For physiological treatable traits (Table 2), these were studied mostly in the setting of asthma, COPD, and bronchiectasis. These studies described traits including airflow limitation, hypoxemia/hypercapnia, lung hyperinflation, and ciliary dysfunction.

The most prominent physiological trait is airflow limitation, being the most common trait in asthma and COPD. The average prevalence was 52.5% in asthma [5,18,49], with the prevalence varying from 45.5–54.5% between studies [5,18,49]. As defined by a post-bronchodilator forced expiratory volume in the first second < 80% predicted, the prevalence in COPD was the highest, at 88.9% [18]. Airflow limitation has prognostic implications on asthma, leading to worsened severity of symptoms and increased exacerbations and healthcare utilisation [1]. Treatment of airflow limitation in asthma with long-acting muscarinic antagonists (LAMA) and bronchial thermoplasty have been shown to decrease exacerbations, improve lung function, and improve disease control [3,19,39], while short-acting anticholinergics and magnesium were found to decrease hospital admissions [1]. Similar treatments with LAMA, long-acting beta-agonists (LABA), inhaled corticosteroids (ICS), and pulmonary rehabilitation have been proposed to treat airflow limitation in COPD [18,42]. Airflow limitation was also described in bronchiectasis, with inhaled saline and airway clearance being the suggested treatment and with an ongoing trial on epithelial sodium channel inhibition [47].

Lung hyperinflation was also a trait targeted in the management of COPD patients, with endobronchial valves and bronchoscopic thermal vapour ablation showing improved lung function and quality of life [56]. 

Type-2 inflammation is widely documented as a treatable trait in chronic airway diseases like asthma and COPD (Table 3), with a prevalence of 42.0% in asthma patients [49]. Type-2 inflammation is characterised by T2-high expression, such as IL-13 induced genes or high eosinophil count. Chung et al. [59] reported that asthma patients with type-2 inflammation were predisposed to corticosteroid insensitivity and may be dependent on oral corticosteroids in severe cases. Treatment options include bronchodilators containing inhaled corticosteroids (ICS), which have been shown to be effective for asthma. ICS-LABA and ICS-LABA-LAMA combinations have similarly been effective for patients with COPD [42]. Anti-T2 biologics have also been shown to significantly reduce the risk of severe asthma exacerbation and improve lung function and quality of life of patients [59].

Specifically, eosinophilia is one of the most prominent biochemical traits studied, with its prevalence ranging from 51.4% to 56.4% in asthma and 22.2% to 60.1% in COPD [18,29,36]. Eosinophil levels can be measured using blood or sputum eosinophils, and high eosinophil levels are associated with increased risk of exacerbations in both asthma and COPD. In particular for asthma, Feng et al. [10] showed that patients with exacerbation-prone asthma had increased blood eosinophil and reduced lung function at baseline. Treatment for asthma and COPD patients with eosinophilia involves corticosteroid usage, which has been shown to be beneficial in acute exacerbations and to improve FEV1 of patients. Among patients with eosinophilia, monoclonal antibodies, such as anti-IL5, have also been reported to reduce exacerbations in COPD [29]. Specifically for asthma, omalizumab has been shown to significantly reduce both eosinophilia and exacerbations, with improved lung function and quality of life [45].

Neutrophil-related inflammation was also prominent in patients with asthma, bronchiectasis, and COPD, and it is identified by high sputum neutrophil counts [18]. It was associated with increased exacerbation risk for each of the above conditions [30], and high sputum neutrophil counts predicted more rapid decline in FEV1 in patients with bronchiectasis. Macrolides were shown to reduce exacerbations in asthma and COPD, while smoking cessation was additionally recommended for asthma patients. Neutrophil elastase inhibitors were also shown to improve lung function and quality of life for patients with bronchiectasis [4].

As for environmental exposure in united airway diseases identified by immunoglobulin E (IgE) levels and skin-prick tests, proposed treatment options included exposure avoidance, respiratory protection devices, and anti-IgE therapy [57]. However, data on the prevalence of these traits were lacking, and studies evaluating the clinical benefits of the proposed treatment strategies were not available either.

Two main psychosocial traits identified were treatment adherence/technique and smoking history (Table 4). Education and medication reconciliation are the main treatment options, targeting inhaler technique, self-management action plans, and minimising the number of inhaler devices [18].

Smoking was prevalent among patients with chronic respiratory diseases, with a mean prevalence of 14.3% in asthma and 19.4% in COPD [18]. Smoking status was usually assessed through interview or the use of exhaled carbon monoxide and was shown to be a significant risk factor for exacerbation in chronic airway diseases [31]. Smoking cessation was shown to reduce lung-function decline and risk of recurrent exacerbations, highlighting the importance of opportunistic implementation of smoking cessation strategies during acute exacerbations [31]. Management options include counselling with pharmacologic adjuncts, such as nicotine replacement therapy, varenicline, and bupropion [18,31,42].

Low socioeconomic status and poor family support in chronic airway disease were also associated with increased symptomatic deterioration and exacerbations, with social support services proposed as a possible treatment option [31].

Microbiological treatable traits were mostly found in asthma, bronchiectasis, COPD, and united (combined upper and lower) airway diseases. The most prevalent trait was chronic respiratory infection in both asthma and COPD, with an average prevalence of 45.0% and a prevalence range of 34.8–47.3% among the studies on asthma [18,21,49]. Various treatment options, such as antibiotics, mucolytics, roflumilast, education, and inhaled interferon-β treatment, were suggested [1,5,18]. However, evidence was lacking regarding their efficacy. In patients with COPD, chronic respiratory infection was present in 55.6% of the patients [18], with prognostic implications on their quality of life and dyspnoea severity [28]. Macrolides have been shown to decrease hospital admissions resulting from exacerbations, but their usage must be balanced against the risk of colonisation with macrolide-resistant organisms [28].

Another prominent microbiological trait is microbial colonisation, present in an average of 18.9% of asthmatics, with a range varying from 12.7 to 55.6% [5,18]. Microbial colonisation was present in an average of 44.8% of COPD patients, with prevalence ranging from 38.9 to 45% [18,27]. This is a separate trait from infection, as colonisation refers to the presence of organisms, while infection refers to the presence of signs and symptoms due to these organisms. Microbial colonisation nonetheless had prognostic significance, demonstrated particularly in COPD patients, with implications on quality of life and increment in dyspnoea [27]. Treatment options for this trait in patients with asthma include education and antibiotic-based written action plans (e.g., using macrolides) [18,19]. However, information regarding treatment options for this trait was inadequate in COPD. Interestingly, patients with microbial colonisation had lower mortality for exacerbations associated with viral infections compared to bacterial infections, though the clinical significance of this is uncertain [27].

Impaired physical function is a comorbidity seen in almost all chronic respiratory conditions, with a prevalence of 36.1% in COPD and 10.9% in asthma [18]. Impaired physical function can present in different forms, such as low appendicular skeletal muscle mass, limitations in mobility, and low muscle strength and has been shown to be an independent predictor of hospital admission and mortality in COPD. Patients with lower 6 min walking distance were also reported to have higher readmission risk [31]. Various management measures targeted at physical function can be implemented. For instance, Hiles et al. [18] recommended a high-protein diet, strength training, and regular pulmonary rehabilitation for patients with low appendicular skeletal muscle mass.

Another prevalent comorbidity trait is the presence of psychiatric conditions, particularly depression and anxiety in asthma and COPD. Treatments included counselling, cognitive behavioural therapy, and paroxetine [18,28].

Nutrition (underweight) is another common comorbidity, with a prevalence of 52.8% in COPD [18] and 38.1% in asthma, with a range of 35.1–58.2% [18]. These traits had similar prognostic implications, with decreased quality of life, increased severity of symptoms, and increased exacerbations [28,30,39,51]. Treatments to normalise body mass index, such as supplementation and weight loss, have also been shown to decrease asthma severity [39]. However, treatment benefits for COPD were not described in the literature.

Some of the other comorbidity traits with high prevalence include systemic inflammation, which was present in 56.4% of asthmatics and 63.9% of COPD patients, and sleep disorders, with a prevalence of 60.0% and 30.6% in patients with asthma and COPD, respectively [18]. For the mitigation of systemic inflammation, McDonald et al. showed that statin therapy improved C-reactive protein levels in COPD patients [2]. Separately, positive airway pressure has been shown to reduce overall mortality and exacerbation risk in COPD patients with sleep disorders, though its efficacy may be limited by patient adherence [28].