## 1 Introduction  
Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory condition characterized by airway inflammation and destruction of lung parenchyma. Patients often experience symptoms such as dyspnea, cough, and sputum production. The development of COPD is strongly associated with gene-environment interplay, with tobacco smoking and inhalation of toxic particles being the main environmental factors. The diagnosis of COPD is usually confirmed through spirometry, which detects airflow obstruction (FEV1/FVC \(<\) 0.7 after bronchodilation), in the relevant clinical context. However, despite clear diagnostic criteria, COPD remains under-diagnosed, and its exact prevalence is elusive. Nevertheless, the global prevalence of COPD is estimated at 10.3% [1], and approximately three million deaths annually are attributed to the disease [2]. The natural progression of COPD involves acute respiratory events characterized by worsening symptoms that call for additional therapeutic measures. Exacerbations are classified as mild when treated with short-acting bronchodilators only, moderate when antibiotics and/or oral corticosteroids are required, and severe when hospitalization is necessary [3]. The debilitating nature of COPD, combined with its numerous comorbidconditions, imposes a significant economic and social burden primarily attributable to exacerbations. COPD exacerbations have long been recognized as crucial factors in determining a patient's treatment plan and overall prognosis. In recent literature, there has been growing interest in exploring biomarkers for COPD that can aid in treatment selection and objectively assess therapeutic response [4]. Currently, a blood eosinophil count \(\geq\)300 cells/\(\mu\)L is used to identify COPD patients likely to benefit from preventive treatment with inhaled corticosteroids. Several studies have also reported a correlation between increased blood eosinophils and future exacerbation risk [5; 6], although the evidence remains inconclusive. Moreover, higher blood eosinophil contents are associated with elevated lung eosinophil numbers and the presence of type-2 inflammation in the airways [7], albeit through an indirect pathway that remains unresolved. Building upon the role of blood eosinophils, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has proposed a strategy called \"Treatable traits\" to classify COPD heterogeneity in clinical practice and integrate phenotypes with endotypes [8]. In the pursuit of patient-oriented COPD treatment supported by objective means, there is a pressing need for additional biomarkers that are easily obtained and applicable in clinical practice. Volatile Organic Compounds (VOCs) present a promising perspective in this regard. VOCs are a diverse group of carbon-based chemicals that are volatile at room temperature, and they offer a safe, easy-to-perform, and non-invasive biomarker. In respiratory conditions, particularly COPD, VOCs are expected to capture certain physiological and pathological processes, such as inflammation, occurring in the airways or alveoli and emitted in exhaled breath. While the literature has shown applications of VOCs in various health conditions, including breast cancer [9], asthma [10], pulmonary arterial hypertension [11], and interstitial lung diseases [12], none of these applications have been implemented in clinical practice. To achieve this, strict standardization is required in the steps involved in obtaining, manipulating, and analyzing VOCs. Solid-phase micro-extraction (SPME) has been successfully used to extract a series of volatile compounds from human breath, including aliphatic and aromatic hydrocarbons [13]. In contrast to alternative preconcentration methods, solid-phase microextraction (SPME) offers a straightforward, cost-effective, and solvent-free solution. It can be seamlessly automated without requiring thermal desorption equipment or modifications to the gas chromatography (GC) apparatus.