Recognition of obesity as a treatable trait of asthma, impacting its development, clinical presentation and management, is gaining widespread acceptance. Obesity is a significant risk factor and disease modifier for asthma, complicating treatment. Epidemiological evidence highlights that obese asthma correlates with poorer disease control, increased severity and persistence, compromised lung function and reduced quality of life. Various mechanisms contribute to the physiological and clinical complexities observed in individuals with obesity and asthma. These encompass different immune responses, including Type IVb, where T helper 2 cells are pivotal and driven by cytokines like interleukins 4, 5, 9 and 13, and Type IVc, characterised by T helper 17 cells and Type 3 innate lymphoid cells producing interleukin 17, which recruits neutrophils. Additionally, Type V involves immune response dysregulation with significant activation of T helper 1, 2 and 17 responses. Finally, Type VI is recognised as metabolic-induced immune dysregulation associated with obesity. Body mass index (BMI) stands out as a biomarker of a treatable trait in asthma, readily identifiable and targetable, with significant implications for disease management. There exists a notable gap in treatment options for individuals with obese asthma, where asthma management guidelines lack specificity. For example, there is currently no evidence supporting the use of incretin mimetics to improve asthma outcomes in asthmatic individuals without Type 2 diabetes mellitus (T2DM). In this review, we advocate for integrating BMI into asthma care models by establishing clear target BMI goals, promoting sustainable weight loss via healthy dietary choices and physical activity and implementing regular reassessment and referral as necessary.

Chronic obstructive pulmonary disease (COPD), a heterogeneous respiratory disease driven by various genetic and environmental factors, presents significant challenges in diagnosis and management. Traditional approaches focused on phenotypic classification, but recent paradigms emphasize identifying and addressing treatable traits to personalize treatment strategies. Treatable traits facilitate personalized interventions, optimizing symptom control, and reducing exacerbation risk. Dyspnea and exacerbations, recognized as key traits, guide treatment decisions and follow-up management. Various interventions, including bronchodilators, corticosteroids, and lifestyle modifications, target specific traits like airway inflammation, mucus overproduction, and emphysema. Strategies for assessing and addressing treatable traits during initial encounters and follow-up visits enhance disease monitoring and treatment efficacy. Comprehensive trait assessment demands resources and specialized monitoring, posing barriers to widespread implementation. The lack of standardized protocols and evolving evidence further complicates decision-making and clinical practice. Despite these challenges, the shift toward treatable traits-based management signifies a pivotal advancement in COPD care, emphasizing holistic approaches tailored to individual patient needs. Recognizing and addressing treatable traits offers personalized interventions, enhancing symptom control and disease management. Embracing treatable traits-based approaches holds promise for improving clinical outcomes and enhancing the quality of life for individuals living with COPD.

To date, the treatable traits (TTs) approach has been applied in the context of managing diagnosed diseases. TTs are clinical characteristics and risk factors that can be identified clinically and/or biologically, and that merit treatment if present. There has been an exponential increase in the uptake of this approach by both researchers and clinicians. Realizing the potential of the TTs approach to pre-clinical disease, this expert review proposes that it is timely to consider acting on TTs present before a clinical diagnosis is made, which might help to prevent development of the full disease. Such an approach is ideal for diseases where there is a long pre-clinical phase, such as in chronic obstructive pulmonary disease (COPD). The term \'pre-COPD\' has been recently proposed to identify patients with respiratory symptoms and/or structural or functional abnormalities without airflow limitation. They may eventually develop airflow limitation with time but patients with pre-COPD are likely to have traits that are already treatable. This review first outlines the contribution of recently generated knowledge into lifetime lung function trajectories and the conceptual framework of \'GETomics\' to the field of pre-COPD. GETomics is a dynamic and cumulative model of interactions between genes and the environment throughout the lifetime that integrates information from multi-omics to understand aetiology and mechanisms of diseases. This review then discusses the current evidence on potential TTs in pre-COPD patients and makes recommendations for practice and future research. At a broader level, this review proposes that introducing the TTs in pre-COPD may help reenergize the preventive approaches to health and diseases.

BACKGROUND: Long COVID (LC) is a global public health crisis affecting more than 70 million people. There is emerging evidence of different pathophysiological mechanisms driving the wide array of symptoms in LC. Understanding the relationships between mechanisms and symptoms helps in guiding clinical management and identifying potential treatment targets.
METHODS: This was a mixed-methods systematic review with two stages: Stage one (Review 1) included only existing systematic reviews (meta-review) and Stage two (Review 2) was a review of all primary studies. The search strategy involved Medline, Embase, Emcare, and CINAHL databases to identify studies that described symptoms and pathophysiological mechanisms with statistical analysis and/or discussion of plausible causal relationships between mechanisms and symptoms. Only studies that included a control arm for comparison were included. Studies were assessed for quality using the National Heart, Lung, and Blood Institute quality assessment tools.
RESULTS: 19 systematic reviews were included in Review 1 and 46 primary studies in Review 2. Overall, the quality of reporting across the studies included in this second review was moderate to poor. The pathophysiological mechanisms with strong evidence were immune system dysregulation, cerebral hypoperfusion, and impaired gas transfer in the lungs. Other mechanisms with moderate to weak evidence were endothelial damage and hypercoagulation, mast cell activation, and auto-immunity to vascular receptors.
CONCLUSIONS: LC is a complex condition affecting multiple organs with diverse clinical presentations (or traits) underpinned by multiple pathophysiological mechanisms. A \'treatable trait\' approach may help identify certain groups and target specific interventions. Future research must include understanding the response to intervention based on these mechanism-based traits.

Disease of the peripheral (or small) airways is fundamental in asthma, being closely related to symptoms (or lack of control of them), airway hyperresponsiveness, spirometric abnormalities, risk of loss of control, or exacerbations and inflammation. Current technology now allows routine measurement of peripheral airway function. Having a working concept of peripheral airways disease in asthma is arguably very useful to clinicians and beneficial to patients because it allows a more comprehensive assessment of asthma severity (rather than just symptoms alone, which is the norm), tracking of progress or deterioration, and assessing response to treatment. Oscillometry is a sensitive way to monitor the peripheral airways, whereas multiple breath nitrogen washout parameters are excellent measures of future risk. In the longer term, physiologic measurements will be crucial in research to define causes and find new disease-modifying treatments.

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BACKGROUND: Breathing pattern disorder (BPD) reflects altered biomechanical patterns of breathing that drive breathing difficulty and commonly accompanies difficult-to-treat asthma. Diagnosis of BPD has no gold standard, but Nijmegen Questionnaire (NQ) >23 is commonly used.
OBJECTIVE: We sought to advance clinical characterization of BPD and better understand the clinical utility of NQ in difficult asthma in patients from the Wessex AsThma CoHort of difficult asthma (WATCH) study.
METHODS: Associations between demographic and clinical factors in difficult asthma and BPD, ascertained by clinical diagnosis (yes/no, n = 476), by NQ scores (≤23: normal [no suggestion of BPD] and >23: abnormal [suggested BPD], n = 372), as well as the continuous raw NQ scores were assessed in univariate models to identify significant risk factors associated with the 3 BPD outcomes. For the clinician-diagnosed and NQ-based BPD, associations of continuous factors were assessed using the independent samples t test or the Mann-Whitney U test as appropriate for the data distribution or by the Spearman correlation test. Dichotomous associations were evaluated using χ2 tests. Multivariable logistic (dichotomous outcomes) and linear regression models (continuous outcomes) were developed to identify predictive factors associated with clinician-diagnosed and NQ-based BPD, dichotomous and continuous. Patients with data on NQ scores were grouped into NQ quartiles (low, moderate, high, and very high). The patterns of association of the quartiles with 4 health-related questionnaire outcomes were assessed using linear regression analyses.
RESULTS: Multivariable regression identified that clinically diagnosed BPD was associated with female sex (odds ratio [OR]: 1.85; 95% confidence interval [CI]: 1.07, 3.20), comorbidities (rhinitis [OR: 2.46; 95% CI: 1.45, 4.17], gastroesophageal reflux disease [GORD] [OR: 2.77; 95% CI: 1.58, 4.84], inducible laryngeal obstruction [OR: 4.37; 95% CI: 2.01, 9.50], and any psychological comorbidity [OR: 1.86; 95% CI: 1.13, 3.07]), and health care usage (exacerbations [OR: 1.07; 95% CI: 1.003, 1.14] and previous intensive care unit (ICU) admissions [OR: 2.03; 95% CI: 1.18, 3.47]). Abnormal NQ-based BPD diagnosis was associated with history of eczema (OR: 1.83; 95% CI: 1.07, 3.14), GORD (OR: 1.94; 95% CI: 1.15, 3.27), or any psychological comorbidity (OR: 4.29; 95% CI: 2.64, 6.95) at multivariable regression. Differences between clinical and NQ-based BPD traits were also found with 42% discordance in BPD state between these definitions. Multivariable linear regression analysis with NQ as a continuous outcome showed positive association with worse asthma outcomes (admission to ICU, P = .037), different phenotypic traits (female sex, P = .001; ever smoker, P = .025), and greater multimorbidity (GORD, P = .002; sleep apnea, P = .04; and any psychological comorbidity, P < .0001).
CONCLUSIONS: BPD is associated with worse health outcomes and negative health impacts in difficult asthma within a multimorbidity disease model. It therefore merits better recognition and prompt treatment. Clinical diagnosis and NQ offer different perspectives on BPD, so this goal may be best addressed by considering clinical features alongside the magnitude of NQ.

BACKGROUND: Frailty associates with increased vulnerability to adverse health outcomes and reduced tolerance to medical interventions. Its impact on patients with chronic respiratory diseases, particularly beyond chronic obstructive pulmonary disease (COPD), remains poorly understood.
OBJECTIVE: To evaluate the association between frailty index and 5-year mortality across different \"spirometric\" patterns and the variation in their occurring frailty determinants.
METHODS: This study analyzed data from the SARA study, which enrolled 1968 older adults, to evaluate the association between frailty and 5-year mortality across different spirometric patterns. Frailty was assessed using the frailty index (FI), and spirometry was performed to determine lung function patterns. Hazard ratios (HRs) were calculated using Cox regression models, adjusting for age and sex.
RESULTS: Among the study participants, 16% were classified as frail. Frailty was associated with a significantly increased risk of mortality across all spirometric patterns. The 5-year mortality rates were 34.3% in subjects with normal spirometry, 45.1% in those with obstructive defects, 55% in those with restrictive defects, and 42.6% in those with mixed airflow defects. The unadjusted HRs for mortality were 2.64 (95% CI 2.10-3.32) for the overall cohort, 2.24 (95% CI 1.48-3.40) for obstructive defects, 2.45 (95% CI 1.12-5.36) for restrictive defects, and 2.79 (95% CI 1.41-3.17) for mixed airflow defects. After adjusting for age and sex, the HRs remained statistically significant: 2.25 (95% CI 1.37-2.84) for the overall cohort, 2.08 (95% CI 1.37-3.18) for obstructive defects, 2.27 (95% CI 1.04-1.17) for restrictive defects, and 2.21 (95% CI 1.20-3.08) for mixed airflow defects.
CONCLUSIONS: Frailty is a common syndrome and is associated with a significantly increased risk of mortality. The FI provides valuable information for risk profiling and personalized interventions beyond age and lung function parameters. Including frailty assessment in clinical evaluations can aid in resource allocation and improve patient care in respiratory diseases.

Systemic sclerosis (SSc) is a chronic systemic disease within the spectrum of connective tissue diseases, specifically characterized by vascular abnormalities and inflammatory and fibrotic involvement of the skin and internal organs resulting in high morbidity and mortality. The clinical phenotype of SSc is heterogeneous, and serum autoantibodies together with the extent of skin involvement have a predictive value in the risk stratification. Current recommendations include an organ-based management according to the predominant involvement with only limited individual factors included in the treatment algorithm. Similar to what has been proposed for other chronic diseases, we hypothesize that a \"treatable trait\" approach based on relevant phenotypes and endotypes could address the unmet needs in SSc stratification and treatment to maximize the outcomes. We provide herein a comprehensive review and a critical discussion of the literature regarding potential treatable traits in SSc, focusing on established and candidate biomarkers, with the purpose of setting the bases for a precision medicine-based approach. The discussion, structured based on the organ involvement, allows to conjugate the pathogenetic mechanisms of tissue injury with the proposed predictors, particularly autoantibodies and other serum biomarkers. Ultimately, we are convinced that precision medicine is the ideal guide to manage a complex condition such as SSc for which available treatments are largely unsatisfactory.

Asthma imposes a significant health and socioeconomic burden with an average prevalence impacting 5-10% of the global population. The aim of this narrative review is to update the current literature on topics related to asthma diagnosis.
Original research articles were identified from PubMed using the search terms \"asthma diagnosis\" and \"asthma misdiagnosis\".
Recently published articles (n = 51) detailing the diagnosis, misdiagnosis of asthma, and the updated recommendations of the European and international asthma guidelines.
Emerging evidence revealed that asthma might represent a rather heterogenous clinical entity with varying underlying molecular mechanisms. Attempts have been made to unravel these traits to better provide accurate diagnosis and a more efficient patient-based management approach. The lack of a gold standard test for asthma diagnosis has contributed to its over- and underdiagnosis. This is problematic, given that overdiagnosis might lead to delay of both diagnosis and prompt treatment of other diseases, while underdiagnosis might substantially impact quality of life due to progression of asthma by increased rate of exacerbations and airway remodeling. In addition to poor asthma control and potential patient harm, asthma misdiagnosis is also associated with excessive costs. As a result, current international guidelines emphasize the need for a standardized approach to diagnosis, including objective measurements prior to treatment.
Future research is warranted to define the optimal diagnostic and treatable traits approach especially for patients with severe asthma, as they may benefit from the advent of newly targeted asthma management.