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

What is the treatable traits approach and why is it necessary?

Biology, thus medicine, is complex [11, 12]. This means that health and disease are emergent properties that result from the interaction of different complex networks at different biological levels (genes, proteins, metabolites, cells, organs and environment) [11, 12]. Therefore, in order to improve medical diagnosis and treatment it is necessary to gain a better understanding of this biomedical complexity [13–15].

An early approach to address this complexity was based on the concept of “clinical phenotypes”, defined as “a single or combination of disease attributes that describe differences between individuals with [the same disease] as they relate to clinically meaningful outcomes” [16]. A strict interpretation of this definition may suggest that “clinical phenotypes” are mutually exclusive, whereas we know that diseases often present with several, nonmutually exclusive characteristics. Accordingly, the concept of “clinical phenotypes” evolved to that of “treatable traits”, defined as therapeutic targets identified by “phenotype” or “endotype” through validated biomarker(s) [6]. The term “endotype” refers to a “subtype of a disease defined functionally and pathologically by a molecular mechanism or by treatment response” [17]. In contrast, a “biomarker” is “a characteristic [not necessarily a molecule; lung function or chest imaging may work as biomarkers too] that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or biological responses to a therapeutic intervention” [18]. We refer to these indicators as trait identification markers.

Importantly, potential treatable traits are not restricted to the lungs. It has been recognised since its original proposal that there are pulmonary, extrapulmonary and even behaviour/lifestyle risk factors that deserve specific treatment if present [6]. In essence, it is hoped that the adoption of a strategy based on the recognition and treatment of validated treatable traits may improve the efficacy and safety of therapies of complex human diseases in general, and chronic airway diseases in particular [7, 19, 20]. Needless to say, this hypothesis requires formal, prospective, validation in appropriately designed clinical trials [7]. The first steps to test/validate this approach are to define how to recognise traits and how to assess their relative importance.

How should we identify candidate treatable traits?

First, it is important to recognise that a given patient may have more than one treatable trait (actually, this is often the case). In other words, treatable traits are not mutually exclusive. Having said this, candidate treatable traits should fulfil three characteristics: 1) clinically relevant, 2) identifiable and measurable, and 3) treatable (table 1).

How can we assess the importance of specific treatable traits?

Are some traits more important than others? Should they receive greater priority in patient assessment and management? How should traits be prioritised? The significant resource requirements for assessing all of the potential pulmonary, extrapulmonary and risk factor/behavioural traits, so that targeted and individualised interventions can be implemented, highlights the need to prioritise certain traits above others [4, 7, 21]. An example of this prioritisation would be to target a few traits exclusively, such as symptoms and exacerbations in COPD (currently recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD)), and adding eosinophilic inflammation, also now recommended by GOLD (shown previously to be a valid identifying marker of the presence of eosinophilic airway inflammation, a higher exacerbation risk and better treatment response to inhaled corticosteroids) [23–27].

But are there other traits that need to be addressed, and with what priority? Traits could be prioritised based on their clinical impact, i.e. their severity, prevalence or their impact on specific outcomes (exacerbations, symptoms and health status, death, etc.). McDonald et al. [4] assessed clinical impact in an analysis of treatable traits in severe asthma using the Australasian Severe Asthma Web-based Database (SAWD) registry. The authors identified treatable traits that were predictive of future exacerbation risk. From 24 identified traits, 10 were associated with an increased risk of future asthma attacks. The strongest predictors were past-year exacerbation, depression, vocal cord dysfunction, inhaler device polypharmacy and obstructive sleep apnoea (figure 1a) [4]. This list of traits could be a potential “hit list” to begin prioritisation for implementation of the treatable traits approach in severe asthma, and also as a model to allow prioritisation in asthma and COPD (figure 1a). However, we also recognise the need to identify the traits that impact other outcomes, particularly the long-term natural history of a diseased state, or the development of a new disease.

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FIGURE 1

a) Treatable traits significantly (p<0.05) associated with increased risk of exacerbations over time. Numbers indicate the incidence rate ratio (95% CI) for the total effect of each trait on exacerbations over time. Adapted with permission from [4]. Illustrations by Olivia J. McDonald. b) An example of an intervention targeting one trait but achieving multiple positive outcomes, including health-related quality of life (HRQoL) and BODE (body mass index, airflow obstruction, dyspnoea and exercise capacity) index [29]. COPD: chronic obstructive pulmonary disease; CVD: cardiovascular disease.

Other ways to prioritise traits include connectivity and patient impact. A trait that is a nodal point in a disease network may influence multiple other traits and therefore would be important to target [11, 13, 28]. For example, in obese COPD patients, targeting treatment to the single trait of obesity led to significant improvements, not only in body weight, but also in several other important traits such as skeletal muscle strength, exercise tolerance, depression, and several cardiovascular and metabolic risk markers (figure 1b) [29].

Patient impact, i.e. a trait rated as a high priority by patients, is another way to prioritise the importance of traits. At present scant data exist to inform this approach in airway diseases. In one study, patients with asthma and COPD aged ≥55 years underwent a multidimensional assessment to characterise traits where patients ranked the importance of their individual traits [30]. The most important from the patient's perspective included dyspnoea, activity limitation, airflow limitation, airway inflammation and obesity [30]. Importantly, these rankings were different from those provided by their physicians. However, after including patients in shared decision making, which involved an explanation of the trait, its impact, how it was treated and sharing the rating of the physician, patients became more engaged in the adoption of a complex treatable trait intervention, which led to improved outcomes [31]. These results highlight the importance of seeking patient preferences in prioritising traits and targeted treatments.

Study outcomes for research: concept of burden

Assessing the impact of a new strategy for managing airway diseases requires some consensus about the end-points that are appropriate for assessing that impact. The concept of “burden of disease” has been used as a common currency for describing the impact of diseases and risk factors. Burden of disease represents a measure of health loss and is estimated in two, mutually exclusive, components: years of life lost due to premature death and years of life lived with disability. The former is the sum of life expectancies, at the time of death, of all people whose death is attributed to the specified disease or risk factor. The latter is the sum of all periods of disability, weighted by the level of disability, attributed to the specified disease or risk factor. These two components are then summed to give the burden of disease, attributed to the specified disease or risk factor, in units of disability-adjusted life years [46]. This approach has been widely used to estimate and analyse the global burden of disease.

A strength of this approach is its generalisability across diseases and global contexts. The holistic approach to assessment of impact is a further strength. One potential limitation of this approach is that descriptors used to assign levels of disability to various stages of disease (mild, moderate and severe) are largely based on regular symptoms and limitations [47]. This does not account for the impact of exacerbations, which are sporadic in nature and are a major component of the impact of the disease that the treatable traits strategy seeks to mitigate. These limitations, particularly the latter, can and should be addressed in future work on the burden of disease measures. Another limitation may be that these are population estimates and, in an era of precision, individualised, medicine there may be substantial interindividual variability [48].

Guidelines as a vehicle to implement a treatable traits strategy

Guidelines present a comprehensive approach to airway disease management and in doing so they may be already dealing with many of the issues identified in the treatable traits approach. However, there are important differences between the treatable traits strategy discussed earlier and the current guidelines approach. So far, guidelines do not advocate the use of biomarkers to select therapy, although based on current evidence this may change in the near future [27]. In general, guidelines tend to be based on “lumping”, with the level of treatment determined by the degree of symptoms and risk of future events. In contrast, the treatable traits approach personalises treatment based on “splitting”, with systematic identification and treatment of the disease characteristics that are evident in each individual and that contribute to poor respiratory health. The consequence of the “lumping” approach is that there may be, for example, untreated eosinophilic inflammation when symptoms alone are used to guide therapy. Eosinophilic inflammation often occurs in patients with COPD but can also occur in those with mild asthma, as well as poor symptom perceivers, where there is a weak association between eosinophilic inflammation and symptoms [49]. Several RCTs now show that biomarker-guided therapy directed at the treatable trait of type 2 airway inflammation is superior to symptom-guided therapy [24, 26, 50]. Moreover, how to efficiently implement this approach in primary or secondary healthcare settings remains unclear [6]. Finally, even though some guidelines, e.g. the New Zealand asthma guidelines [51], already recommend the novel approach of assessing treatable traits in a systematic manner within four domains (overlapping disorders, comorbidities, environmental and lifestyle factors) at each consultation, and before using the stepwise approach to asthma drug treatment, the successful implementation of existing guidelines remains a challenge [52, 53].

Pulmonary rehabilitation as a vehicle to implement a treatable trait strategy

Pulmonary rehabilitation, defined as the delivery of “patient-tailored therapies … designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviors” is a highly effective intervention to improve wellbeing in people with chronic respiratory disease [54]. Although pulmonary treatable traits are infrequently addressed directly in pulmonary rehabilitation, many important extrapulmonary and behavioural/lifestyle traits are addressed routinely. Examples include the extrapulmonary treatable trait of deconditioning, addressed through provision of an individualised exercise training programme, and behavioural treatable traits related to inhalation technique, adherence to treatment, smoking cessation, and family and social support.

Pulmonary rehabilitation is a complex, multicomponent intervention that can be considered as a “stacked” approach to management [7]. This provides the opportunity to address multiple treatable traits at once, which may be of particular advantage in people with more severe airway disease. Such an approach requires patients to make health behaviour changes across multiple domains. Pulmonary rehabilitation programmes provide an environment where this can be supported by case management and coordination of care. Another advantage of embedding the treatable traits approach in pulmonary rehabilitation is that measurement of patient-centred outcomes (e.g. health status) is strongly embedded in routine rehabilitation practice.

While pulmonary rehabilitation offers opportunities for implementation of the treatable traits approach, there are some potential limitations that need to be considered. The “stacked” nature of pulmonary rehabilitation could be one by limiting our understanding of the mechanisms of treatment response. For example, there is strong evidence of improvement in the extrapulmonary treatable traits of anxiety and depression following pulmonary rehabilitation, but it is not clear which components of rehabilitation confer these benefits [55]. Another potential limitation is that the treatable traits approach should span the spectrum of airway diseases, but the benefits of pulmonary rehabilitation for those with mild disease have not been convincingly demonstrated [56, 57]. Finally, access and uptake of pulmonary rehabilitation remain suboptimal across the world [58], which may limit its utility as a vehicle to deliver the treatable traits approach.

Multidisciplinary teams as a vehicle to implement a treatable traits strategy

Evidence suggests that optimal management of patients with chronic airway diseases requires a multidimensional assessment and targeted treatments [31, 54, 59, 60]. Engaging a multidisciplinary team enables the management of the complexities that characterise this patient population, and could be a useful platform to identify treatable traits and to implement a targeted treatment programme based on these traits. A multidisciplinary team approach for management of severe asthma and COPD has been shown to reduce hospital admissions, improve health status, reduce exacerbations and reduce the number of bed days [61–63].

The minimum recommended personnel for the multidisciplinary team within the severe asthma clinic include a respiratory physician/pulmonologist, a specialist nurse and a pulmonary function scientist, but a speech pathologist, dietician, psychologist and physiotherapist are also necessary to address the complexities associated with the disease [59]. Referral pathways to other specialities for the treatment of common comorbidities or traits (e.g. gastro-oesophageal reflux disease, sinusitis and cardiovascular disease) should also form part of a multidisciplinary team protocol. In COPD the team is very similar. Using a multidisciplinary team meeting format, patients can be presented by the case manager to discuss the individual's identified treatable traits using a multidimensional assessment approach, then treatment of the identified traits can be planned and treatment pathways actioned [5, 31, 64].

While there is good evidence for the benefits of the multidisciplinary team approach in managing airway diseases, there are no published RCTs that have utilised the multidisciplinary team in the evaluation of the treatable traits approach. This identifies another important area for future research.

Knowledge translation

A further important consideration for the implementation of the treatable traits strategy is knowledge translation. We must consider ways of bringing about behaviour change of multidisciplinary clinicians to successfully create a paradigm shift in disease management. In an era of social media, artificial intelligence and information technology these strategies need to be embraced to launch public health campaigns promoting the approach and to provide training for clinicians. These strategies could be supported by our international respiratory communities such as the European Respiratory Society and perhaps even the World Health Organization.