Fungal-Associated Endotypes as a Treatable Trait in Bronchiectasis.

Background: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be assessed using registry data, the prevalence of traits in severe and non-severe asthma, and whether particular treatable traits were associated with future exacerbation risk. Methods: The Australasian Severe Asthma Web-based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 with non-severe. Published treatable traits were mapped to registry data fields and their prevalence described. Participants were characterised at baseline and each 6 months for 24 months. Results: In SAWD, 24 treatable traits were identified in three domains: pulmonary (7 traits), extrapulmonary (13 traits) and behavioural/risk-factors (4 traits). People with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitisation, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being exacerbation prone (IRR 2.07 (1.66, 2.58), depression (IRR 1.63 (1.31, 1.88), inhaler-device polypharmacy (IRR 1.51 (1.31, 1.75), vocal cord dysfunction (IRR 1.51 (1.22, 1.88) and obstructive sleep apnoea (IRR 1.41 (1.05, 1.89). Conclusion: Treatable traits can be assessed using severe asthma registry data. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating clinical utility of assessing treatable traits.

BackgroundSpecialist intervention in COPD is often reactive, resulting in inequalities in the provision of care. A proactive approach, in which individuals with modifiable disease are identified from primary care records, may help to tackle this inequality in access.AimTo estimate the prevalence of “treatable traits” in COPD in a primary care research database and to assess health service usage.MethodsWe performed a secondary analysis of individuals with either 1) a primary care diagnosis of COPD or 2) obstructive spirometry and history of ever smoking in a large observational study recruiting individuals aged 40–69 years old in Leicestershire, UK. Spirometry, height, weight and smoking history were collected prospectively and linked to individuals’ primary care records. “Treatable traits” were identified from primary care records (frequent exacerbations, current smoking, low body mass index, respiratory failure, severe breathlessness, potential suitability for lung volume reduction or psychological comorbidity). Differences in demographics and health usage between those with and without “treatable traits” were assessed.ResultsIn total, of the 347 individuals with COPD, 186 had at least one “treatable trait”. Compared to those without treatable traits, individuals with treatable traits were younger (61 vs 64 years, p<0.001), had more severe airflow obstruction (FEV1 86% vs 94% predicted, p=0.002), higher eosinophil count (0.32 vs 0.27 cells/μL, p=0.04) and were more socioeconomically deprived (UK Indices of Multiple Deprivation decile 4.3 vs 5.8, p<0.001). Individuals with treatable traits had a higher annual primary care health usage (47 vs 30 visits per year, p=0.001). Referrals rates to specialist respiratory services were low in both groups.ConclusionTreatable traits are common in COPD and can be identified from routinely collected primary care data. Treatable traits are associated with younger age and greater deprivation. These individuals pose a significant burden to primary care yet are rarely referred to specialist respiratory services.

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma-allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a "treatable traits" approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Background: Bronchiectasis is a chronic respiratory condition characterized by permanent bronchial dilation, recurrent infections, and progressive lung damage. A subset of patients, known as frequent exacerbators, experience multiple exacerbations annually, leading to accelerated lung function decline, hospitalizations, and reduced quality of life. The aim of this study is to identify distinct phenotypes and treatable traits in bronchiectasis frequent exacerbators, since it could be crucial for optimizing patient management. Research question: Could clinically distinct phenotypes and treatable traits be identified among frequent exacerbators with bronchiectasis to guide personalized management strategies? Methods: We analysed a cohort of 56 bronchiectasis frequent exacerbator patients using 21 clinically relevant variables, including pulmonary function tests, radiological patterns, and microbiological data. Hierarchical clustering and k-means algorithms were applied to identify subgroups. Key outcomes included cluster-specific characteristics, treatable traits, and their implications for management. Results: Four distinct clusters were identified: 1. Mild, idiopathic bronchiectasis (Cluster 1): Predominantly mild disease (FACED), idiopathic etiology (93.3%), and cylindrical bronchiectasis with moderate obstruction (60%). 2. Rheumatological and NTM-associated bronchiectasis (Cluster 2): Patients with systemic inflammatory diseases (50%) and NTMever (50%) but minimal infections by Pseudomonas aeruginosa. 3. Mild, post-infective bronchiectasis (Cluster 3): Exclusively mild disease, mixed idiopathic and post-infective etiologies, and preserved lung function. 4. Severe, chronic infection phenotype (Cluster 4): Severe disease with high colonization rates of Pseudomonas aeruginosa (71.4%), advanced structural damage (57.1% varicose, 50% cystic bronchiectasis), and frequent exacerbations. Interpretation: This analysis highlights the heterogeneity of bronchiectasis and its frequent exacerbator phenotype. The treatable traits framework underscores the importance of aggressive infection control and management of airway inflammation in severe cases, while milder clusters may benefit from preventive strategies. These findings support the integration of precision medicine in bronchiectasis care, focusing on phenotype-specific interventions to improve outcomes.

IntroductionThe present study assessed the prevalence of nine treatable traits (TTs) pinpointing nonpharmacological interventions in patients with COPD upon first referral to a pulmonologist, how these TTs co-occurred and whether and to what extent the TTs increased the odds having a severely impaired health status.MethodsData were collected from a sample of 402 COPD patients. A second sample of 381 patients with COPD was used for validation. Nine TTs were assessed: current smoking status, activity-related dyspnoea, frequent exacerbations <12 months, severe fatigue, depressed mood, poor physical capacity, low physical activity, poor nutritional status and a low level of self-management activation. For each TT the odds ratio (OR) of having a severe health status impairment was calculated. Furthermore, a graphic representation was created, the COPD sTRAITosphere, to visualise TTs prevalence and OR.ResultsOn average 3.9±2.0 TTs per patient were observed. These TTs occurred relatively independently of each other and coexisted in 151 unique combinations. A significant positive correlation was found between the number of TTs and Clinical COPD Questionnaire total score (r=0.58; p<0.001). Patients with severe fatigue (OR: 8.8), severe activity-related dyspnoea (OR: 5.8) or depressed mood (OR: 4.2) had the highest likelihood of having a severely impaired health status. The validation sample corroborated these findings.ConclusionsUpon first referral to a pulmonologist, COPD patients show multiple TTs indicating them to several nonpharmacological interventions. These TTs coexist in many different combinations, are relatively independent and increase the likelihood of having a severely impaired health status.

This position paper has been drafted by experts from the Czech national board of diseases with bronchial obstruction, of the Czech Pneumological and Phthisiological Society. The statements and recommendations are based on both the results of randomized controlled trials and data from cross-sectional and prospective real-life studies to ensure they are as close as possible to the context of daily clinical practice and the current health care system of the Czech Republic. Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable heterogeneous syndrome with a number of pulmonary and extrapulmonary clinical features and concomitant chronic diseases. The disease is associated with significant mortality, morbidity and reduced quality of life. The main characteristics include persistent respiratory symptoms and only partially reversible airflow obstruction developing due to an abnormal inflammatory response of the lungs to noxious particles and gases. Oxidative stress, protease-antiprotease imbalance and increased numbers of pro-inflammatory cells (mainly neutrophils) are the main drivers of primarily non-infectious inflammation in COPD. Besides smoking, household air pollution, occupational exposure, low birth weight, frequent respiratory infections during childhood and also genetic factors are important risk factors of COPD development. Progressive airflow limitation and airway remodelling leads to air trapping, static and dynamic hyperinflation, gas exchange abnormalities and decreased exercise capacity. Various features of the disease are expressed unequally in individual patients, resulting in various types of disease presentation, emerging as the "clinical phenotypes" (for specific clinical characteristics) and "treatable traits" (for treatable characteristics) concept. The estimated prevalence of COPD in Czechia is around 6.7% with 3,200-3,500 deaths reported annually. The elementary requirements for diagnosis of COPD are spirometric confirmation of post-bronchodilator airflow obstruction (post-BD FEV1/VCmax <70%) and respiratory symptoms assessement (dyspnoea, exercise limitation, cough and/or sputum production. In order to establish definite COPD diagnosis, a five-step evaluation should be performed, including: 1/ inhalation risk assessment, 2/ symptoms evaluation, 3/ lung function tests, 4/ laboratory tests and 5/ imaging. At the same time, all alternative diagnoses should be excluded. For disease classification, this position paper uses both GOLD stages (1 to 4), GOLD groups (A to D) and evaluation of clinical phenotype(s). Prognosis assessment should be done in each patient. For this purpose, we recommend the use of the BODE or the CADOT index. Six elementary clinical phenotypes are recognized, including chronic bronchitis, frequent exacerbator, emphysematous, asthma/COPD overlap (ACO), bronchiectases with COPD overlap (BCO) and pulmonary cachexia. In our concept, all of these clinical phenotypes are also considered independent treatable traits. For each treatable trait, specific pharmacological and non-pharmacological therapies are defined in this document. The coincidence of two or more clinical phenotypes (i.e., treatable traits) may occur in a single individual, giving the opportunity of fully individualized, phenotype-specific treatment. Treatment of COPD should reflect the complexity and heterogeneity of the disease and be tailored to individual patients. Major goals of COPD treatment are symptom reduction and decreased exacerbation risk. Treatment strategy is divided into five strata: risk elimination, basic treatment, phenotype-specific treatment, treatment of respiratory failure and palliative care, and treatment of comorbidities. Risk elimination includes interventions against tobacco smoking and environmental/occupational exposures. Basic treatment is based on bronchodilator therapy, pulmonary rehabilitation, vaccination, care for appropriate nutrition, inhalation training, education and psychosocial support. Adequate phenotype-specific treatment varies phenotype by phenotype, including more than ten different pharmacological and non-pharmacological strategies. If more than one clinical phenotype is present, treatment strategy should follow the expression of each phenotypic label separately. In such patients, multicomponental therapeutic regimens are needed, resulting in fully individualized care. In the future, stronger measures against smoking, improvements in occupational and environmental health, early diagnosis strategies, as well as biomarker identification for patients responsive to specific treatments are warranted. New classes of treatment (inhaled PDE3/4 inhibitors, single molecule dual bronchodilators, anti-inflammatory drugs, gene editing molecules or new bronchoscopic procedures) are expected to enter the clinical practice in a very few years.

See related Article

Treatable Traits That Predict Health Status and Treatment Response in Airway Disease

In the last years, disease classification of chronic respiratory diseases (CRD) has been vivaciously discussed and new concepts have been introduced, namely asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO). Controversially the GOLD consensus document of 2020 considered that we should no longer refer to ACO, as they constitute two different diseases that may share some common traits and clinical features. The treatable traits approach has numerous strengths that are applicable to several levels of health care. In this paper we review the application of the treatable traits to CRD and describe in detail the ones already identified in patients with asthma and COPD. Treatable traits in CRD can be divided in pulmonary, extra-pulmonary and behavior/lifestyle risk factors. Patients with both asthma and COPD patients have clearly recognized treatable traits in all these subtopics but it is notorious the severe and frequent exacerbations, the associated cardiovascular disease and the low health related quality of life and productivity of these patients.

Introduction and objectives Asthma is a complex chronic respiratory disease which is characterised by several identifiable and treatable traits. The most clinically impactful being airway inflammation and airflow limitation. Asthma management plans are often impacted by many pulmonary and extra-pulmonary co-morbidities, risk factors and triggers. A multidimensional assessment1 of ‘treatable traits’ could be an effective strategy to assess disease heterogeneity in severe asthma, enabling the application of precision medicine to chronic airways disease.2 We reviewed new referrals to our severe asthma clinic over a 6 week period to evaluate how those approaches can help in the management of our own patients. Methods We performed a systematic, case-notes review of prospectively-collected data from all consecutive referrals collected over a 6 week period. Results Over a 6 week period, we reviewed 37 new-patient referrals. The average age was 54 years old, with a male:female ratio of 2:3. From the fourteen traits considered, an average of 3.8 traits per person (range 2 to 10) were identified. The three most dominant traits were found to be atopy (72% of those analysed), anxiety/depression (62.5%), and airflow limitation (59.5%) whereas the three least dominant traits were identified as dysfunctional breathing (3%), smoking (13.9%) and poor inhaler technique (26.9%). Of the dominant traits, 0% of patients were treated for anxiety/depression compared with 50% and 45.5% for atopy and airflow limitation respectively. Conclusions New referrals to our severe asthma clinic are complex and have a number of comorbid conditions or traits in addition to airflow limitation and airway inflammation. Identification of these is potentially important as they may be driving symptoms which will not be responsive to increased therapy targeting airflow limitation and airway inflammation. Evidence-based interventions targeted at the identified traits are required for a multi-dimensional treatment approach. References Clark V, Gibson P, Genn G, Pavord I, McDonald V. Multidimensional assessment in severe asthma: A systematic review. European Respiratory Journal 2017;501090. doi:10.1183/1393003.congress-2017.PA1090 Agusti A, Bafadhel M, Beasley R, Bel EH, Faner R, Gibson PG, Louis R, McDonald V, Sterk PJ, Thomas M, Vogelmeier C, Pavord ID. Precision medicine in airway diseases: Moving to clinical practice. European Respiratory Journal 2017;50(4):1701655. doi:10.1183/13993003.01655–2017

Journal Club - Bronchiectasis/COPD Overlap: Syndrome Versus Treatable Trait?

Exacerbations of bronchiectasis are heterogeneous events characterized by worsening symptoms and increased infection. These episodes impair patients' quality of life and increase mortality. They also serve as crucial indicators when monitoring disease progression and assessing therapeutic interventions. The Treatable traits' strategy is a model of care that targets multiple modifiable characteristics to deliver precision medicine and improve clinical prognosis. This study focuses on treatable traits including respiratory infections, airway inflammation, respiratory symptoms, comorbidities, underlying aetiologies, and behavioural or lifestyle factors. It examines their association with bronchiectasis exacerbations, with the aim of enabling the clinical implementation of this framework for reducing exacerbation frequency.

Asthma continues to be a major cause of illness with a significant mortality, despite its increasing range of treatments. Adoption of a treatable traits approach in specialist centres has led to improvements in control of asthma and reduced exacerbations in patients with severe asthma. However, most patients with this illness, particularly those with mild-to-moderate asthma, are cared for in primary care according to guidelines that emphasise the use of pharmacotherapeutic ladders uniformly implemented across all patients. These pharmacotherapeutic ladders are more consistent with a "one-size-fits-all" approach than the treatable traits approach. This can be harmful, especially in patients whose symptoms and airway inflammation are discordant, and extra-pulmonary treatable traits are often overlooked. Primary care has extensive experience in patient-centred holistic care, and many aspects of the treatable traits approach could be rapidly implemented in primary care. Blood eosinophil counts, as a biomarker of the treatable trait of eosinophilia, are already included in routine haematology tests and could be used in primary care to guide titration of inhaled corticosteroids. Similarly, poor inhaler adherence could be further assessed and managed in primary care. However, further research is needed to guide how some treatable traits could feasibly be assessed and/or managed in primary care, for example, how to best manage patients in primary care, who are likely suffering from breathing pattern disorders and extra-pulmonary treatable traits, with frequent use of their reliever inhaler in the absence of raised T2 biomarkers. Implementation of the treatable traits approach across the disease severity spectrum will improve the quality of life of patients with asthma but will take time and research to embed across care settings.

Background: "Treatable traits (TTs)" is a precision medicine strategy for the management of chronic airway diseases. However, data on TTs in hospitalized AECOPD patients are limited. This study aimed to determine the prevalence of TTs in Chinese patients hospitalized with AECOPD and which traits predict future exacerbation risk, and to develop an exacerbation prediction model. Methods: This multicenter, cohort study recruited patients hospitalized with AECOPD from January 2022 to April 2023. Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for one year. Cox regression analyses were used to determine the association between TTs and future exacerbations and develop a prediction model. Results: Finally, 28 TTs, including pulmonary (n=11), extra-pulmonary (n=12) and behavioral/risk factors (n=5) were identified. Five traits were associated with increased risk of future AECOPD readmission, including frequent exacerbations in the past year (adjusted HR: 2.079, 95% CI: 1.246-3.469), O2 desaturation (adjusted HR: 1.754, 95% CI: 1.001-3.075), eosinophilic airway inflammation (adjusted HR: 1.731, 95% CI: 1.078-2.777), pathogen colonization (adjusted HR: 1.852, 95% CI: 1.147-2.990) and gastroesophageal reflux (adjusted HR: 5.500, 95% CI: 1.923-15.730). Furthermore, one regression model was developed to predict personalized exacerbation risk and showed acceptable performance. Conclusion: TTs can be systematically assessed in Chinese patients hospitalized with AECOPD, some of which are associated with future exacerbation-related readmission.