiological and inflammatory measures of disease control and both asthma and COPD, 24,26 although more strongly with psycho-social measures, multi-morbidities and psychological factors. 25oth pharmacological and non-pharmacological treatments are available for comorbid psychological dysfunction when recognized.Breathing control exercises have been shown to improve the quality of life in patients with asthma of all levels of severity who remain uncontrolled on standard treatments, [45][46][47] and simple on-line self-help programmes are clinically and cost effective, 48 yet are frequently not a part of usual clinical care.

Behaviours
Common reasons for poor control relate to inhaler use, either failure to take inhaled treatment as recommended, 49 or failure to use the device correctly. 50Although many clinicians find it mystifying and irritating that many of their patients do not use their medication as directed, 51 particularly ICS, in 'real-life', adherence problems are ubiquitous, with adherence rates reported to range from 30% to 70% in all age groups. 49he reasons for non-adherence are complicated, including 'non-intentional', driven by misunderstanding of instructions or forgetfulness, or 'intentional', a conscious decision not to use medication as prescribed, due to poor understanding of the rationale for use, doubt about the effectiveness or need for treatment, concern about side-effects and medication cost.From the patient perspective, these decisions may seem rational, and based on their (often ill-informed) assessment of benefits and risks.Over-estimation of ICS-related risks and lack of appreciation of the dangers of non-adherence seem common.The relatively slow onset of action of ICS may lead some to conclude that they are ineffective, particularly compared with the instantly perceptible effects of bronchodilators.
Non-adherence can be viewed (and is by many patients) as self-management, although when based on misunderstandings and inadequate information can be counter-productive and result in harm.As such, it is fundamentally driven by inadequate patient-clinician communication, and the failure to provide key information to the patient in an understandable and persuasive way to enable effective selfmanagement.Although some clinicians 'blame' patients for non-adherence and feel it is beyond their ability to influence, 50 there is good evidence that the behaviour can be improved by effective communication strategies, for example, through self-management education, 52 involving patients in decision making 53 simplified treatment regimens 54 and discussion of non-adherence when detected (e.g., through monitoring of refill prescription rates). 22nformation Technology systems may be used to support self-management and education. 55imilarly, good inhaler technique is required for effective medication delivery, yet surveys reveal that in 'real life', many patients use their inhaler badly, most will make some errors, and many make 'critical errors' that result in little or no medication delivery, 56 with a relationship reported between the number of errors and poor outcomes such as control and risk of exacerbations, and greater health economic burden. 57,58Inhalers differ in their cost, ease of use and in the ease of tuition, and sometimes the cheapest devices are hardest to use and teach. 59Education in inhaler technique by suitably qualified professionals when first prescribed plus periodic checks should ideally occur, but in 'real-life' often does not, with some patients only ever receiving instruction from printed packaging inserts, and some clinicians cannot demonstrate correct technique.Assessment of adherence and technique should always be part of an assessment of poor control in any clinical setting.
Smoking is a behaviour that sadly remains common in patients with airways disease.However, it should always be in the awareness of the primary care clinician, who is in an ideal position to monitor, to provide the impetus to cessation at the right moment and to support their patients quitting efforts in a variety of pharmacological and nonpharmacological ways.

Key treatable traits in primary care
Although the time available, training and access to investigations is more limited in primary than specialist care, the treatable traits approach remains viable, with key traits both possible to assess and to treat when identified.The treatable traits approach involves an assessment in three broad areas, discussed below: Pulmonary In primary care, the key pulmonary objective treatable traits assessments (in addition to physical examination) are lung function and airways inflammation.Basic lung function measurement should be possible in all primary care settings as peak expiratory flow, and in most by quality assured spirometry.In poorly controlled patients, evidence of obstruction and bronchodilator reversibility are reliable guides to escalation in treatment.Inflammation can be assessed by the measurement of blood eosinophil levels, an indicator of exacerbation risk and of steroid responsiveness.[62] Extra-pulmonary (comorbidities) As discussed above, a number of comorbidities are relevant and may impact on symptoms and risk, 63 including but not limited to anxiety and depression, cardiovascular disease, upper airways disease, obesity and dysfunctional breathing.When control is poor, consideration of comorbidities is logical, even if evidence of abnormal airways physiology or inflammation is absent.

Behavioural factors
In any poorly controlled patient, adherence and inhaler technique should be assessed.In primary care settings in some parts of the world, refill prescription rates can be used to assess adherence.All patients should have at least a basic selfmanagement plan, and providing appropriate information on the treatments prescribed and on how to react to worsening control is a fundamental patient need.
Feasibility of a treatable traits approach in primary care Some have said that the treatable traits approach, although suitable for specialists, is too complicated for primary care.We disagree with this assessment, and indeed have found general practitioners (GPs) and practice nurses generally very receptive to the treatable traits approach when it is presented.As generalists who are close to their patients and their families, and who see their patients about all of their various ailments, primary care clinicians are used to complexity and heterogeneity, to multimorbidity and to the impact of behaviours on overall health.The simple key treatable traits approach may not in fact necessitate new investigations or procedures, and good primary care clinicians already try to practice in such a holistic fashion, although probably in an 'instinctive' rather than a structured way.However, use of a structured template has the potential to provide a check-list for the important areas to be covered in a consultation, and a way of teaching good practice to colleagues and juniors.

SECONDARY CARE
The assessment and management of treatable traits in adults with obstructive airways disease in secondary care is different from primary care in many respects.Firstly, all patients referred to secondary or tertiary care will probably require an assessment of treatable traits, because their asthma or COPD is likely to be problematic, and are in poor respiratory health despite standard treatment, and thus the referral will necessitate such an approach.In contrast, many patients in primary care will have well controlled asthma or COPD with no recent exacerbations, in which case a systematic assessment of treatable traits may not be routinely required.For this reason, in secondary care the assessment of treatable traits on an individual basis is likely to have a higher reward than in primary care in terms of identifying clinically important issues that can be treated to the benefit of the patient.
Fortunately, it is likely that in secondary (and tertiary) care the health system allows more time in the consultation, and depending on the health care system, better availability and funding for investigations, or access to further specialist referral.This may facilitate a more comprehensive review, investigation and management of the patient with asthma or COPD in poor respiratory health.
There is an emerging evidence base for interventions comprehensively targeting treatable traits in the tertiary care setting, but not in secondary care.A recent systematic review and meta-analysis identified 11 studies, all of which were undertaken in the tertiary care setting, including six controlled trials (five in COPD, [64][65][66][67][68] and one in asthma 69 with a total of 947 participants). 70The findings are informative not only in regard to the clinical improvement in quality of life and the reduced hospitalization risk with the multidimensional interventions over other models of tertiary care in patients with obstructive airways disease, but also the paucity of evidence in secondary care, risk of bias, complexity and uncertainties remaining that limit understanding and implementation.The number of targeted trait intervention components per study ranged from 3 to 7, whereas the number of targeted traits ranged between 13 and 36 per study, with some interventions such as self-management education, pulmonary rehabilitation and management of comorbidities used to target multiple traits. 70

Prevalence of treatable traits
The patient with obstructive airways disease referred to secondary (or tertiary) care is likely to have key differences in the prevalence and severity of the spectrum of treatable traits than in primary care.In an international observational study, the number of specific treatable traits increased with increasing severity in populations with diagnosed asthma, asthma + COPD and COPD, with both differences and similarities in the patterns observed between these diagnostic groups (Table 1). 71hile many traits are positively associated with severe disease, others are independent or negatively associated with disease severity.
The reported prevalence of the specific treatable traits in severe airways disease is informative in terms of their likely occurrence in the secondary (and tertiary) care settings, with the proviso that these will vary according to the patterns of referral from different communities.Also, the prevalence data depends on the specific investigations undertaken in the populations from which these data were obtained.For example, though data were presented on the prevalence of 30 treatable traits in the above international survey, 71 additional traits such as vocal cord dysfunction, medication adherence and inhaler technique were not included, although these are important features to investigate and treat in patients with severe disease.Furthermore, there may be other important clinical issues that may need consideration during the consultation and investigation, such as lung cancer risk in smokers, which are not classically considered as treatable traits.
Another consideration is the association between specific traits and exacerbation risk.In a severe asthma registry, it was reported that ten traits predicted exacerbations, the strongest of which were a past history of exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. 72In addition, the number of canisters of shortacting beta 2 -agonist (SABA) collected by patients is positively associated with increasing risk of both exacerbations and mortality. 73Other factors for mortality risk in asthma are a recent hospital admission, an ICU admission ever, and the lack of, or discontinuity with, ICS treatment. 74,75In COPD, recent exacerbations are the strongest predictor of future exacerbations, and the rate at which exacerbations occur appears to reflect an independent susceptibility phenotype. 76Numerous traitsbased indices including body mass index (BMI), airflow limitation, symptom burden and functional capacity, exacerbation frequency, smoking status and age predict mortality risk in COPD and have been used in riskpredictor models. 77,78erarchy of treatable traits In the face of the 40+ treatable traits that have been proposed in obstructive lung disease [1][2][3][4][5] it is necessary to give thought to a hierarchy of importance.This hierarchy may be influenced by numerous factors including but not limited to the prevalence, severity, ease of diagnosis and the effectiveness of treatments for the different traits. 4Numerous population, health service delivery and systems issues will also influence the hierarchy, such as the referral population, together with the cost and availability of investigations and treatments.
The hierarchy concept has been considered in the setting of a severe asthma registry, from which it was possible to produce a list of 'key' traits' using arbitrary 'cut-off 'criteria, for example a prevalence of >5%, an independent predictor of risk of exacerbations, and treatment responsiveness. 72,79Using this hypothetical triage schema, the key treatable traits for severe asthma might include eosinophilic inflammation, exacerbation prone, variable airflow obstruction, upper airway disease, vocal cord dysfunction, obstructive sleep apnoea, depression, anxiety and inhaler device polypharmacy.However, recognition needs to be given to other traits, such as enquiry into occupational exposures which would be an essential requirement in adults with obstructive airways disease, particularly adult-onset asthma.Similarly, recognising that lung cancer and cardiovascular disease are important causes of mortality in COPD, 80 their consideration needs to be incorporated in any systematic approach in patients with features of COPD.
It would also be possible to exclude some traits on the basis that identification is not feasible (such as neutrophilic airway inflammation because sputum induction is not available in routine clinical practice) or if there is insufficient evidence that treatment is effective (such as treatment of systemic inflammation for which statins do not lead to clear clinical benefit). 81Investigations such as high-resolution computed tomography to identify bronchiectasis is not feasible as a standardized investigation in all patients with severe airways disease seen in secondary care, due to the cost, risk of cumulative radiation exposure and the requirement to then follow up on the incidental findings. 4Further complexity presents with traits with a high prevalence and burden but for which the optimal treatment regimens have yet to be adequately elucidated, such as vocal cord dysfunction. 82A B L E 1 This leads to the concept of 'key' investigations which are routinely undertaken to identify a portfolio of traits, including the 'key traits' as outlined above.These key investigations need to be inexpensive and simple to perform and interpret, thereby being feasible to undertake in most adult patients referred with obstructive airways disease.In this way, in addition to a thorough history and examination, measurement of spirometry with flow volume loops and bronchodilator reversibility, blood eosinophil count and total and/or specific serum immunoglobulin E (IgE), FeNO, sputum culture (routine and/or in the setting of an exacerbation) and chest radiograph (CXR) would allow initial investigation of many of the treatable traits in severe asthma (Table 2).Gas transfer might replace IgE and FeNO measurements in those with suspected predominant COPD.

Clinic assessment
One approach in secondary or tertiary care is to establish a multidisciplinary outpatient team, in some respects similar to the approach taken in cystic fibrosis services.This could be led by a respiratory or internal medicine physician and involve allergists, respiratory scientists, ear, nose and throat (ENT) surgeons, psychiatrists/psychologists, physiotherapists, dieticians and/or specialist nurses depending on whether predominantly asthma or COPD-based.While this approach may be optimal in theory, it is resource intensive and potentially wasteful, and unlikely to be funded by resource-limited health systems.
A variation of this approach is a single respiratory or internal medicine physician model, with specialist nurse support.This could be structured to include the key investigations outlined above, together with questionnaires that could be completed prior to the consultation to detect comorbidities and overlapping disorders, with the specific questionnaires chosen on the basis of the information provided in the referral letter. 83,84Questionnaires are available for the detection of sinonasal disease (allergic rhinitis and chronic rhinosinusitis), dysfunctional breathing, cord dysfunction, gastroesophageal reflux, obstructive sleep apnoea, anxiety and depression. 83Most of these questionnaires have a sensitivity and specificity in excess of 80%, giving both high negative predictive and high positive predictive values.Together these questionnaires take about 40 min to complete, and when administered prior to clinical consultation, the detection of all six comorbidities is significantly enhanced. 84These questionnaires are no substitute for a proper history; rather the doctor uses the results of the questionnaires to guide their clinical history, and ensure that these comorbidities can be identified and managed early to guide management.

Optimizing asthma/COPD treatment
For both asthma and COPD, the doctor often faces the conundrum of needing to decide how to prioritize the treatment of asthma and/or COPD versus the multiple treatable traits that are being investigated and/or may have been identified.This difficulty may have complexity, for example, many treatable traits may have presentations similar and overlapping with asthma and/or COPD. 85A case can be made to optimize airways disease treatment early, while further exploring other treatable traits.
For asthma, this approach is straightforward, with the routine use of the ICS/formoterol maintenance and reliever therapy (MART) regimen rather than ICS/long-acting betaagonist (LABA) maintenance and a SABA reliever regimen.In moderate and severe asthma, ICS/formoterol MART reduces the risk of a severe exacerbation by between 32% and 23% compared with the same baseline or higher dose of maintenance ICS/LABA therapy plus SABA reliever, respectively. 86In addition to its effect in reducing severe exacerbation risk, it also treats many other traits, such a reliever overuse, airways inflammation, poor ICS adherence and the regimen is simple to use with the requirement for only one inhaler device even in patients with severe disease. 87,88For these reasons a case can be made to transfer patients with asthma, or asthma/ COPD overlap, across to the ICS/formoterol MART regimen, as an initial standard therapeutic approach.
The equivalent initial standardized approach in COPD, without features of asthma, is less certain, with the requirement to consider the different therapeutic approaches outlined in international COPD guidelines depending on patient characteristics. 89

Traits to guide asthma/COPD treatment
Treatable traits can be used to select specific treatments used in the management of severe obstructive airways disease.The best recognized clinical situation is with the prescription of monoclonal antibody therapies which have transformed the management of severe asthma.Measurements of total serum IgE, blood eosinophil counts and FeNO, enable the identification of specific Th2-high phenotypes responsive to specific biologic therapies. 3,90,91These measurements can both identify responders to specific biologic treatments and those at greatest risk of severe exacerbations who are likely to obtain the greatest absolute benefit in terms of reduction in severe exacerbation risk, as illustrated with the use of mepolizumab (Figure 1). 92ore broadly, multiple patient characteristics can be used to not only identify patients likely to have an enhanced response, but also those who likely to obtain minimal benefit from biologic treatments. 93Such characterization is important, to improve the cost-effectiveness of these expensive therapies, and address the current practice of use beyond their evidence base for efficacy and safety. 94n important example relevant to COPD is the utility of measurement of the blood eosinophil count to help identify in the clinic those patients with COPD who are likely to benefit most from ICS use at the lowest risk of undesired side effects. 95,96reatable traits may also be used to titrate treatment to achieve greater efficacy or reduce the risks with treatment, thereby allowing personalized management to balance potential benefit with harm.Particular interest has focussed on airflow limitation (and associated symptoms) and airways inflammation which are linked to the key treatments of inhaled long-acting bronchodilator and ICS therapy. 3,97n asthma, titrating ICS dose through the use of FeNO reduces the likelihood of asthma exacerbations, although this approach does not affect asthma control or lung function. 62The potential of inflammation-guided management was illustrated in patients with refractory asthma, in which this approach led to a reduction in exacerbation frequency in an inflammation-dominant group, and a reduction in ICS exposure in the symptom-predominant group, without compromising asthma control. 23hese findings have led to the proposal that treatment decisions are driven by objective assessment of key treatable mechanistic traits. 97However, there is a risk that this approach may lead to excessive corticosteroid therapy, if the goal is to 'normalize' the key treatable mechanistic traits. 98his represents an inherent risk with stepwise algorithm regimens, such as the escalation of ICS and LABA treatment in an attempt to achieve 'total control', as even 'well-controlled' asthma might only be achieved in about two thirds of patients despite a progressive increase in maintenance ICS/LABA to a maintenance ICS dose that causes the same magnitude of systemic side effects as oral prednisone at a 5-mg daily dose. 995][66][67][68][69] The impact of such a broad approach can be substantial, with almost 90% of patients undergoing systematic assessment and treatment for difficult asthma obtaining significant improvement in at least one key asthma outcome, and with the halving of oral corticosteroid burden independent of, and comparable in magnitude with, that achieved by monoclonal biologics. 100In support of this approach, there is substantive evidence from randomized controlled trials of the efficacy of specific interventions of specific treatable traits in patients with asthma and/or COPD, illustrating their utility if treatable traits were investigated and managed in a systematic way. 101For most of the treatable traits there is level I or II evidence of efficacy (Tables 3-5).

Templates
Based on the above considerations, templates can be derived for use in secondary or tertiary care.One simple option for both asthma and COPD is to use standardized checklists for selected traits, and to treat any clinical trait identified according to proven management approaches.
A more comprehensive framework for implementation in a tertiary asthma or COPD service, is to link the list of traits and the associated trait identification markers with specific investigations and interventions using a predetermined template (Figure 2). 69This traditionally involves a multidisciplinary team including a manager to coordinate the communication between health professionals, and the frequent follow up clinic or telephone consultations required. 102This enables the integration of care between hospitals, primary care and community service for patients who are particularly vulnerable to care fragmentation, and need to access care from various healthcare disciplines.The major limitation of this approach is the substantive resources required, suitable for tertiary care, but not necessarily secondary care.Other models that have been proposed include a one-off, one day assessment in a tertiary asthma clinic, without long-term supervision by a specialized team. 103lternative frameworks for use by respiratory or internal medicine physicians in a secondary asthma or COPD service where lesser resourcing is likely to be available than in tertiary care urgently need assessment.In the validation of such simplified templates, whether some of the traits can be assessed through simpler means than the gold standard investigations needs to be determined.For example, whether a targeted history supported by flow volume loops with evidence of extra-thoracic airflow obstruction might to be sufficient to diagnose vocal cord dysfunction in most patients, without the requirement for laryngoscopy which is unlikely to be widely available in secondary care.It will also be necessary to develop systems to ensure the comprehensive assessment of traits beyond the systematic assessment of 'key traits', so that those such as occupational exposures might be identified. 104,105Simpler modified templates will need to be assessed for use in middle-and low-income countries, where the importance of different traits may differ and resources may be severely limited. 106inally, special mention should be made of pulmonary rehabilitation which is some respects can be considered the original treatable traits approach to the management of COPD, even though the assessment and management of treatable traits can be variable and often underutilized 107 As pulmonary rehabilitation has such marked benefits, including increased survival in COPD, it should be considered as one method by which multiple traits can be managed in a standardized way. 108,109Furthermore, novel methods of pulmonary rehabilitation need to be considered to increase availability and provide choice for patients. 110,111A B L E 4 The level of evidence for the treatment of treatable traits within the extrapulmonary domain.

CONCLUDING COMMENTS
The investigation and treatment of treatable traits in obstructive lung disease is based on the recognition that many pulmonary, extrapulmonary, environmental and lifestyle factors contribute to poor respiratory health, and that their investigation and treatment can lead to improved clinical outcomes.However, how best to implement this personalized medicine approach in primary and secondary care within existing resource constraints remains uncertain.The priority now is to assess different prototype templates for the identification and management of treatable traits in both asthma and COPD, in primary, secondary and tertiary care, to provide the evidence that will guide their use in clinical practice in different health care systems.

F I G U R E 1
Predictive modelling of rate of exacerbations.The predictive modelling is based on the blood eosinophil count at baseline, history of exacerbations and treatment with mepolizumab or placebo.Reproduced with permission from Pavord et al.Lancet 2012.92

5
Pharmacotherapy based on osteoporosis guidelines, vitamin D supplementation and resistance training I b , II Sarcopenia Appendicular skeletal muscle mass index: Diet (high protein), resistance training I b , II Males <7.26 kg m À2 Females <5.45 kg m À2 Note: 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).Reproduced with permission from Duszyk et al.Breathe 2021. 101a NHMRC level of evidence currently available for the management/treatment of each trait.b Evidence from the general population.F I G U R E 2 Components of the multidisciplinary assessment intervention.CBT, cognitive behavioural therapy; CPAP, continuous positive airways pressure; HS, hypertonic saline; PEP, positive expiratory pressure; WAP, written asthma plan.Reproduced with permission from McDonald et al.Eur Respir J 2020. 69 Prevalence of treatable traits by disease label and level of severity.
T A B L E 1 T A B L E 2 Key investigations of treatable traits in obstructive airways disease.
101 B L E 3 The level of evidence for treatments of treatable traits within the pulmonary domain.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).Reproduced with permission from Duszyk et al.Breathe 2021.101Abbreviations:CT,computed tomography; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting β 2 -agonists; LAMA, long-acting muscarinic antagonist; PaO 2 , partial pressure of oxygen; SABA, short-acting β 2 -agonists; SAMA, short-acting muscarinic antagonist.National Health and Medical Research Council (NHMRC) level of evidence currently available for the management of each trait.
Note:a bStudies examining the effectiveness of different treatments in bronchiectasis in general, not specifically in chronic airways disease patients with coexisting bronchiectasis.
TRAITS IN PRIMARY AND SECONDARY CARET A B L E 5 The level of evidence for the treatment of treatable traits within the behaviour/risk-factor domain.
Note: 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).Reproduced with permission from Duszyk et al.Breathe 2021. 101bbreviations: 6MWT, 6-min walk test; BMI, body mass index; CBT, cognitive behavioural therapy; CPAP, continuous positive airway pressure; CRP, C-reactive protein; GADS, Goldberg Anxiety and Depression Scale; GORD, gastro-oesophageal reflux disease; HADS, Hospital Anxiety and Depression Scale; Hb, haemoglobin; OSA, obstructive sleep apnoea; VCD, vocal cord dysfunction.aNHMRC level of evidence currently available for the management/treatment of each trait.bCurrent research only.cEvidence from the general population.TREATABLE pragmatic clinical research, and has published and lectured widely on these topics.Past roles he has occupied include Chief Medical Officer of the charity Asthma UK and research chairman of the International Primary Care Respiratory Group.He has acted as an expert advisor on several UK NICE evaluations in the respiratory field, and has been involved in a number of UK, European and International guidelines on airways disease diagnosis and management.Richard Beasley is a physician at Wellington Regional Hospital, Director of the Medical Research Institute of New Zealand, and Professor of Medicine at Victoria University of Wellington.He is an Adjunct Professor at the University of Otago and Visiting Professor, University of Southampton, United Kingdom.He was previously the Deputy Chair of the Health Research Council of New Zealand, and is currently Chair of the New Zealand adolescent and adult asthma guidelines.His research interests in respiratory medicine are primarily in the fields of epidemiology and clinical management.How to cite this article: Thomas M, Beasley R. The treatable traits approach to adults with obstructive airways disease in primary and secondary care.Respirology.2023;28(12):1101-16. https://doi.org/10.1111/resp.14610