Chronic obstructive pulmonary disease (COPD), known in Italian as malattia polmonare ostruttiva cronica (BPCO), is a progressive and largely preventable respiratory condition characterized by persistent airflow limitation that worsens over time [1]. This obstruction results from chronic inflammation of the airways and destruction of lung tissue, primarily caused by long-term exposure to irritants such as tobacco smoke, air pollution, and occupational dusts and chemicals [2]. The disease encompasses two main clinical components: chronic bronchitis, defined by a productive cough for at least three months in two consecutive years, and pulmonary emphysema, involving the destruction of alveolar walls and loss of lung elasticity [3]. Diagnosis is confirmed through spirometry, where a post-bronchodilator FEV1/FVC ratio below 0.7 indicates irreversible airflow obstruction [4]. Key symptoms include chronic cough, sputum production, and progressive dyspnea, which significantly impair quality of life. Management focuses on slowing disease progression and alleviating symptoms through smoking cessation, pharmacological treatments such as bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation programs. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides evidence-based guidelines for diagnosis, classification, and treatment, emphasizing a personalized approach based on symptom burden and exacerbation risk [5]. Additional strategies include vaccination against influenza and pneumococcus, long-term oxygen therapy for severe hypoxemia, and non-invasive ventilation in advanced cases. The disease is associated with significant comorbidities such as cardiovascular disease, osteoporosis, and depression, which complicate prognosis and require integrated care. In Italy, COPD affects approximately 3–5.6% of the adult population, with underdiagnosis being a major public health challenge [6]. Environmental factors such as air pollution in the Po Valley and occupational exposures contribute significantly to disease burden. Emerging research highlights the role of the lung microbiome and systemic inflammation in disease progression, opening new avenues for targeted therapies. Despite its high morbidity and mortality, early detection through spirometry and comprehensive management can significantly improve patient outcomes and reduce hospitalizations.

Definition and Pathophysiology

Chronic obstructive pulmonary disease (COPD), known as malattia polmonare ostruttiva cronica (BPCO) in Italian, is a progressive and largely preventable respiratory condition characterized by persistent, partially reversible airflow limitation that worsens over time [1]. This obstruction arises from chronic inflammation of the airways and destruction of lung tissue, primarily due to long-term exposure to irritants such as tobacco smoke, air pollution, and occupational dusts and chemicals [2]. The disease encompasses two major clinical components: chronic bronchitis and pulmonary emphysema, which together contribute to the hallmark symptoms of cough, sputum production, and progressive dyspnea.

Core Pathophysiological Mechanisms

The pathophysiology of COPD involves a complex interplay of inflammatory processes, oxidative stress, protease-antiprotease imbalance, and structural remodeling of the lungs. Chronic exposure to noxious particles and gases, especially cigarette smoke, triggers an exaggerated and persistent immune response in the airways and lung parenchyma. This leads to the recruitment and activation of key immune cells such as macrophages, neutrophils, and T lymphocytes, which release a cascade of pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) [9]. This chronic inflammation results in structural damage and functional impairment.

Chronic Bronchitis and Airway Remodeling

Chronic bronchitis is defined by the presence of a productive cough for at least three months in each of two consecutive years. It is characterized by inflammation and hyperplasia of the bronchial mucous glands, leading to increased mucus production and impaired mucociliary clearance. This mucus plugging contributes significantly to airway obstruction. The inflammatory process also causes thickening of the airway wall due to fibrosis, smooth muscle hypertrophy, and infiltration of inflammatory cells, a process known as airway remodeling. This structural change narrows the airways, increases resistance to airflow, and predisposes patients to recurrent respiratory infections [10].

Pulmonary Emphysema and Parenchymal Destruction

Pulmonary emphysema involves the permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls without significant fibrosis. This leads to a loss of lung elasticity and a reduction in the surface area available for gas exchange, impairing oxygenation. A central mechanism in emphysema is the protease-antiprotease imbalance. Proteases, such as neutrophil elastase and matrix metalloproteinases (MMPs), are released by inflammatory cells and degrade the elastin fibers in the alveolar walls. Under normal conditions, these enzymes are inhibited by antiproteases like alpha-1 antitrypsin. In COPD, this balance is disrupted due to an overproduction of proteases and/or a deficiency in antiproteases, leading to uncontrolled tissue destruction [11].

Oxidative Stress and Systemic Inflammation

Oxidative stress plays a critical role in COPD pathogenesis. Cigarette smoke and activated inflammatory cells generate an excess of reactive oxygen species (ROS), which overwhelm the body's antioxidant defenses. This oxidative stress damages cellular components, inactivates antiproteases like alpha-1 antitrypsin, and activates pro-inflammatory signaling pathways such as nuclear factor-kappa B (NF-κB), thereby amplifying the inflammatory response [12]. Furthermore, the inflammation in COPD is not confined to the lungs; it has systemic effects, contributing to comorbidities such as cardiovascular disease, osteoporosis, and muscle wasting.

The Role of the Lung Microbiome

Emerging research highlights the importance of the lung microbiome in the pathophysiology of COPD. A dysbiosis, characterized by a reduced microbial diversity and an increase in potential pathogens like Streptococcus and Haemophilus, is commonly observed. This altered microbiome can perpetuate chronic inflammation, stimulate immune responses, and contribute to the frequency and severity of exacerbations [13]. The interaction between the microbiome, the host immune system, and environmental factors is a key area of ongoing investigation for the development of targeted therapies.

In summary, the pathophysiology of COPD is a multifaceted process driven by chronic inflammation, protease-antiprotease imbalance, oxidative stress, and structural remodeling of the airways and lung parenchyma. These processes lead to the characteristic airflow obstruction and gas exchange abnormalities. Understanding these mechanisms is essential for developing strategies to modify disease progression and improve patient outcomes.

Causes and Risk Factors

Chronic obstructive pulmonary disease (COPD) arises from a complex interplay of environmental exposures, genetic predispositions, and behavioral factors that lead to chronic inflammation and structural damage in the lungs. The disease is largely preventable, with risk factors often being modifiable through public health interventions and individual lifestyle changes. Understanding these causes and risks is critical for early detection, prevention, and effective management of the condition.

Tobacco Smoking: The Primary Cause

Tobacco smoking is the leading cause of COPD, responsible for approximately 80–90% of cases [14]. The harmful chemicals in cigarette smoke trigger a cascade of inflammatory responses in the airways and lung parenchyma, resulting in the destruction of alveolar walls (emphysema) and chronic bronchial inflammation with mucus hypersecretion [15]. This process leads to irreversible airflow limitation, the hallmark of COPD. The relationship between smoking and COPD is dose-dependent, meaning the risk increases with the duration and intensity of tobacco use [16]. Even secondhand smoke exposure contributes to disease development in non-smokers, highlighting the broader public health implications [17]. While smoking cessation is the most effective intervention to slow disease progression, it does not fully reverse existing damage, underscoring the importance of early intervention [18].

Environmental and Occupational Exposures

Long-term exposure to air pollutants is a significant contributor to COPD, particularly in regions with high levels of urban or industrial pollution. Fine particulate matter (PM2.5 and PM10), nitrogen oxides (NOx), and ozone from traffic and industrial emissions are strongly associated with the onset and exacerbation of COPD [19]. These pollutants induce oxidative stress and chronic inflammation, accelerating lung function decline. In Italy, for example, the Po Valley's high pollution levels contribute significantly to the national burden of respiratory disease [20].

Occupational exposure to dusts, fumes, and chemical vapors also increases COPD risk. Workers in mining, construction, agriculture, textiles, and metal industries face prolonged inhalation of irritants such as silica, coal dust, and welding fumes, which cause airway remodeling and parenchymal damage [21]. Poor ventilation in workplaces amplifies these effects, and the risk is further heightened in individuals who also smoke, demonstrating a synergistic interaction between occupational and lifestyle factors [22]. Indoor air pollution, especially from biomass fuels like wood or coal used for cooking and heating in poorly ventilated homes, is a major risk factor in low- and middle-income countries [23].

Genetic Predisposition

While environmental factors dominate, genetic susceptibility plays a crucial role in determining who develops COPD among those exposed to risk factors. The most well-defined genetic condition linked to COPD is alpha-1 antitrypsin deficiency (AATD), a hereditary disorder that reduces levels of a protective protein that inhibits neutrophil elastase [24]. Without sufficient alpha-1 antitrypsin, unchecked proteolytic enzymes destroy lung elastin, leading to early-onset emphysema, even in non-smokers [25]. AATD is relatively rare but represents a clear example of gene-environment interaction in COPD pathogenesis.

Beyond AATD, genome-wide association studies have identified multiple genetic loci associated with COPD risk, often overlapping with those involved in lung development and function [26]. The disease is considered polygenic, with risk arising from the cumulative effect of numerous genetic variants interacting with environmental exposures [27]. This genetic complexity explains why only a subset of smokers develop clinically significant COPD, highlighting the importance of individual susceptibility.

Other Contributing Risk Factors

Several additional factors influence COPD development and progression. Age is a key determinant, as the disease typically manifests after age 40, reflecting the cumulative nature of lung damage [28]. Recurrent respiratory infections, particularly in childhood, may impair lung development and increase vulnerability to COPD later in life. Comorbidities such as cardiovascular disease, diabetes, and hypertension do not directly cause COPD but worsen its prognosis and complicate management [29].

The interaction between these risk factors is often synergistic. For instance, a smoker working in a dusty environment has a much higher risk than either exposure alone [30]. Similarly, air pollution and smoking act together to amplify lung inflammation and oxidative stress, accelerating disease progression [22]. This multifactorial etiology underscores the need for comprehensive public health strategies that address tobacco control, environmental regulation, occupational safety, and early genetic screening to reduce the global burden of COPD.

Symptoms and Disease Progression

Chronic obstructive pulmonary disease (COPD), known as malattia polmonare ostruttiva cronica (BPCO), is characterized by a progressive and irreversible decline in lung function, leading to worsening respiratory symptoms over time. The disease manifests through a constellation of key symptoms that evolve in severity as the condition advances, significantly impacting daily life and overall health. Early recognition of these symptoms and understanding their progression is crucial for timely diagnosis and effective management.

Core Symptoms of COPD

The hallmark symptoms of COPD are chronic and typically worsen gradually. The most common include:

  • Chronic cough, often productive of mucus (sputum), particularly in the morning. This cough can persist for years before other symptoms become apparent [32].
  • Dyspnea (shortness of breath), initially occurring only during physical exertion but progressing to affect even routine activities and eventually occurring at rest in advanced stages [10].
  • Wheezing, a whistling or squeaky sound during breathing, caused by the narrowing of the airways.
  • Chest tightness, a sensation of pressure or constriction in the chest, often accompanying breathing difficulties [34].

These symptoms are primarily the result of two underlying pathological processes: chronic bronchitis, defined by inflammation of the airways and increased mucus production, and emphysema, which involves the destruction of alveolar walls and loss of lung elasticity [35].

Disease Progression and Staging

COPD is a progressive disease, meaning its severity increases over time, especially if risk factors like smoking persist. The progression is typically categorized into four stages, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, based on the degree of airflow limitation measured by spirometry (specifically, the post-bronchodilator FEV1 value):

  1. GOLD 1 (Mild): Patients experience mild symptoms such as a chronic cough and sputum production. Lung function, as measured by FEV1, is only slightly reduced (FEV1 ≥ 80% of predicted) [36].
  2. GOLD 2 (Moderate): Shortness of breath becomes noticeable during physical activity. There is a more significant reduction in FEV1 (50% ≤ FEV1 < 80% of predicted), and the diagnosis is often made at this stage.
  3. GOLD 3 (Severe): Dyspnea worsens, significantly limiting daily activities. The FEV1 is further reduced (30% ≤ FEV1 < 50% of predicted).
  4. GOLD 4 (Very Severe): Patients experience severe respiratory impairment, with a high risk of respiratory failure, frequent exacerbations, and a substantial decline in quality of life. FEV1 is less than 30% of predicted [10].

Exacerbations and Clinical Variability

A critical aspect of disease progression is the occurrence of exacerbations—acute episodes where symptoms suddenly worsen beyond normal day-to-day variations. These events, often triggered by respiratory infections or environmental pollutants, accelerate the decline in lung function, increase the risk of hospitalization, and are a major cause of mortality [38]. Each exacerbation can lead to a stepwise loss of lung function, contributing to the overall progression of the disease.

The rate of progression is highly variable among individuals. While some patients experience a rapid decline in lung function, others have a more stable or slower course, even with similar risk factor exposures. This heterogeneity underscores the need for a personalized approach to management, as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [39]. Factors such as ongoing exposure to irritants (especially tobacco smoke), the frequency of exacerbations, and the presence of comorbidities like cardiovascular disease or osteoporosis can significantly influence the trajectory of the disease [40].

In advanced stages, additional symptoms may appear, including peripheral edema (swelling of the ankles) due to right-sided heart failure (cor pulmonale) and cyanosis (a bluish tint to the lips or skin) resulting from low blood oxygen levels [41]. The progressive nature of COPD means that without intervention, the disease will continue to impair respiratory function, leading to increasing disability and a reduced life expectancy. Early diagnosis, smoking cessation, and appropriate treatment are essential to slow this progression and improve patient outcomes.

Diagnosis and Diagnostic Criteria

The diagnosis of chronic obstructive pulmonary disease (COPD) requires a comprehensive approach that integrates clinical evaluation, patient history, and objective testing. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the cornerstone of diagnosis is the confirmation of persistent airflow limitation through spirometry, particularly in individuals with respiratory symptoms and a history of exposure to risk factors such as tobacco smoke or environmental pollutants [42]. The diagnostic process aims to distinguish COPD from other respiratory conditions and to assess the severity and impact of the disease on the patient’s life.

Clinical Evaluation and Patient History

Diagnosis begins with a thorough clinical assessment, focusing on the presence of characteristic symptoms and relevant risk factors. Key symptoms include chronic cough, sputum production, and progressive dyspnea, especially during physical exertion [10]. A detailed patient history is essential to identify long-term exposure to inhaled irritants, particularly cigarette smoking, which is responsible for the majority of COPD cases [15]. Other important exposures include occupational dusts and chemicals, indoor air pollution from biomass fuels, and outdoor air pollution, especially fine particulate matter (PM2.5) [19]. The combination of symptoms and a history of exposure forms the initial basis for suspecting COPD and warrants further investigation.

Spirometry: The Gold Standard for Diagnosis

Spirometry is the definitive test for diagnosing COPD and is considered the gold standard in clinical practice [4]. This non-invasive pulmonary function test measures the volume and speed of air exhaled from the lungs. The key parameters are the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). The critical diagnostic criterion is a post-bronchodilator FEV1/FVC ratio of less than 0.70, which indicates irreversible or only partially reversible airflow obstruction [47]. This fixed ratio is recommended by GOLD guidelines to ensure consistency and reliability in diagnosis, regardless of age-related changes in lung function [48].

The test involves the patient taking a deep breath and then exhaling forcefully and completely into a spirometer for at least six seconds. To confirm the diagnosis, the test is performed before and after the administration of a short-acting bronchodilator (such as salbutamol) to assess reversibility. In COPD, the obstruction is typically poorly reversible, with only a modest improvement in FEV1 (an increase of less than 12% and 200 mL from baseline), which helps differentiate it from asthma, where bronchodilator response is usually more pronounced [49]. The severity of airflow limitation is then classified based on the post-bronchodilator FEV1 as a percentage of the predicted value: GOLD 1 (mild, ≥80%), GOLD 2 (moderate, 50–79%), GOLD 3 (severe, 30–49%), and GOLD 4 (very severe, <30%) [47].

Additional Diagnostic Tests

While spirometry is essential, other tests are used to complete the clinical picture, assess disease severity, and rule out alternative diagnoses. A chest X-ray is commonly performed to exclude other conditions such as lung cancer or heart failure and to identify signs of COPD, such as hyperinflation of the lungs, a flattened diaphragm, or increased retrosternal space [51]. However, a chest X-ray alone is not sufficient for diagnosis. For a more detailed evaluation, especially in cases with atypical features or suspected complications, a computed tomography (CT) scan of the chest can be used to visualize emphysema, bronchiectasis, or other structural abnormalities [52].

Arterial blood gas analysis is crucial for patients with severe symptoms or during exacerbations, as it measures the levels of oxygen (PaO₂), carbon dioxide (PaCO₂), and pH in the blood. This test is vital for identifying chronic respiratory failure, characterized by hypoxemia (PaO₂ < 60 mmHg) and/or hypercapnia (PaCO₂ > 45 mmHg), which guides the need for long-term oxygen therapy or non-invasive ventilation [53]. Additional pulmonary function tests, such as lung volume measurements and the diffusing capacity of the lung for carbon monoxide (DLCO), provide a more comprehensive assessment of lung function and are particularly useful in differentiating emphysema from other obstructive lung diseases [54].

Symptom Assessment and Disease Stratification

Beyond spirometry, the evaluation of symptom burden and the risk of exacerbations is critical for disease management. Validated questionnaires are used to quantify the impact of COPD on a patient's daily life. The COPD Assessment Test (CAT) is an 8-item questionnaire that measures the effect of the disease on cough, phlegm, chest tightness, breathlessness, activity limitation, sleep, and energy levels, providing a total score from 0 to 40 [55]. The modified Medical Research Council (mMRC) dyspnea scale is a simpler tool that grades breathlessness from 0 (no breathlessness except with strenuous exercise) to 4 (too breathless to leave the house) [56]. These tools are integrated into the GOLD classification system, which combines symptom assessment and exacerbation history to assign patients to groups A, B, C, or D, guiding personalized treatment decisions [57].

Differential Diagnosis

An essential part of the diagnostic process is differentiating COPD from other conditions that present with similar symptoms. The most common differential is asthma, which is characterized by variable airflow obstruction and a more significant response to bronchodilators [58]. Other conditions to consider include heart failure, bronchiectasis, pulmonary fibrosis, and lung cancer. A careful history, physical examination, and appropriate use of diagnostic tests are necessary to rule out these alternatives and ensure an accurate diagnosis of COPD.

In summary, the diagnosis of COPD is a multifaceted process that relies on the integration of clinical symptoms, exposure history, and objective spirometric confirmation of airflow obstruction. The use of standardized guidelines, such as those from the Global Initiative for Chronic Obstructive Lung Disease (GOLD), ensures a consistent and evidence-based approach to diagnosis, enabling effective management and improved patient outcomes [59].

Treatment and Management Strategies

Chronic obstructive pulmonary disease (COPD), or malattia polmonare ostruttiva cronica (BPCO), is a progressive and largely preventable respiratory condition that, while not curable, can be effectively managed to slow progression, alleviate symptoms, and improve quality of life. Management strategies are multifaceted, combining pharmacological and non-pharmacological interventions tailored to the individual patient's symptoms, risk of exacerbations, and overall health status. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides the primary international framework for a personalized, multidimensional approach to treatment [60].

Pharmacological Treatment

Pharmacological therapy for COPD focuses on bronchodilation to relieve airflow obstruction and reduce symptoms. The mainstay of treatment includes inhaled medications, with the choice of agent guided by the severity of symptoms and the patient's history of exacerbations. The two primary classes of long-acting bronchodilators are long-acting beta2-agonists (LABA) and long-acting muscarinic antagonists (LAMA). These are often used in combination (LABA/LAMA) as a first-line therapy for many symptomatic patients, as this dual bronchodilation has been shown to be more effective than monotherapy in improving lung function, reducing symptoms, and preventing exacerbations [61]. This approach is supported by the updated GOLD guidelines and is considered a new standard of care [62].

For patients with a high risk of exacerbations (typically defined as two or more moderate/severe exacerbations or one hospitalization per year), the addition of inhaled corticosteroids (ICS) is considered. ICS are anti-inflammatory agents that are most beneficial when combined with bronchodilators, particularly in patients with elevated blood eosinophil levels (≥300 cells/µL), which is a key biomarker predicting a positive response to corticosteroid therapy [63]. The combination of ICS, LABA, and LAMA, known as triple therapy, is indicated for patients who remain uncontrolled on dual therapy. However, the use of ICS is associated with an increased risk of pneumonia and other side effects, so their use must be carefully weighed against the benefits, particularly in patients with low eosinophil counts (<100 cells/µL) [64]. For patients with severe emphysema and chronic bronchitis who experience recurrent exacerbations, the anti-inflammatory drug roflumilast may be prescribed [65]. The prescription of these advanced therapies in Italy is regulated by the AIFA's Nota 99, which defines strict criteria for eligibility and requires spirometric confirmation of the diagnosis [66].

Non-Pharmacological Interventions

Non-pharmacological strategies are fundamental to COPD management and often have as significant an impact on outcomes as medication. The most critical intervention is smoking cessation, which is the single most effective measure to slow the accelerated decline in lung function characteristic of COPD. Even after diagnosis, quitting smoking can significantly reduce the risk of exacerbations and improve survival [67]. The general practitioner plays a central role in this process, using structured counseling models like the "5A" (Ask, Advise, Assess, Assist, Arrange) and connecting patients with specialized resources such as the national anti-smoking helpline (800 554088) and local Centri Anti Fumo (CAF) [68].

Vaccination is another cornerstone of preventive care. Annual influenza vaccination and pneumococcal vaccination are strongly recommended to prevent respiratory infections that can trigger acute exacerbations. More recently, vaccination against the respiratory syncytial virus (RSV) has been introduced for vulnerable patients [60].

Pulmonary rehabilitation is a highly effective, multidisciplinary program for patients with moderate to severe symptoms. It typically includes supervised exercise training, education about the disease and its management, and psychological support. This intervention has been proven to reduce dyspnea, improve exercise tolerance and quality of life, and decrease the risk of hospitalization and mortality, particularly in the year following an exacerbation [70]. Programs can be delivered in outpatient clinics, hospitals, or even in the home, and their benefits are maximized when followed by a long-term maintenance plan [71].

Oxygen and Ventilatory Support

For patients with advanced disease and chronic respiratory failure, long-term oxygen therapy (LTOT) is a life-prolonging intervention. It is indicated for patients with severe hypoxemia, defined as a partial pressure of arterial oxygen (PaO₂) ≤ 55 mmHg or an oxygen saturation (SpO₂) ≤ 88% while breathing room air. Administering oxygen for at least 15 hours per day has been shown to improve survival, reduce cardiovascular complications, and enhance quality of life [72]. This therapy requires a prescription and ongoing monitoring by a specialist.

For patients with chronic hypercapnia (elevated carbon dioxide levels), non-invasive ventilation (NIV) is a key therapeutic option. Devices such as CPAP and BIPAP provide ventilatory support without the need for intubation, improving gas exchange, reducing respiratory muscle fatigue, and preventing hospitalizations. NIV is particularly effective during acute exacerbations and for long-term home management of chronic respiratory failure [73].

Management of Exacerbations and Advanced Therapies

Acute exacerbations of COPD, characterized by a sudden worsening of symptoms, require prompt treatment. This typically includes short-acting bronchodilators (nebulized or inhaled), a short course of oral corticosteroids, and antibiotics if a bacterial infection is suspected. Controlled oxygen therapy and NIV are used for patients with respiratory failure [74].

In select cases of severe emphysema, surgical or endoscopic interventions may be considered. Surgical lung volume reduction (LVRS) removes the most damaged portions of the lung to improve the function of the remaining tissue. For patients who are not surgical candidates, bronchoscopic lung volume reduction (BLVR) offers a less invasive alternative using techniques such as endobronchial valves, coils, or thermal vapor ablation to collapse hyperinflated areas of the lung [75].

Role of Pulmonary Rehabilitation

Pulmonary rehabilitation is a cornerstone of the multidisciplinary management of chronic obstructive pulmonary disease (COPD), playing a fundamental role in improving patients' quality of life, physical functionality, and reducing morbidity and mortality [71]. It is a structured, evidence-based intervention that integrates supervised physical exercise, patient education, psychological and behavioral support, and nutritional interventions. The primary goal of pulmonary rehabilitation is to reduce symptoms such as dyspnea and fatigue, enhance exercise tolerance, increase functional independence, and improve overall quality of life in individuals affected by COPD [77].

The central component of pulmonary rehabilitation is exercise training, particularly aerobic conditioning, which serves as the foundation of the program. This includes activities such as walking, cycling, and stair climbing, tailored to the patient's baseline fitness level. In patients with significant muscle atrophy, resistance training is also incorporated to improve muscle strength and endurance. Interval training strategies are especially beneficial for highly dyspneic or deconditioned patients, allowing them to achieve higher workloads with lower perceived exertion [78]. These exercises help counteract the skeletal muscle dysfunction commonly seen in COPD, a condition known as sarcopenia, which contributes to reduced physical performance and increased disability [79].

Benefits and Clinical Outcomes

Pulmonary rehabilitation has been shown to deliver a wide range of clinically significant benefits. These include a measurable reduction in dyspnea and fatigue, improved exercise capacity as demonstrated by increased distance in the 6-minute walk test, decreased frequency of exacerbations, and fewer hospitalizations [70]. Notably, studies have demonstrated that pulmonary rehabilitation can reduce mortality at one year post-exacerbation, particularly in patients recovering from acute episodes [70].

Additionally, pulmonary rehabilitation enhances patients’ ability to self-manage their condition through comprehensive education. This includes instruction on proper use of inhaled medications, recognition of early signs of exacerbations, and techniques for airway clearance and energy conservation. Patients also receive guidance on smoking cessation, which remains the most effective intervention to slow disease progression [82]. Psychological support is another critical element, addressing common comorbidities such as anxiety and depression, which are present in up to 40% of COPD patients and significantly impact symptom perception and treatment adherence [83].

Indications and Patient Selection

Pulmonary rehabilitation is strongly recommended for patients with COPD who remain symptomatic—particularly those experiencing dyspnea or activity limitation—despite optimal pharmacological therapy [84]. It is indicated across stages GOLD II, III, and IV, especially when symptom scores such as the COPD Assessment Test (CAT) or the Modified Medical Research Council (mMRC) scale indicate significant respiratory impairment. The program is particularly effective when initiated after an acute exacerbation, provided the patient is clinically stable. In this context, early rehabilitation significantly reduces the risk of subsequent hospitalizations and mortality [70].

While rehabilitation may also be considered in patients with mild COPD (GOLD I) who report a meaningful impact on quality of life, it is contraindicated in cases of clinical instability, such as uncontrolled heart failure, unstable angina, or other severe unmanaged comorbidities [77]. Patient selection is therefore based not only on spirometric severity but also on symptom burden and functional limitation.

Program Delivery and Long-Term Maintenance

Pulmonary rehabilitation programs can be delivered in various settings, including outpatient clinics, hospitals, or through home-based models, often involving multidisciplinary teams comprising pulmonologists, physiotherapists, nurses, dietitians, and psychologists. In Italy, specialized centers such as those within the ICS Maugeri network and other public and private facilities offer structured programs aligned with European Respiratory Society (ERS) and American Thoracic Society (ATS) guidelines [87].

A typical program lasts between 6 and 12 weeks, with sessions held two to three times per week. The effectiveness of rehabilitation is maximized when patients adhere regularly and participate in long-term maintenance programs that sustain the gains achieved during the initial intervention [88]. Maintenance strategies may include supervised sessions, community-based exercise groups, or tele-rehabilitation platforms that support ongoing physical activity and self-management.

{{Image|A diverse group of COPD patients participating in a supervised pulmonary rehabilitation session, including treadmill walking, resistance training with bands, and educational discussion with healthcare professionals in a clinical gym setting.|Pulmonary rehabilitation session with patients and healthcare team})

In summary, pulmonary rehabilitation is a vital non-pharmacological intervention in the comprehensive management of COPD. Its integration into routine care is essential for improving functional status, reducing hospital admissions, and enhancing survival, particularly in symptomatic patients across moderate to severe disease stages. As a first-line treatment, it should be systematically incorporated into the long-term therapeutic strategy for individuals with COPD [89].

Comorbidities and Systemic Effects

Chronic obstructive pulmonary disease (COPD) is not merely a disorder of the lungs but a systemic condition with widespread effects on multiple organ systems. The presence of comorbidities significantly influences the clinical course, prognosis, and management complexity of patients with COPD. These comorbidities are often interrelated through shared pathogenic mechanisms such as chronic systemic inflammation, oxidative stress, and the impact of common risk factors like tobacco smoke. A comprehensive understanding of these associated conditions is essential for effective, integrated patient care.

Cardiovascular Disease

Cardiovascular comorbidities are among the most prevalent and impactful in COPD, affecting up to 60–70% of patients. Conditions such as hypertension, ischemic heart disease, heart failure, and arrhythmias are frequently observed. The link between COPD and cardiovascular disease is underpinned by shared pathophysiological mechanisms, including systemic inflammation, endothelial dysfunction, and oxidative stress [90]. Patients with both COPD and cardiovascular disease face a higher risk of acute events such as myocardial infarction or decompensated heart failure, which in turn increases hospitalization rates and mortality [91]. Therefore, a coordinated approach involving both pulmonologists and cardiologists is crucial for optimal management.

Chronic Respiratory Failure

Chronic respiratory failure is a severe complication of advanced COPD, resulting from progressive airway obstruction and parenchymal destruction that impair gas exchange. It is characterized by chronic hypoxemia (low blood oxygen levels) and, in later stages, hypercapnia (elevated carbon dioxide levels) [82]. Long-term oxygen therapy (LTOT) is a cornerstone of treatment for patients with severe hypoxemia, defined as a partial pressure of arterial oxygen (PaO₂) ≤ 55 mmHg or oxygen saturation (SpO₂) ≤ 88%. LTOT has been shown to improve survival, reduce pulmonary hypertension, and enhance quality of life [93]. Management often requires close monitoring through arterial blood gas analysis and may involve the use of non-invasive ventilation in hypercapnic patients.

Pulmonary Hypertension and Cor Pulmonale

Pulmonary hypertension is a common consequence of advanced COPD, particularly in patients with severe emphysema and chronic hypoxemia. It results from vascular remodeling and increased pulmonary vascular resistance, leading to right ventricular strain. When this progresses to structural changes in the right ventricle, it is termed cor pulmonale, or right-sided heart failure [94]. The prognosis is particularly poor when pulmonary hypertension is disproportionate to the degree of airflow limitation, as long-term oxygen therapy may not fully reverse the vascular changes [95]. Diagnosis typically involves echocardiography, and management focuses on optimizing COPD treatment and oxygenation, though specific pulmonary vasodilators have limited efficacy in this context.

Osteoporosis

Osteoporosis affects 35–60% of COPD patients and significantly increases the risk of fractures, particularly vertebral ones, which can further impair respiratory function and mobility. Contributing factors include chronic systemic inflammation, long-term use of inhaled corticosteroids, smoking, physical inactivity, and nutritional deficiencies [96]. The resulting fractures can exacerbate dyspnea, reduce exercise tolerance, and increase the risk of hospitalization and death. Early screening for bone mineral density and interventions such as calcium and vitamin D supplementation, weight-bearing exercise, and pharmacological treatments like bisphosphonates are recommended components of comprehensive COPD care.

Sarcopenia and Malnutrition

Sarcopenia, the progressive loss of skeletal muscle mass and strength, affects 29–48% of COPD patients and is closely linked to malnutrition. This condition arises from an imbalance between energy expenditure and intake, compounded by systemic inflammation and hormonal changes. The resulting muscle wasting contributes to exercise intolerance, increased fatigue, and a higher frequency of exacerbations [97]. Assessment tools such as bioelectrical impedance analysis (BIA) can help identify at-risk individuals. Nutritional support, including high-calorie, high-protein diets and anabolic therapies, combined with resistance training, are essential to counteract this catabolic state and improve functional outcomes.

Psychological Comorbidities: Anxiety and Depression

Anxiety and depression are highly prevalent in COPD, affecting up to 40% of patients. Chronic dyspnea, fear of suffocation, and functional limitations contribute to the development of these conditions, which in turn worsen symptom perception, reduce adherence to treatment, and increase the frequency of exacerbations [83]. The bidirectional relationship between mental health and respiratory symptoms underscores the need for integrated care. Management includes psychological support, cognitive behavioral therapy, and, when indicated, pharmacological treatment. Pulmonary rehabilitation programs have been shown to improve both respiratory function and psychological well-being, highlighting the importance of a multidisciplinary approach.

Other Common Comorbidities

Several additional conditions frequently coexist with COPD and influence its clinical trajectory:

  • Diabetes mellitus and metabolic syndrome: These are linked to systemic inflammation and the use of corticosteroids, and they increase cardiovascular risk [42].
  • Gastroesophageal reflux disease (GERD): GERD may worsen respiratory symptoms and trigger exacerbations through microaspiration [100].
  • Lung cancer: Shared risk factors, especially smoking, make lung cancer a significant concern in COPD patients, with an elevated risk independent of tobacco exposure [101].

Impact on Prognosis and Clinical Management

The presence of comorbidities is a strong independent predictor of mortality in COPD, surpassing the prognostic value of spirometric measures alone [42]. Patients with multiple comorbidities face higher risks of hospitalization, reduced quality of life, and increased healthcare utilization. The complexity of managing polypharmacy also raises the risk of drug interactions and adverse effects.

Modern guidelines, including those from the Global Initiative for Chronic Obstructive Lung Disease (GOLD), emphasize a holistic, patient-centered approach that includes active screening for comorbidities and the development of integrated care pathways. These pathways often involve collaboration among various specialists, including nutritional counselors, psychologists, and rehabilitation specialists, to ensure comprehensive management [103].

Key interventions include:

  • Annual influenza vaccination and pneumococcal vaccination to prevent respiratory infections.
  • Regular participation in pulmonary rehabilitation programs.
  • Routine screening for osteoporosis, cardiovascular disease, and psychological disorders.

In conclusion, comorbidities are not incidental findings in COPD but integral components of the disease that define its clinical severity and outcomes. A multidimensional assessment and a coordinated, multidisciplinary management strategy are essential to improve survival, reduce hospitalizations, and enhance the quality of life for patients living with this complex chronic condition.

Epidemiology and Public Health Impact

Chronic obstructive pulmonary disease (COPD), known as malattia polmonare ostruttiva cronica (BPCO) in Italian, represents a significant public health burden both in Italy and globally, with substantial impacts on morbidity, mortality, and healthcare systems. The disease affects millions of individuals, often with a high rate of underdiagnosis, and its burden is shaped by a complex interplay of behavioral, environmental, and socioeconomic factors [6]. In Italy, the prevalence of COPD is estimated at 5.6% of the adult population, corresponding to approximately 3.5 million people [6]. This figure aligns with the global prevalence, which ranges between 4% and 6% of adults, although some estimates suggest it may affect up to 10% of the global adult population [106]. The Global Burden of Disease Study 2019 identifies COPD as a leading cause of death and disability worldwide, with projections indicating a potential rise to 600 million cases by 2050 [107].

Prevalence and Incidence in Italy and Europe

The epidemiology of COPD in Italy is marked by a high rate of underdiagnosis, with millions of cases remaining undetected, particularly in the early stages of the disease [6]. This underdiagnosis is attributed to patient underestimation of symptoms, such as chronic cough and dyspnea, which are often dismissed as signs of aging or smoking, and to limited access to diagnostic tools like spirometry in primary care settings [109]. The prevalence is particularly high in northern regions, where factors such as air pollution in the Po Valley and occupational exposures contribute to the disease burden [22]. At the European level, the median prevalence is approximately 3,230 cases per 100,000 men and 2,202 per 100,000 women, with an estimated 36 million people affected [111]. However, broader estimates suggest that chronic respiratory diseases impact nearly 82 million people in Europe, many of whom are undiagnosed [112].

Global Disparities and Risk Factor Contributions

The burden of COPD varies significantly between high-income countries (HICs) and low- and middle-income countries (LMICs), reflecting differences in risk factors, socioeconomic conditions, and access to healthcare [112]. In HICs like Italy, cigarette smoking is the predominant risk factor, responsible for over 70% of COPD cases [114]. The disease is more common among older adults and those with lower socioeconomic status, where smoking rates are typically higher [115]. In contrast, in LMICs, the prevalence of COPD is often higher and affects younger working-age populations. This is due to a combination of factors, including indoor air pollution from the use of biomass fuels (wood, coal, dung) for cooking and heating in poorly ventilated homes, and occupational exposures to dusts, fumes, and vapors in industries such as mining, construction, agriculture, and textiles [112]. The contribution of these environmental and occupational factors is substantial, with occupational exposures alone estimated to account for about 15% of all COPD cases [117].

Disease Burden in Terms of DALYs and Hospitalizations

The burden of COPD is also measured in terms of disability-adjusted life years (DALYs), which quantify the years of healthy life lost due to premature mortality and disability. In Italy, COPD is the seventh leading cause of years of life lost (YLL), contributing to over 81 million DALYs [118]. This high burden reflects not only the disease's mortality but also the significant disability caused by progressive respiratory impairment, reduced quality of life, and associated comorbidities such as cardiovascular disease, osteoporosis, and depression. COPD is the second leading cause of avoidable hospitalizations in Italy, following heart failure, with over 3.5 million hospital admissions attributed to the disease [6]. Acute exacerbations, often triggered by respiratory infections or air pollution, are the primary reason for these hospitalizations and are a strong predictor of short- and long-term mortality [118].

Economic and Social Costs

The economic impact of COPD on the Italian healthcare system is immense. The total social cost of chronic respiratory diseases, with COPD as a major component, is estimated at approximately 45.7 billion euros annually [121]. Direct costs, including hospitalizations, medications (such as bronchodilators and inhaled corticosteroids), long-term oxygen therapy, and home care, constitute a significant portion of this burden. A cost analysis estimates an average annual expenditure of about 2,700 euros per patient, with 80% of costs linked to hospitalizations and acute treatments [122]. Indirect costs, such as lost productivity, disability, and informal care provided by family members, represent a substantial but often underestimated socioeconomic burden. The high rate of undiagnosed cases further exacerbates this burden, as delayed diagnosis leads to more severe disease, increased hospitalizations, and higher overall costs [123].

Prevention and Public Health Strategies

Effective public health policies are crucial for reducing the incidence and progression of COPD. Smoking cessation is the single most effective intervention, as it can slow the accelerated decline in lung function characteristic of the disease [82]. Successful tobacco control strategies include increasing tobacco taxes, implementing smoke-free public spaces, running public awareness campaigns, and providing access to cessation support services, including behavioral counseling and pharmacological therapies like nicotine replacement therapy and varenicline [1]. Reducing air pollution through regulations on industrial and vehicular emissions and promoting sustainable transportation is another key preventive measure [126]. In the workplace, enforcing safety standards, providing personal protective equipment (PPE), and conducting health surveillance for at-risk workers are essential for preventing occupational COPD [127]. For LMICs, sustainable and low-cost strategies include community-based cessation programs, public education, and the use of digital health technologies like telemonitoring to improve access to care [122]. The integration of these multifaceted approaches is vital for reducing the global burden of COPD and improving the sustainability of healthcare systems.

Prevention and Screening

Chronic obstructive pulmonary disease (COPD) is largely preventable, and early detection through systematic screening can significantly reduce morbidity and mortality. Effective prevention and screening strategies focus on eliminating exposure to risk factors, identifying at-risk individuals, and implementing timely interventions to halt or slow disease progression. The cornerstone of prevention lies in public health policies and individual behavioral changes, while screening relies on targeted use of diagnostic tools, particularly spirometry, in high-risk populations.

Primary Prevention: Eliminating Risk Factors

Primary prevention aims to reduce the incidence of COPD by addressing its major environmental and behavioral causes. The most impactful intervention is tobacco cessation, as cigarette smoking is responsible for over 70% of COPD cases in high-income countries and up to 90% globally [129]. Smoking cessation remains the single most effective measure to slow the accelerated decline in lung function associated with COPD, even though it may not fully reverse existing damage [82]. Public health strategies that have proven effective include increasing tobacco taxes, enforcing smoke-free laws in public spaces, running mass media campaigns, and providing accessible smoking cessation services, including behavioral counseling and pharmacological support such as nicotine replacement therapy and varenicline [1].

Beyond tobacco, reducing exposure to air pollution is a critical component of primary prevention. Long-term exposure to ambient pollutants such as fine particulate matter (PM2.5), nitrogen oxides (NOx), and ozone is strongly linked to the development and progression of COPD [22]. Policies that regulate industrial emissions, promote sustainable transportation, and improve urban air quality are essential for population-level prevention. In Italy, areas like the Po Valley, known for high levels of atmospheric pollution, face a disproportionate burden of respiratory disease, highlighting the need for targeted environmental interventions [20].

Occupational exposure to dusts, fumes, and chemical vapors accounts for approximately 15% of COPD cases [117]. Prevention in the workplace involves enforcing safety regulations, ensuring proper ventilation, and mandating the use of personal protective equipment (PPE) such as respirators in high-risk industries like mining, construction, agriculture, and textiles [127]. Regular health surveillance of workers in these sectors is crucial for early detection and intervention.

In low- and middle-income countries, indoor air pollution from the use of biomass fuels (wood, coal, dung) for cooking and heating in poorly ventilated homes is a major risk factor, particularly for women and children [23]. Interventions to reduce this risk include promoting cleaner cooking technologies, improving home ventilation, and public education on the health hazards of indoor smoke.

Secondary Prevention: Early Detection and Screening

Secondary prevention focuses on early diagnosis in individuals who are at high risk but may be asymptomatic or have mild symptoms, allowing for timely intervention to alter the disease course. The primary tool for screening is spirometry, which measures airflow obstruction by calculating the ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC). A post-bronchodilator FEV1/FVC ratio of less than 0.70 confirms the presence of persistent airflow limitation, the hallmark of COPD [59].

Despite its importance, systematic screening for COPD in Italy remains limited and is not yet integrated into routine primary care programs [138]. The target population for screening includes adults over 40 years of age who are current or former smokers, as well as those with a history of occupational exposure to lung irritants [65]. The Programma R.I.S.P. (Rete Italiana Screening Polmonare), led by the National Cancer Institute of Milan, is a significant national initiative that, while primarily focused on lung cancer screening with low-dose CT scans, also provides an opportunity to identify COPD in high-risk individuals, such as those with a significant smoking history [140].

Barriers to Screening and Early Diagnosis

Several barriers hinder the widespread implementation of COPD screening in Italy. A major obstacle is the under-recognition of symptoms by patients, who often attribute chronic cough, sputum production, and shortness of breath to aging or smoking, leading to delayed medical consultation [138]. This is compounded by the limited availability of spirometry in primary care settings. Many general practitioners lack access to spirometry equipment or the training to perform and interpret the test accurately, creating a bottleneck in the diagnostic pathway [138].

Geographic disparities in healthcare access further exacerbate the problem, with rural and southern regions of Italy having fewer specialized respiratory services and diagnostic facilities compared to urban and northern areas [143]. This results in delayed diagnoses and suboptimal management, particularly for vulnerable populations. The absence of a coordinated national screening program, unlike those for other chronic diseases, contributes to a fragmented and inconsistent approach to early detection.

Integrated Prevention Strategies

Effective prevention requires a comprehensive, multi-sectoral approach. In Italy, the Ministry of Health promotes integrated programs that combine public education, clinical interventions, and policy measures [144]. These include the development of structured care pathways (Percorsi Diagnostico-Terapeutici Assistiti, PDTA) that ensure continuity of care between general practitioners and specialists, and the promotion of patient education on self-management and adherence to therapy [103].

For low-resource settings, adaptable strategies include low-cost smoking cessation counseling, community-based education, and the use of simple tools like the COPD-PS questionnaire to identify at-risk individuals before spirometry. Telemonitoring and digital health technologies are emerging as promising tools to improve disease management and reduce hospitalizations, particularly in remote areas [122].

In conclusion, preventing COPD is highly achievable through the elimination of key risk factors, primarily tobacco smoke and environmental pollutants. Early detection via targeted spirometry screening in high-risk populations is essential for timely intervention. Overcoming the barriers of under-recognition, limited access to diagnostics, and healthcare disparities requires a sustained, integrated effort involving public health policy, healthcare system strengthening, and patient empowerment. By implementing these strategies, the significant burden of COPD on individuals and health systems can be substantially reduced.

Emerging Research and Future Directions

Chronic obstructive pulmonary disease (COPD) remains a major global health challenge, but ongoing research is rapidly advancing our understanding of its underlying mechanisms and opening new avenues for targeted therapies. Emerging research focuses on unraveling the complex interplay between the lung microbiome, systemic inflammation, and immune responses, aiming to shift the treatment paradigm from symptom management to disease modification and personalized medicine [147].

The Lung Microbiome and Innate Immunity

One of the most transformative areas of research involves the role of the lung microbiome in COPD pathogenesis. Once thought to be sterile, the lower airways are now known to host a dynamic microbial community. In COPD, a state of dysbiosis occurs, characterized by reduced microbial diversity and an overgrowth of potential pathogens such as Streptococcus, Haemophilus, and Moraxella [148]. This altered microbiota is not a passive bystander but an active driver of chronic inflammation, contributing to disease progression and frequent exacerbations. The interaction between these microbes and the host's innate immune system is critical. Pattern recognition receptors, such as Toll-like receptors (TLRs), on epithelial cells and macrophages detect microbial components, triggering a cascade of inflammatory responses. A key emerging mediator is interleukin-32 (IL-32), a pro-inflammatory cytokine whose expression is elevated in smokers and COPD patients and is linked to tissue damage [149]. Furthermore, the triad of viral, bacterial, and fungal interactions within the airway can create a vicious cycle of inflammation, with viral infections like rhinovirus disrupting the microbiome and facilitating bacterial overgrowth [150].

Inflammatory Biomarkers and Precision Medicine

The future of COPD management lies in precision medicine, guided by biomarkers that can stratify patients into distinct phenotypes and endotypes. Beyond the established use of blood eosinophils to predict response to inhaled corticosteroids, research is identifying a broader panel of systemic inflammatory markers. Elevated levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are associated with more severe disease, faster lung function decline, and higher mortality [151]. Similarly, acute-phase reactants like C-reactive protein (CRP) and fibrinogen are linked to frequent exacerbations and comorbidities. The integration of these biomarkers with microbiome profiles and clinical data is paving the way for a multidimensional diagnostic approach based on "treatable traits" [152]. This approach has already yielded results, with the European approval of the biologic drug dupilumab, an anti-IL-4Rα monoclonal antibody, for a subset of patients with uncontrolled COPD and high blood eosinophil counts, marking a significant step toward targeted therapy [153].

Novel Therapeutic Strategies

Emerging research is driving the development of innovative therapeutic strategies. Efforts to modulate the microbiome include clinical trials exploring the use of probiotics and prebiotics to restore a healthy microbial balance and reduce inflammation [154]. More radically, research is investigating the potential of fecal microbiota transplantation (FMT) to influence the gut-lung axis, recognizing the gut microbiome's role in regulating pulmonary immunity [155]. For patients with alpha-1 antitrypsin deficiency, a genetic cause of early-onset emphysema, augmentation therapy with purified alpha-1 antitrypsin is a form of targeted treatment, and research continues to refine its use [156]. Looking forward, the development of specific inhibitors for key proteases like matrix metalloproteinase-9 (MMP-9) and potent antioxidants to counteract oxidative stress are promising areas of investigation aimed at halting the protease-antiprotease imbalance that drives parenchymal destruction [157].

The future of COPD research is also embracing non-invasive monitoring. The analysis of exhaled breath condensate (EBC) allows for the collection of volatile and non-volatile biomarkers from the airways, providing a real-time, non-invasive snapshot of local inflammation [158]. This technology, combined with digital health tools like telemonitoring systems that track symptoms and vital signs at home, holds the potential for early detection of exacerbations and dynamic adjustment of therapy [122]. These advances, from understanding the microbiome to developing biologics and digital health solutions, are converging to create a future where COPD can be managed with unprecedented precision, ultimately aiming to modify the disease course and significantly improve patient outcomes.

References