Abstract

The treatable traits approach represents a strategy for patient management. It is based on the identification of characteristics susceptible to treatments or predictive of treatment response in each individual patient. With the objective of accelerating progress in research and clinical practice relating to such a treatable traits approach, the Portraits event was convened in Barcelona, Spain, in November 2022. Here, while reporting the key concepts that emerged from the discussions during the meeting, we review the current state of the art related to treatable traits and chronic respiratory diseases management, and we describe the possible actions that clinicians can take in clinical practice to implement the treatable traits framework. Furthermore, we explore the new concept of GETomics and the new models of research in the field of COPD.

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This review describes the state of the art of the treatable traits approach in chronic respiratory diseases management and suggests possible actions that clinicians can undertake to implement this treatable traits approach in clinical practice. https://bit.ly/3Mkca4E

Introduction

Over the past decade, the concept of “treatable traits” has been largely spread as the basis of a precision medicine approach for chronic airway diseases, in general, and asthma and COPD in particular [1]. This approach is based on the identification of the characteristics susceptible to treatments or predictive of treatment response in each individual patient [1]. Therefore, it has been proposed as a strategy of personalised medicine in the complex setting of airway diseases, beyond the concepts of phenotypes, and incorporating the treatable element into the endotypes [2]. Acknowledging that better insight into this concept, which has sometimes been wrongly perceived as theoretical, may lead to a practical way to manage patients with COPD, a 2-day international event was organised in Barcelona. This event (named Portraits) comprised a 2-day meeting with presentations by internationally recognised experts in the fields of treatable traits. The aim of the meeting was to extensively explore the concept of treatable traits and to reframe chronic respiratory disease management with a novel and comprehensive targeted approach based on treatable traits. The event provided a comprehensive analysis of these topics that led to the development of this article. Here, we summarise those discussions, review the current state of the art related to treatable traits and chronic respiratory disease management, and focus on the applicable implementation in specialist and general clinical practice.

The treatable traits conceptPrecision medicine in chronic respiratory disease

Both asthma and COPD are prevalent diseases that can be considered as representing a continuum of different pathological conditions which may share biological mechanisms and present similar or overlapping features. The unmet needs in this area include achieving the proper diagnosis earlier, finding biomarkers for activity and progression monitoring, tackling heterogeneity in order to move towards precision medicine and expanding the knowledge around mechanisms to cure these diseases. COPD and asthma are complex and heterogeneous conditions. In this field, “complex” means that they encompass several components with nonlinear relationships between them (e.g. forced expiratory volume in 1 s (FEV1) is a key component for diagnosis, although it is not always directly associated with the others), whereas “heterogeneous” indicates that not all of these components are present in all patients or, even in a given patient, at all time points (dynamic) [1]. In 2010, a definition of “clinical phenotype” was proposed, as a single or combination of disease attributes that describe the differences between individuals with COPD as they relate to clinically meaningful outcomes (e.g. symptoms, exacerbations, response to therapy, rate of disease progression or death) [3]. Over the years, different COPD clinical phenotypes have been described. However, these clustering approaches have shown limitations; for example, due to the fact that clinical phenotypes are not stable over time and the lack of reproducibility of phenotypes across cohorts. “Endotype” is a different concept, defined as a subtype of a condition, characterised by a distinct functional or pathobiological mechanism [4]; the major drawback is the poor knowledge of the endotypes in airway disease. In 2016, Agustí et al. [1] described the concept of treatable traits, which derives from phenotype and endotype previous concepts, of which it represents an evolution based on phenotypic recognition and a deep understanding of the critical causal pathways (endotypes). These traits can be “treatable”. Treatable traits, by definition, should be clinically relevant, identifiable and treatable [5]. In the context of treatable traits, the goal is the achievement of precision medicine, which is defined as “treatments targeted at the needs of individual patients on the basis of genetic, biomarker, phenotypic or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations” [1]. The traditional approach needs to evolve towards a novel personalised approach. Indeed, according to the analysis of data from the World Health Organization mortality database from 46 countries (1993–2012), in the past 10–15 years no improvement in asthma mortality among young people has been recorded [6]. In respiratory medicine, the development of new drugs has been somehow disappointing over the past 40 years, with many failures occurring in phase 2 and 3 and a 3% cumulative market entry probability of the tested drugs [7]. This might be explained by the fact that a precision medicine-based approach requires different types of clinical trials that should establish not only the efficacy and safety of therapies overall, but also the characteristics of the patients for whom treatment is effective. The studies evaluating mepolizumab, an anti-interleukin (IL)-5, in asthma support this hypothesis. In fact, the first study on mepolizumab failed to demonstrate any clinical or statistical benefit in unselected patients with asthma and persistent symptoms despite inhaled corticosteroid therapy [8]. Afterwards, two studies published in the same issue of the New England Journal of Medicine [9, 10] described the efficacy of mepolizumab when administered to patients with refractory eosinophilic asthma. Anti-IL-5 is now suggested as a possible treatment for airway eosinophilic inflammation, which is one of the most relevant and well-characterised pulmonary treatable traits [2].

Treatable traits and diagnostic labels in a real-world setting: the NOVELTY study

Clinicians should develop knowledge about the prevalence and the groups of treatable traits that can be seen in real-world settings and about the relationship between treatable traits and diagnostic labels in real-world patients. Treatable traits in chronic respiratory disease can be ordered into three domains; namely pulmonary, extrapulmonary and risk factor/behavioural traits [2]. In this regard, in 2022, a proof-of-concept study was conducted to explore the 30 treatable traits identified from the NOVELTY study cohort (NOVEL Observational Longitudinal Study), a large (n=11 226), global, real-world study that uniquely collects data both in primary care clinics and specialised centres from 19 countries, for patients with “asthma” (n=5932), “COPD” (n=3898) or both “asthma+COPD” (n=1396) [11]. The aim of the study was to analyse the different treatable traits in relation to the specific clinical labels and the severity. Diagnosis and severity assignments were both provided by physicians. The 30 treatable traits were classified into three domains (pulmonary, extrapulmonary or risk factor/behavioural). The diagnostic criteria used for the identification of the treatable traits are detailed in table 1. There were multiple findings from this study, overall showing that treatable traits exist across chronic respiratory disease [11], as follows. 1) The prevalence of the 30 treatable traits evaluated varied widely across the groups; n=12 treatable traits (40%) were associated with disease labels and were defined as diagnostic treatable traits. Pattern traits were designed as those specific for each disease; figure 1 shows the pattern recognition heatmap in relation to diagnostic label and severity assessment. 2) There were differences in treatable trait prevalence by disease severity in each diagnostic label. 3) Eventually, the authors identified a network of treatable trait co-occurrence (i.e. the percentage of patients presenting several individual traits) by disease label with a co-expression of different traits for each condition and with the co-occurrence network being most complex in patients diagnosed with asthma+COPD [11].

TABLE 1

Diagnostic criteria used for the identification of treatable traits in the NOVELTY (NOVEL Observational Longitudinal Study) study

FIGURE 1

Pattern recognition heatmap in relation to diagnostic label (left three columns) and severity assessment (right three columns). For this analysis, treatable traits were dichotomised as binary variables (present/absent) and their associations with diagnostic labels and severity of disease were explored using Chi-squared tests. Coloured cells indicate statistically significant associations (p<0.05), where cell colour corresponds to OR >1 (i.e. presence of the treatable trait) or OR <1 (i.e. absence of the treatable trait). PRISm: preserved ratio impaired spirometry; Th2: type-2 airway inflammation. Reproduced from [11] with permission.

Clinical relevance of treatable traits

Clinical relevance represents a key feature of treatable traits, meaning that they are associated with relevant clinical outcomes, such as exacerbations, lung function decline or quality of life [2] (table 1).

Pulmonary traits

Pulmonary traits are well recognised as dominant among the three domains and their treatment can profoundly impact patients’ lives. In 2016, Pavord and Agustí [12] proposed a simple approach to managing airway diseases, incorporating two major pulmonary traits: airflow limitation and eosinophilic airway inflammation, as shown in figure 2. This paradigm was confirmed in clinical trials establishing the efficacy and safety of a treatment for chronic respiratory disease as well as the characteristics of patients who benefit from that.

FIGURE 2

A new risk stratification approach to airway diseases. ICS: inhaled corticosteroid; OCS: oral corticosteroid; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist. Reproduced and modified from [12] with permission.

Inflammation

The CAPTAIN study is a randomised phase 3A study in which participants with inadequately controlled asthma were randomly assigned to once-daily inhaled fluticasone furoate plus vilanterol (100/25 μg or 200/25 μg) or fluticasone furoate plus umeclidinium plus vilanterol (100/31.25/25 μg, 100/62.5/25 μg, 200/31.25/25 μg or 200/62.5/25 μg). The trial showed that increasing inhaled corticosteroids (ICS) has a greater effect in patients with higher levels of eosinophilic inflammation [13]. This effect is particularly clear with severe exacerbations using a combined fraction of exhaled nitric oxide (FENO) and blood eosinophil status (i.e. type 2 (T2) inflammation) [13]. In agreement with these data, the IMPACT study in COPD demonstrated that regimens containing ICS have a greater effect in reducing rates of moderate and severe exacerbations among those with a higher blood eosinophil count [14]. Therefore, biomarkers are becoming crucial in risk stratification in the context of precision medicine to treat airway diseases. Recently, a risk scale predicting the asthma attack rate by Global Initiative for Asthma (GINA) step, based on the biomarkers blood eosinophil count and FENO has been developed (Oxford Risk of Asthma Attack Scale).

This is a post hoc analysis of multiple clinical trials across the spectrum of asthma severity showing that blood eosinophils and exhaled nitric oxide are consistently, independently and additively associated with an increased risk of exacerbations. This biomarker associated risk is important as it is modifiable with treatment [15]. Estimation of the risk derived from these complementary biomarkers is important, since it is modifiable by therapeutic interventions removing the excess risk. In fact, the authors suggest that the tool can quantify the excess risk of asthma attacks in a T2-high population and that the risk can be removed using anti-inflammatory treatment [2, 15]. Together with biological biomarkers, additional potentially relevant pulmonary, behavioural and environmental treatable traits have to be considered and recognised. Among them, persistent airway infection (which can benefit from long-term macrolide therapy) [16, 17] and refractory chronic cough (for which the P2X3 receptor antagonist has been showing encouraging results) [18] have to be taken into consideration.

Chronic mucus hypersecretion

Chronic bronchitis, classically defined as a chronic cough and sputum production for ≥3 months per year for two consecutive years [19], is characterised by anatomical lesions, such as inflammation of the airways, damaged cilia and excess mucus, and is considered as a pulmonary treatable trait. Inflammatory cells, oxidative stress, as well as viral and bacterial infections can lead to an excess of mucus production, while other factors, such as poor ciliary clearance and airway occlusion reduce mucus elimination [20]. A central point in evaluating consequences of chronic bronchitis and the possible treatment implications is the definition of chronic bronchitis, which was originally established for epidemiological rather than mechanistic or clinical purposes: it may be argued that the 2-year period of time that patients must take into consideration when self-reporting their condition is too restrictive [21]. In this context, the St George's Respiratory Questionnaire (SGRQ) definition of chronic bronchitis as both cough and phlegm “almost every day” or “several days a week” over the past 4 weeks has shown to be a better predictor of COPD exacerbation compared to the classical definition [22].

Several studies found that current smoking represent the main risk factor for chronic bronchitis [23–25]. The prevalence of chronic bronchitis has been estimated between 3.4% and 22% of adults, and its variability may be due to the different definitions of chronic bronchitis (i.e. chronic phlegm versus chronic cough and phlegm) [19]. Patients with COPD may display different combination of symptoms: cough alone (17%), cough and phlegm (31%), phlegm alone (12%) and no cough or phlegm (40%) [26]. Depending on the definition of chronic bronchitis, i.e. cough and sputum or sputum alone, prevalence of chronic bronchitis may vary greatly, in this case from 31% to 43%. In the NOVELTY study, a frequent productive cough has been found as a common pulmonary treatable trait with a prevalence of 34% [11]. A large cohort Spanish study in individuals aged >40 years has recently shown a difference in the prevalence of chronic mucus hypersecretion (CMH) (13%) and chronic bronchitis (5%), which might be explained by the different definitions of the two conditions [27]. Moreover, a clear association between sputum production and sputum bacterial count has been established [28, 29]. Putcha et al. [26] observed up to 18% of individuals with cough and phlegm having lower respiratory tract infections. An analysis on the NOVELTY population found that a frequent productive cough increased the risk of all exacerbation-related outcomes [30]. The risk of COPD occurrence was statistically higher in the presence of a chronic cough and phlegm in a cohort of young adults [31], and patients with a greater number of CMH episodes displayed a deeper decline in FEV1 with the development of COPD [25]. Chronic bronchitis related symptoms have also been associated with worse quality of life [22, 32], showing that control of these symptoms may significantly impact the wellbeing of the patients. Consistent with these data, several factors, such as anxiety, depression, fatigue, physical functioning, social abilities and sleep disturbances, are affected by the presence and severity of cough and phlegm [33]. Mortality has been analysed in six longitudinal studies on chronic bronchitis [20]. Guerra et al. [34] showed that chronic bronchitis before the age of 50 years predicts mortality risk; Putcha et al. [26] demonstrated a higher rate of mortality among smokers with early COPD; and Lahousse et al. [35] found better survival in the absence of chronic bronchitis rather than in the presence of chronic bronchitis in patients with COPD. To date, possible treatments for patients with CMH are mucociliary clearance techniques with a physiotherapist; inhaled hypertonic saline; and macrolides [2].

Pre-COPD

The term “pre-COPD” refers to clinical conditions where airway obstruction is absent, by definition. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report proposed a definition of pre-COPD as a condition with respiratory symptoms with or without detectable structural and/or functional abnormalities, in the absence of airflow limitation in patients who may (or not) develop persistent airflow limitation (e.g. COPD) [36]. Therefore, several types of pre-COPD might occur. Pre-COPD, previously identified as GOLD 0 (by the 2001 GOLD report) now extends to a broader range of conditions (described earlier) and presents a variable association with 1) increased risk of COPD; 2) increased mortality; and 3) acute lower respiratory tract episodes [37]. To date, there is growing evidence that (ex-)smokers with no airway obstruction have symptoms and more “exacerbations” than asymptomatic (ex-)smokers and asymptomatic GOLD 1–2 COPD patients. Importantly, these patients exhibit increased airway wall thickness on computed tomography (CT) scans [38]. Pre-COPD includes interactions among symptoms, structure and function, and represents a very heterogeneous condition with many possible profiles [37]. As such, it is intimately embedded with the treatable traits concept; indeed, the term “pre-COPD” encompasses at-risk subjects with isolated chronic bronchitis/mucus hypersecretion, asymptomatic subjects with emphysema, subjects with CT-scan or lung-function evidence of small airways disease, but normal FEV1/forced vital capacity ratio. Each of these characteristics represent a treatable trait, and for most of these traits the interruption of the exposure to risk factors is the disease-modifying approach at this stage of disease development. Indeed, while the knowledge of pre-COPD natural history is rapidly increasing, the effect of early intervention in these traits has been seldom studied. Only one study (the RETHINC trial) targeted the pre-COPD population, assessing the effect of bronchodilators (indacaterol plus glycopyrrolate) versus placebo in symptomatic subjects exposed to cigarette smoking and with normal lung functions, but it did not show any convincing results [39]. In terms of future targets, diagnostic criteria of pre-COPD need to be better defined and standardised, also considering additional diagnostic parameters, such as dyspnoea or lower respiratory tract infections. It will be important to confirm whether pre-COPD is an early stage of COPD or a different entity and to find more sensitive tools to diagnose it. Martinez et al. [40] proposed interesting steps to design and conduct intervention studies of young patients at risk with pre-COPD, with new potential outcomes to investigate, such as time to onset of COPD or time to worsening in COPD Assessment Test or SGRQ [40]. Large observational cohort studies and intervention studies are needed to expand the knowledge of pre-COPD. Importantly, since pre-COPD is inherently associated to increased risk of COPD, it is of utmost importance to consider COPD risk factors and aetiologies when addressing the multi-faces of this condition, since most of them consist of potential treatable or preventable traits. Their classification has been revisited recently [19, 41, 42] and now comprises genetically determined COPD; COPD due to abnormal lung development; environmental COPD related to cigarette smoke and/or to biomass and pollution exposure; COPD due to infections; COPD and asthma; and COPD of unknown cause.

COPD exacerbations and oxidative stress

Oxidative stress has a pivotal role in respiratory disease and increases during exacerbation, both in asthma and COPD. This paragraph focuses on COPD, given the stronger evidence supporting treatment targeting the oxidative trait. A COPD exacerbation is defined as any acute worsening of respiratory symptoms that leads to incremental therapy [29, 36]. A large number of COPD outcomes are influenced by exacerbations. Patients who experience frequent exacerbations have impaired health status in COPD, as assessed using the SGRQ score [43], and are at higher risk of exacerbations (e.g hospitalisation) [44]. COPD mortality rates increase as exacerbations increase in frequency or severity, and even one moderate exacerbation can affect the risk of mortality [45], and lung function declines as the number of exacerbations per year increases [46]. Viruses, bacteria and noninfective agents activate inflammatory responses (macrophages, neutrophils, eosinophils), which determine oxidative stress and maintain the inflammatory status. Infective agents are central factors in this process; respiratory viruses in particular. N-acetylcysteine (NAC) has multiple activities: it acts as a reactive oxygen species scavenger and as a precursor of reduced glutathione, and it has mucolytic properties [47, 48]. In the BRONCUS study, NAC at a dose of 600 mg once daily reduced the risk of exacerbations in patients not receiving ICS [49]. The 1-year HIACE study showed that high-dose NAC (600 mg twice daily) significantly decreased exacerbation frequency in patients with COPD [50]. The PANTHEON trial showed the efficacy of NAC (600 mg twice daily) added to standard of care treatment in reducing COPD exacerbations (p<0.05) [51]. A meta-analysis in 2015 summarised the results of 13 studies that showed that the treatment with low and high doses of NAC significantly reduced the frequency of exacerbations (relative risk 0.75, 95% CI 0.66–0.84; p<0.01) [52]. Oxidative stress represents an important treatable trait and requires proper management.

Extrapulmonary traits

Extrapulmonary traits are mostly related to comorbidities, such as depression, anxiety, overweight/obesity, deconditioning, rhinosinusitis, vocal cord dysfunction, systemic inflammation, anaemia, cardiovascular disease, gastro-oesophageal reflux disease and obstructive sleep apnoea. Also included is exercise intolerance.

Behavioural/risk factors

Behavioural are those traits that relate to disease self-management issues, such as suboptimal inhaler technique, suboptimal adherence, absence of a written plan of action, and poor knowledge of disease. These are extremely important traits, impacting the other traits. This domain also includes risk factors and behaviours that worsen symptoms, control and disease outcome, or even modify disease. Examples include smoking, physical inactivity, sedentary behaviour, decreased bone mineral density and sarcopenia.

Impact of treatable traits on outcomes

The importance of these traits cannot be undervalued due to the relationship with poor outcomes in asthma and COPD. This was demonstrated in a study by Sarwar et al. [53], who performed an analysis of a longitudinal evaluation of COPD patients using data from 3726 participants in the English Longitudinal Study of Ageing to determine the prevalence and impact of treatable traits. A total of 21 treatable traits were identified: five pulmonary, 13 extrapulmonary and three behavioural. Two outcomes were analysed: lung function and quality of life. The traits that predicted lung function were chronic bronchitis, breathlessness, underweight, sarcopenia and current smoking, while those predicting quality of life were depression, disability, cardiovascular disease, arthritis, anaemia and poor family and social support.

In asthma data from a 2-year prospective study involving 434 participants with severe asthma and a comparison group of 102 participants with nonsevere asthma showed that the treatable traits predictive of future asthma attack were largely related to extrapulmonary and behavioural risk factor domains. In order of risk, these included being prone to attacks, depression, inhaler device polypharmacy, vocal cord dysfunction, obstructive sleep apnoea, systemic inflammation, underweight, anxiety and upper airway disease [54].

Interesting findings resulted from an analysis that combined data from two parallel-group clinical trials (one in COPD and one in severe asthma): 22 treatable traits were identified by multidimensional assessment. When treatable trait interventions were compared with usual care, the health-related quality of life (HRQoL) outcome, measured by SGRQ, improved in the COPD and asthma groups. Using Bayesian model averaging to examine the associations between treatable traits and HRQoL, the traits most frequently associated were frequent chest inflection, dysfunctional breathing, inadequate inhaler technique and systemic inflammation, thereby further demonstrating the importance of extrapulmonary and behavioural traits [55].

The implementation of treatable traits in clinical practice

In clinical practice patients, present a combination of treatable characteristics [56]. Treatment guidelines for airway diseases have historically adopted a one-size-fits-all stepwise or stratified approach [36], although this does not correspond to individual patients’ reality. As mentioned, treatable traits are assessed in three domains: pulmonary, extrapulmonary and behavioural/lifestyle factors. Each domain presents a large number of traits that require assessment. In this context, it is important for clinicians to make an effort to find and treat clinically relevant traits from each domain (e.g. severe eosinophilic inflammation and airway limitation from the pulmonary domain; self-management skills for behavioural factors), which often represent the causal factor of the condition, instead of only treating disease labels. Progress with implementation of treatable traits into clinical practice and guidelines has been rapid in severe asthma and COPD and there is already evidence of impact, with a reduction in oral corticosteroid use in severe asthma and more economical and effective use of ICS in COPD. However, in less-severe asthma, GINA regards this approach as being too complex, and biomarker assessment is not recommended. We believe that making progress towards significant outcomes and implementing treatments tailored to specific traits in patients with low symptoms but high risk will remain challenging until this perspective changes.

Primary care and role of general practitioners

Whether and how the treatable traits approach can be applied in everyday practice, and specifically in primary care, still needs to be clarified. Although this approach is most often associated with severe asthma and specialist care, most patients are treated in the community by generalists. Respiratory symptoms, such as breathlessness, cough, sputum production, chest tightness and recurrent lower respiratory tract infections/acute respiratory episodes, are very common in primary care, where access to diagnostic tests is variable. Not only mild, but also severe diseases are managed in primary care. Different tests to detect core treatable traits from the three domains are widely available for primary care, as shown in tables 1 and 2.

1) With regard to lung function assessment, the spirometric assessment can be performed in the primary care setting, although the availability and use of spirometry varies markedly between countries and healthcare systems. Spirometry is required to make a diagnosis of COPD and has a fundamental role in asthma diagnosis [36]. Although concerns about the quality of spirometry in primary care do exist, proper support and training could ensure high quality.

2) As for airway inflammation, blood eosinophil count and FENO assessment are feasible in primary care. The former is a simple and easy-to-measure test, with the count being directly correlated to the risk of airway inflammation. The latter is a simple and cheap test, but its implementation is not yet well defined. FENO assessment has been shown to be technically easy to perform and could be cost-effective if used in primary care [57]. Therefore, in this context, the two fundamental pulmonary traits (i.e. inflammation and airflow inflammation) can be measured by general practitioners (GPs), and their assessment should become routine. GPs are used to assessing comorbidities (namely extrapulmonary traits) that affect asthma and COPD control, such as cardiovascular disease, obesity and anxiety. Among the behavioural traits, nonadherence and poor inhalation technique represent very common issues and should be assessed regularly in every patient during follow-up visits in primary care. Additional important treatable traits are smoking and other behaviours linked to environmental exposures, as well as self-management. Issues relating to adherence and inhalation technique are often not addressed by clinicians despite their importance. This is a major cause of concern since nonadherence strongly influences outcomes [58], and can be improved using strategies such as patient-centred communication, motivational interviewing [59, 60], shared decision-making [61] and simplification of drug regimens [62]. Despite the critical importance of optimal inhalation technique [63, 64] data suggest that the proportion of people with suboptimal technique is high, and this has not improved over the past 40 years [65]. Furthermore, healthcare professionals often lack the required knowledge and skills [66]. Interventions directed at improving both adherence and inhalation technique could include e-health tools including electronic monitoring devices and apps [67].

3) In stable COPD, anxiety and depression are very common [68]. Anxiety and depression play a role in increasing fatigue and decreasing physical function in patients with COPD [69]. The potential impact that interventions might have in these settings has been described by Heslop-Marshall et al. [70]. In a study including 279 patients with COPD, nurse-led cognitive behavioural therapies improved anxiety-related outcomes (measured by the Hospital Anxiety and Depression Scale anxiety subscales) significantly more than self-help leaflets.

4) Obesity, a common condition with a prevalence varying across different countries, is a treatable trait. In COPD, the treatment of obesity (using a very low-calorie diet and resistance exercise training) lead to multiple outcomes being improved: not only an improvement in body weight (6% loss), but also COPD disease outcomes, and improvements in other traits [71].

TABLE 2

Suggestions by a panel of experts for the implementation of the treatable traits approach in chronic respiratory disease clinical practice

Extrapulmonary and behavioural traits are critically important, and clinicians need to invest in them (assessment and personalised intervention). A selection of six essential treatable traits that GPs should be able to implement and map has been suggested and includes adherence, inhaler technique, smoking, airway obstruction (measurable by spirometry), eosinophilic airway inflammation and significant comorbidities (table 3). In this way, a more efficient patient pathway might be created, in which only selected patients will be referred to specialist clinics.

TABLE 3

Assessment of treatable traits in primary care

Multidisciplinary team

A multidisciplinary team (MDT) is ideally responsible for delivering care for all three domains of treatable traits, addressing each patient's specific needs. The patients are central to the MDT as their needs and/or preferences need to fully be taken into consideration.

A randomised controlled trial of a treatable traits approach in a severe asthma population (n=55) has been reported by McDonald et al. [72]. In this study people with severe asthma underwent a multidimensional assessment to identify traits. The MDT then developed a personalised treatment plan to target each of the traits identified and implementation of the plan in partnership with the patients was supported by a case manager. This MDT treatable trait approach lead to significant improvements in asthma quality of life and asthma control, and reduced primary care visits for asthma attacks.

Pulmonary rehabilitation provides another example of a MDT approach for chronic respiratory disease. There are opportunities to use this model of care as a vehicle for implementation of treatable traits; however, these opportunities may be lost. A systematic review conducted by Holland et al. [73] in 2022 included 116 pulmonary rehabilitation trials to determine which treatable traits had been addressed. Treatable traits from the three domains (pulmonary, extrapulmonary and behavioural/lifestyle) were categorised into three groups: definitely delivered, probably delivered and not delivered. Deconditioning was definitely delivered in 97% of programmes. Behavioural/lifestyle traits were poorly implemented, with nonadherence being addressed more than any other trait in this domain, but still only “definitely delivered” in 23% of studies. Therefore, this multidisciplinary model of care could address potentially assess and treat more traits effectively.

A potential model of implementation has been proposed recently, taking into account the different groups of patients, services, resources and healthcare teams. According to this model, primary care might address many focused treatable traits (e.g. anxiety, smoking, nonadherence) and if there is a lack of sufficient improvement, e.g. in terms of exacerbations, patients should be referred to secondary and tertiary care [74], where more comprehensive assessments and therapies could be provided within the context of an MDT. McDonald et al. [75] described in detail the multidisciplinary care in chronic respiratory disease, explaining the main characteristics of this approach: the interventions are determined based on a multidimensional assessment and are provided by an MDT, and care is personalised according to the traits identified. The staff of the MDT includes many professionals (e.g. nurse, psychologist, dietitian, physiotherapist), and although not everyone will have access to all, there will be members with crossover roles (for example, both nurse and physiotherapist can provide breath retraining). In conclusion, MDT management might represent a way in which significant gains could be made in the field of treatable traits, and it needs to be implemented to offer the best outcomes to patients.

Considering all the current evidence, concrete actions can be taken in clinical practice in order to implement a treatable traits approach in the management of these patients (table 2). In primary care, more financial investment to support GPs’ activities would be important. Furthermore, in order to facilitate the treatable traits approach in the primary care setting, the development of a checklist, including the aspects that GPs should consider during a consultation, might assist them while taking care of patients with chronic respiratory disease. In addition, simplified interaction with specialists would be beneficial to GPs. To implement an MDT approach, professional development and redefinition of each clinician's skills together with financial support to healthcare services is advisable.

A step forward: the GETomics approach

Any human disease is the end result of the interaction of genes and environment, which can be represented by the “G×E” equation. However, this equation lacks a crucial element: time. By adding this factor, the final equation would become “G×E×T”, paving the way for the new concept of GETomics [76]. The concept of GETomics provides a new dynamic and integrated understanding of the pathogenesis of human diseases in general, and respiratory diseases in particular. As such, it refers to the mechanisms underlying the clinical presentation, i.e. governing the treatable traits present in any given patient. Analysing low lung function (defined as FEV1<lower limit of normal) in different age groups, a large number of factors related to this outcome was observed. These factors appeared to interact over time and the complexity of this network clearly increased with age [77]. According to the GETomics approach, gene–environment interactions start from conception and continue until death, inducing biological responses (namely endotypes), such as innate or acquired immune responses, that modulate organ structure (development, maintenance and repair, ageing) and function. Therefore, two additional key factors should be considered: age and biological memory [76] (figure 3).

FIGURE 3

A GETomics approach to understand COPD and other chronic human diseases, where treatable traits are the end result of gene–environment interaction, and its accumulation, at different ages. Reproduced from [76] with permission.

Many studies have now shown that there is a range of lung function trajectories over the life course, which is defined as the “trajectome”. In healthy persons, the FEV1 peak is achieved around the age of 20 years, and, after a short plateau, a physiological decline occurs (“normal”). Approximately 10% of the general population never reaches this peak (“below normal”). This latter trajectory crosses the one of those presenting an “early decline” at ∼65–70 years, when a COPD diagnosis is often formulated [78]. To differentiate these two trajectories, specific biomarkers, and not spirometry, are necessary. The Tasmanian Longitudinal Health Study measured spirometry and followed-up individuals from childhood to late adulthood; it was found that circulating C-reactive protein (CRP) and CC16 could differentiate rapid decliners from normal decliners who had low peak lung function. Interestingly, levels of CRP were higher among rapid decliners, while levels of CC16 were lower in normal decliners [79]. In subjects in whom a non-properly developed lung function interacts with any detrimental environmental factor, such as smoking, a “premature death” trajectory could be possible. In addition, “supranormal trajectories” might be associated with very healthy ageing, or just evolve towards “pseudonormal trajectories” when developing COPD. Finally, children with low lung function can recover and achieve a normal trajectory during adolescence (“catch-up”) [78]: this is still poorly known but represents a crucial condition to further explore. There are data showing that the prevalence of concomitant cardiovascular and metabolic diseases in early adulthood (specifically at the age of 25 years) is much higher in patients with low lung function, and following them over time, comorbidities will occur 10 years earlier compared to those without compromised lung function development, with a greater rate of associated mortality [80]. There is, therefore, growing interest in the developmental origins of health and disease, which is an approach based on the concept that what happens in early life matters, and, consequently, on the role of prenatal and perinatal exposure to environmental factors [81].

Conclusions

An in-depth understanding of the treatable traits approach in the field of chronic respiratory disease results in concrete suggestions for its implementation in daily clinical practice within primary, secondary and tertiary care. The foundations for this holistic approach based on the range of interactions between genes and the environment occurring over an individual's lifespan, denominated GETomics, have already been laid and need to be transferred to clinical practice.

Footnotes

Provenance: Submitted article, peer reviewed.

Conflicts of interest: A Papi reports honoraria from AstraZeneca, Chiesi Farmaceutici, Boehringer Ingelheim, GlaxoSmithKline, Gentili, Pfizer, Novartis, Mundipharma, Novartis, TEVA and Zambon; research grants from AstraZeneca, Chiesi Farmaceutici, Boehringer Ingelheim, GlaxoSmithKline, Menarini, Fondazione Maugeri and Fondazione Chiesi; participation in a company sponsored bureau with AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Edmondpharma, GlaxoSmithKline, Mundipharma, Novartis, Sanofi/Regeneron, TEVA and Zambon. R. Faner reports honoraria from AstraZeneca and Chiesi, and research grants from GSK, AstraZeneca and Menarini. I. Pavord reports honoraria from AstraZeneca, Boehringer Ingelheim, Aerocrine, Chiesi, Novartis, Sanofi, Regeneron and GSK; research grants from Boehringer Ingelheim, GSK, AstraZeneca, Chiesi and Napp; participation in a company sponsored bureau with Almirall, AstraZeneca, Boehringer Ingelheim, GSK, MSD, Schering-Plough, Novartis, Dey, Napp, Sanofi and Regeneron. F. Baraldi reports no conflicts. V.M. McDonald reports honoraria from GSK and AstraZeneca; research grants from NHMRC and the Medical Reseach Futures Fund; other support or other potential conflict of interest: committee member for the COPD X guideline committee. M. Thomas reports honoraria from GSK, Boehringer Ingelheim and Chiesi. M. Miravitlles reports honoraria from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Inhibrx, Laboratorios Esteve, Ferrer, Menarini, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi and Grifols; research grants from Grifols; participation in a company sponsored bureau with AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Kamada, Takeda, Sandoz, Zambon, CSL Behring, Specialty Therapeutics, Janssen, Grifols and Novartis. N. Roche reports honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Zambon, Novartis, Pfizer, Sanofi, Teva, MSD and Austral; research grants from GSK, Novartis, Pfizer and Boehringer Ingelheim; other support or other potential conflict of interest: GOLD science committee, Respiratory Effectiveness Group, European Respiratory Society. A. Agustí reports honoraria from AstraZeneca, Chiesi, GSK, Menarini, MSD, Sanofi and Zambon; and research grants from AstraZeneca, GSK and Menarini.

Support statement: Editorial assistance was funded by Zambon SpA, with an unconditional grant.

Received July 13, 2023.Accepted October 24, 2023.Copyright ©The authors 2024http://creativecommons.org/licenses/by-nc/4.0/

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