The Complex Interplay: Unfolding the Mechanisms of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a widely prevalent respiratory ailment that can be prevented. It is characterized by the chronic restriction of airflow caused by lung abnormalities resulting from exposure to toxic chemicals or particles. COPD is a respiratory disorder characterized by a gradual and incapacitating progression, impacting a significant number of individuals on a global scale. COPD is distinguished by the presence of chronic bronchitis and emphysema, resulting in considerable morbidity and mortality. The etiology of COPD is multifaceted, encompassing genetic, environmental, and physiological variables. In spite of the existence of global health objectives, the incidence and mortality rates of COPD persistently escalate, exhibiting disparities influenced by factors such as gender, geographical location, and age. The increasing prevalence of COPD, therefore, necessitates a pressing requirement for enhancing treatment approaches and patient outcomes.

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a prevalent and avoidable chronic respiratory condition. It is characterized by persistent obstruction of airflow in the airway, resulting from abnormalities in the lungs that are induced by harmful gases or particles [1]. The expiratory muscles responsible for generating contraction force, the elastic recoil pressure of the lung, and the airways are critical factors influencing the normal flow rate in healthy adults. However, individuals with COPD experience significant impairments in these factors, leading to a reduced quality of life [2]. The etiology of COPD is intricate, encompassing a diverse interplay of genetic, environmental, and physiological elements. The field of respiratory physiology, which encompasses the intricate mechanisms that regulate lung function, is of utmost importance in understanding the development and progression of COPD. The interplay at hand encompasses complex processes that involve structural changes in the airways, modifications in lung tissue elasticity, and dysregulation of immune responses. In 2012, the World Health Assembly introduced a health target known as the “25 by 25 goal.” This objective sought to achieve a 25% reduction in premature deaths resulting from COPD and other non-communicable diseases by the year 2025. However, the global incidence of COPD has consistently risen, resulting in higher rates of morbidity, mortality, and overall disease burden. According to the GBD Chronic Respiratory Disease Collaborators [3], the global prevalence of COPD increased by 5.9% from 1990 to 2017. This period also saw the disease being attributed to a minimum of 2.9 million annual deaths. Based on projections made by the World Health Organization (WHO), it is anticipated that COPD will emerge as one of the top three leading causes of mortality on a global scale by the year 2030. The prevalence, mortality, and overall impact of COPD exhibit variations based on factors such as gender, geographical location, and age demographics. The incidence of COPD tends to rise with advancing age in the majority of regions. However, in certain regions, such as Uganda, the disease is more prevalent among children and young adults [4]. Despite the relatively low prevalence of COPD in certain Asian countries, such as India, the mortality rate associated with this condition remains alarmingly high [5]. COPD presents a significant disease burden in low-income countries, where healthcare resources primarily focus on addressing acute conditions like infectious diseases, rather than chronic ailments. Evaluating the COPD burden and identifying key risk factors across various levels can facilitate the identification of shared characteristics among high-risk areas and populations. This knowledge can provide valuable guidance for the efficient allocation of healthcare resources and the formulation of effective strategies for prevention and treatment.

2. Lung development and aging in the risk of COPD

The process of lung development is a meticulously coordinated event that commences during fetal development and continues throughout childhood and adolescence. Genetic and epigenetic factors play a crucial role in the intricate development of the respiratory system, which includes the branching airways and the complex alveolar network. Disruptions or insults experienced during crucial developmental periods can result in lasting structural changes that may increase the likelihood of respiratory diseases, such as COPD, in adulthood [6]. Differences in genetic factors related to the growth and maturation of the lungs, specifically involving the fibroblast growth factor (FGF) and transforming growth factor beta (TGF-β) signaling pathways have been linked to changes in lung development and heightened susceptibility to COPD in later stages of life [7].

The developmental origins of COPD have received significant attention due to the potential programming effects that arise from adverse fetal and early-life environments. Various factors, including maternal smoking, malnutrition, and exposure to pollutants, can influence lung growth and hinder typical structural development. Consequently, this influence can lead to compromised lung function and an elevated vulnerability to COPD during adulthood [8]. Furthermore, epidemiological studies have indicated a correlation between suboptimal lung function during early adulthood and an increased susceptibility to COPD later in life [9]. This highlights the significance of optimizing lung development as a strategy to mitigate the risk of COPD.

2.1 The interplay between aging and COPD

The process of aging is an unavoidable phenomenon that is marked by a gradual deterioration in physiological function across various organ systems, including the respiratory system. The susceptibility to COPD among older individuals is often attributed to age-related changes in lung structure and function, commonly known as “senile emphysema” [10]. The modifications encompass a reduction in lung elastic recoil, changes in chest wall compliance, and a decrease in the number of functioning alveoli. These factors collectively result in diminished lung efficiency and heightened susceptibility to airway obstruction [11].

In addition, the aging process is accompanied by a condition known as “inflammaging,” which refers to chronic low-grade systemic inflammation. This systemic inflammation is characterized by elevated levels of pro-inflammatory cytokines, oxidative stress, and dysregulation of immune cells [12]. The phenomenon of inflammation is not limited to the respiratory system but rather affects the entire body. It has been identified as a contributing factor in the development of various age-related illnesses, such as COPD [13]. The presence of inflammation in older individuals contributes to an environment that promotes the continuation of inflammation and tissue damage associated with COPD, ultimately leading to an accelerated progression of the disease [14].

2.2 Genetic factors and risk of COPD

The influence of genetic predisposition on the risk of developing COPD has received significant acknowledgment. Evidence suggests that genetic variations in the genes responsible for encoding proteins involved in lung development, inflammation, and oxidative stress may contribute to an elevated vulnerability to COPD [15, 16]. Polymorphisms in the SERPINA1 gene, which encodes alpha-1 antitrypsin, and an increased risk of early-onset COPD [17]. The presence of genetic variations plays a role in the development of imbalances between proteases and antiproteases, ultimately leading to tissue damage and changes in immune responses [18]. However, genetic factors alone are not sufficient to cause COPD. Instead, they interact in complex ways with environmental exposures to influence the development and progression of the disease [19].

2.2.1 Environmental exposures

Environmental exposures play a crucial role in the development of COPD, as they result from the interaction between genetic factors and external triggers [20]. The inhalation of harmful particles and gases, particularly from cigarette smoke, continues to be a significant factor in the risk of developing COPD [21]. The inhalational insult leads to a series of events that involve inflammation, tissue remodeling, and oxidative stress, creating an environment that promotes damage to the airways and lung tissue [22]. Gene-environment interactions can increase the susceptibility to diseases, thereby enhancing the complex interplay between inherited vulnerabilities and external triggers [23].

2.2.2 Alterations in structure and function

The structural and functional changes within the respiratory system are essential in understanding the pathophysiology of COPD [24]. Chronic inflammation stimulate airway remodeling, which is characterized by increased production of mucus, thickening of the submucosal layer, and constriction of the airway lumen [25]. These modifications collectively contribute to the restriction of airflow and an increase in the effort required for breathing. Emphysema, a condition marked by the destruction of alveolar walls and loss of alveolar attachments, reduces lung elasticity and compliance. As a result, it negatively impacts both ventilation and gas exchange [10].

2.2.3 Immune dysregulation

An altered immune response is a key aspect of the intricate nature of COPD [26]. Resident immune cells, such as macrophages and neutrophils, contribute to the maintenance of chronic inflammation by releasing pro-inflammatory mediators [27]. The participation of T and B lymphocytes in the adaptive immune system contributes to the continuation of immune responses [28]. The complex immunological coordination is disrupted in individuals with COPD, frequently resulting in an imbalance between pro-inflammatory and anti-inflammatory pathways [22]. The exploration of modulating these immunological nuances presents a promising opportunity for therapeutic interventions [29].

3. The interplay between airway microbiome and the risk of COPD

The field of chronic respiratory diseases has experienced significant changes due to the study of the human microbiome, which refers to the extensive collection of microorganisms that inhabit our bodies. The study of the airway microbiome has become an intriguing area of research, providing valuable insights into the development and risk factors associated with COPD.

In the past, it was commonly believed that the lower respiratory tract lacked any microbial presence, while the upper airways were predominantly inhabited by bacteria that coexist harmlessly with the human body. Advancements in culture-independent techniques, such as high-throughput sequencing, have revealed a wide range of microorganisms present in the bronchial tree [30]. The airway microbiome comprises a diverse range of microorganisms, including bacteria, viruses, fungi, and other microbial entities. These microorganisms form intricate communities within the airway, displaying unique patterns that vary between states of health and disease [31]. The correlation between the prevalence of particular microbial taxa and the diversity of the airway microbiome has been observed with various respiratory conditions, such as COPD. A discernible disparity exists in the microbiome of the respiratory tract between individual with and without COPD. In addition, the composition of the microbiome changes exacerbations of COPD [32, 33], with notable variations observed among different subtypes of exacerbations [34, 35]. The aforementioned observations provide compelling evidence of a significant association between the lung microbiome and the underlying pathophysiology of COPD. This connection likely involves the interplay of host immunity and inflammatory responses. Dysbiosis, which refers to the disturbance of the microbiome, is thought to initiate an uncontrolled immune response in the host, resulting in heightened vulnerability to infections, inflammation, and negative impacts on the host’s biology [36].

Typically, the airway microbiome in individuals who are in good health maintains a harmonious and well-balanced composition [37]. As airway diseases progresses, the microbial equilibrium is noticeably disrupted. Two primary metrics are utilized to measure microbial diversity, namely alpha-diversity (α-diversity) and beta-diversity (β-diversity) [35]. Alpha-diversity quantifies the overall diversity of microbial species present in a particular ecological niche, taking into account both richness (the number of taxonomic groups) and evenness (the distribution of abundances among these groups) [35]. In most lung diseases and instances of lung damage, α-diversity is notably decreased when compared to the airways of individuals with healthy lungs. In contrast, β-diversity quantifies the diversity of bacterial communities within a given ecological niche. As a result, β-diversity facilitates the evaluation of bacterial diversity across various ecological niches, such as the upper and lower airway, as well as different diseases. For instance, it allows for the comparison of the lower airway microbiome in patients with COPD to that of healthy individuals.

While the overall quantity of microorganisms in the upper and lower airways is comparable between individuals with and without COPD, there is a notable presence of dysbiosis in the lower airways of COPD patients [38]. A notable decrease in the diversity of the airway microbiome is primarily attributed to a reduction in the number of observed species. Additionally, the airway microbiome in COPD patients is characterized by a higher prevalence of bacteria from the Proteobacteria, Firmicutes, and Actinobacteria phyla, while the presence of bacteria from the Bacteroidetes phylum is comparatively lower [38]. At the genus level, the airways of individuals with COPD tend to harbor more bacteria belonging to the Hemophilus genus. Interestingly, although the Moroxella genus is seldom detected in the lower airways of individuals in good health, it is observed in the airways of approximately 2% of patients with COPD in their airways. The data collectively suggests that Hemophilus, Moraxella, and Pseudomonas are more abundant in individuals with COPD, whereas Prevotella is less abundant.

The α-diversity, specifically in species richness, decrease as the airflow limitation and burden of emphysema increases. However, this reduction is correlated with a concurrent decrease in the overall alveolar surface area [39].

4. Identifying risk factors for COPD

• Smoking: Smoking is widely recognized as the primary risk factor associated with the development of COPD. The majorities of individuals diagnosed with COPD are either current smokers or have a history of smoking. Individuals with a familial predisposition to COPD are at an increased likelihood of developing the condition if they engage in smoking behavior.

• Irritant: Additional lung irritants can encompass prolonged exposure to air pollution, chemical fumes, and environmental or occupational dust. Furthermore, inadequate ventilation when utilizing home cooking and heating fuels can contribute to lung irritation, as can exposure to secondhand smoke, which refers to the inhalation of smoke emitted by individuals who engage in smoking.

• Alterations to pulmonary growth and development: Pathologies impacting the respiratory system during prenatal development or early childhood can heighten the susceptibility [40].

• Infections: Certain infections, such as HIV and tuberculosis, are associated with an increased susceptibility to COPD.

• Age: The individual’s age may contribute to their risk of developing COPD, particularly if they have other risk factors such as smoking. The onset of symptoms for individuals with COPD typically occurs in individuals aged 40 years or older [41].

• Alpha-1 antitrypsin (AAT) deficiency: This is a genetic disorder that elevates the susceptibility to COPD upon exposure to smoke, fumes, or dust. Alpha-1 antitrypsin (AAT) deficiency can also increase the susceptibility to COPD at an earlier stage in life [42].

• Asthma: Asthma is a respiratory condition characterized by inflammation and constriction of the airways. Approximately 20% of individuals diagnosed with COPD also present with asthma [43].

• Gender Differences: Gender is a significant factor in the risk of developing COPD, as research suggests that women are more vulnerable to the detrimental impacts of tobacco smoke and environmental pollutants [44]. The disparity can be attributed to hormonal factors, variations in lung anatomy, and differences in inflammatory responses.

• Socioeconomic Factors: The risk of developing COPD is closely associated with an individual’s socioeconomic status. Individuals belonging to lower socioeconomic strata are at a higher risk of being exposed to environmental pollutants and occupational hazards. They also face limited access to healthcare resources and exhibit higher rates of smoking [45]. These various factors collectively contribute to an elevated risk of COPD among socioeconomically disadvantaged populations.

The aforementioned causes and risk factors have been found to elevate the likelihood of developing COPD. However, individuals residing in impoverished conditions and rural areas exhibit a higher susceptibility to COPD [46]. Additionally, COPD may exhibit varying impacts on women in comparison to men. In comparison to their male counterparts, older women may exhibit a higher propensity for experiencing severe symptoms of COPD, such as pronounced difficulty in breathing, despite having smoked less throughout their lifetime. Females diagnosed with COPD exhibit a higher propensity for experiencing symptoms at earlier stages of life and requiring hospitalization due to symptom severity, in comparison to their male counterparts with COPD [47].

Females diagnosed with COPD exhibit a reduced prevalence of smoking and possess a lower body mass index (BMI) compared to their male counterparts who are also afflicted with COPD [48].

The underlying factors contributing to the disparities in COPD prevalence and outcomes between males and females remain unclear. Researchers suggest that the cause could be attributed to hormonal or other physiological disparities between males and females [47, 48, 49]. Women have smaller lungs than men, which also may cause their airways to narrow those of more than men [50].

5. The significance of inflammation in the risk of COPD

Inflammation is a crucial physiological response to detrimental stimuli, intended to eliminate pathogens and facilitate tissue repair. However, in the context of COPD, the inflammatory process undergoes dysregulation and becomes persistent, thereby playing a significant role in the observed structural and functional abnormalities experienced by affected individuals. The key contributors to inflammation in COPD are immune cells, including neutrophils, macrophages, and T lymphocytes. These cells release various pro-inflammatory mediators, cytokines, and chemokines [51]. Additionally, it is worth noting that inflammatory mediators can also be produced by various lung cells, including epithelial cells. The primary inflammatory mediators comprise tumor necrosis factor-alpha, interleukin-1, interleukin-6, reactive oxygen species, and proteases.

The inflammatory process in COPD persists even after smoking cessation and continues to worsen over time. Hogg et al. [25] have demonstrated that patients with COPD experience progressive small airflow obstruction for several years following smoking cessation. The small airflow obstruction was caused by two factors: the accumulation of inflammatory mucous exudates in the lumen and an increase in the tissue volume of the bronchial wall. The augmentation of the tissue volume of the bronchial wall was distinguished by the infiltration of the wall by both innate immune cells (macrophages/neutrophils) and adaptive inflammatory immune cells (CD4, CD8, and B lymphocytes) that are organized into lymphoid follicles.

The precise determinants of inflammation in COPD following smoking cessation have yet to be definitively established. However, various factors, including autoimmunity, the presence of embedded particles/heavy metals from smoking, and chronic bacterial infection, have all been suggested as potential contributors [52]. Autoimmunity is widely recognized as the primary factor associated with lung inflammation in individuals with COPD.

The lung contains an intricate network of inflammatory mediators that are generated by both inflammatory and structural cells. These mediators encompass chemokines, growth factors, and lipid mediators. The factors that are most strongly linked to pathogenic inflammation in COPD include cytokines, reactive oxygen species, and proteases. The activation of toll-like receptors (TLRs) and lymphocyte antigen receptors triggers the production of inflammatory mediators. This process involves intracellular signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) and signal transducers and activators of transcription (STATs), which ultimately result in the release of these mediators (Figure 1).

Figure 1.

The interplay of inflammatory process and COPD risk. The presence of embedded particles/heavy metals from smoking, and chronic bacterial infection activate cell recognition receptors (PRRs) like toll-like receptors (TLRs), nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), and Interleukin-1 receptors (IL-1R). Stress-induced cell apoptosis and necrosis in COPD release damage-associated molecular patterns (DAMPs), recognized by IL-1 receptors, triggering inflammation. Microbial components release pathogen-associated molecular patterns (PAMPs) recognized by TLRs, activating NLRP inflammasomes. NLRP inflammasome activation leads to caspase 1 conversion, maturing pro-cytokines, exacerbating inflammation in COPD. The P2X7 receptor, elevated in COPD, activates NLRP inflammasomes, creating feedback loops of inflammation.

COPD is characterized by a significant systemic immune response, which becomes more prominent in the advanced stages of the disease and during exacerbations. Systemic inflammation is characterized by the presence of elevated levels of inflammatory/immune response mediators in the peripheral blood of individuals with COPD compared to smoking controls that do not have COPD.

The innate immune system serves as the initial defense against microbial infections, employing various cells (neutrophils, macrophages, dendritic cells, natural killer cells, monocytes, and mast cells) and humoral factors. These cells are equipped with pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), and Interleukin-1 receptor (IL-1R) on their membranes. Cell apoptosis and necrosis triggered by stressors like smoking in individuals with COPD result in the liberation of molecules known as Damage-Associated Molecular Patterns (DAMPs). These DAMPs, recognized by the IL-1 receptor on immune cells, trigger inflammatory responses. In contrast, Pathogen-Associated Molecular Patterns (PAMPs) released by microbial components are recognized by TLRs, initiating a cascade of events in the cell. This cascade begins with the aggregation of NLRP inflammasomes in the cell due to activation of TLRs and IL-1R. Activation and aggregation of NLRP inflammasomes in response to DAMPs or PAMPs leads to the conversion of pro-caspase 1 to caspase 1, facilitating the maturation of pro-cytokines into their active forms. These active cytokines exacerbate inflammation in COPD when released from immune cells. Additionally, the P2X7 receptor, increasingly expressed in COPD, can activate NLRP inflammasomes upon binding with ATP, which accumulates due to heightened inflammation. This highlights a feedback loop where inflammation begets further inflammation in COPD as demonstrated in Figure 1.

6. The diagnosis and management of COPD

6.1 Clinical evaluation

The diagnostic process often commences with a clinical evaluation to identify symptoms. Frequent manifestations of COPD encompass persistent cough, production of sputum, dyspnea (characterized by a sensation of breathlessness), and wheezing.

The acquisition of a comprehensive medical history, encompassing aspects such as smoking habits and exposure to potential risk factors, is crucial in the process of diagnosing a patient.

The physical examination may reveal certain clinical manifestations such as diminished breath sounds, the presence of wheezing, and observable indications of respiratory distress.

Pulmonary function tests (PFTs) are a set of diagnostic procedures used to assess the functioning of the respiratory system.

Spirometry serves as the fundamental diagnostic tool and severity assessment measure for COPD. The test quantifies the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). The ratio of FEV1 to forced vital capacity FVC is employed as a diagnostic measure to validate the presence of airflow restriction. One application of spirometry is post-bronchodilator testing, which evaluates lung function both before and after the administration of a bronchodilator. This procedure is valuable in distinguishing between reversible and irreversible airflow obstruction.

The combination of before and after measurements provides useful diagnostic information for the clinician that would not be known if only the measurement without bronchodilation were taken, specifically, the post-bronchodilator test which can help to:

6.1.1 Difference between asthma and COPD

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines suggest that the diagnosis of COPD should be confirmed by spirometry. The presence of a post-bronchodilator FEV1 < 80% of the predicted value is indicative of COPD, while a post-bronchodilator FEV1 > 80% of the predicted value suggests asthma [53].

6.1.2 Assess bronchodilator responsiveness

A bronchodilator may be administered to assess responsiveness if an obstructive defect is present. The post-bronchodilator test can help to determine how much the bronchodilator medication helped with breathing. If the test shows that the airways have responded to the medicine, it can help to confirm a diagnosis of asthma [53, 54].

6.1.3 Treatment implications

• The diagnosis of reversible airflow obstruction indicates that bronchodilators and anti-inflammatory medications may be effective treatments. Clinicians can tailor the treatment plan to focus on managing airway inflammation and bronchoconstriction.

• The diagnosis of irreversible airflow obstruction suggests that the focus of treatment should be on managing symptoms and preventing disease progression. Smoking cessation and other interventions to slow down the structural changes in the airways may be prioritized.

6.2 Imaging

Chest radiography: Radiographic imaging of the chest may demonstrate signs of hyperinflation, flattened diaphragms, or other pathological findings.

Chest computed tomography (CT) scans offer a comprehensive evaluation of lung tissue, allowing for enhanced detection of conditions such as emphysema and bronchiectasis. These high-resolution scans give a more intricate analysis of the lungs.

6.3 The analysis of blood gases

The study of arterial blood gases (ABGs) aids in the evaluation of the levels of oxygenation and ventilation. Some of the gases measured in ABGs and the indicative range of values for each gas includes:

Partial Pressure of Oxygen (PaO₂).

Normal Range: 75–100 mm Hg.

COPD Implications: A decrease in PaO₂ is common in COPD due to impaired gas exchange in the lungs. As COPD severity worsens, PaO₂ levels may decrease. In severe cases, it can fall below 60 mm Hg, indicating severe hypoxemia (low oxygen levels).

Partial Pressure of Carbon Dioxide (PaCO₂).

Normal Range: 35–45 mm Hg.

COPD Implications: In COPD, elevated PaCO₂ (hypercapnia) is often observed, especially in more advanced stages of the disease. Increased PaCO₂ is a sign of inadequate ventilation and impaired CO₂ removal. A PaCO₂ greater than 45 mm Hg is indicative of respiratory acidosis, which is a sign of more severe COPD.

pH

Normal Range: 7.35–7.45.

COPD Implications: As PaCO₂ levels increase in COPD, the pH of the blood decreases, leading to respiratory acidosis. A pH below 7.35 is indicative of acidosis, which can be a sign of more severe COPD.

6.4 Alternative assessments

Testing for Alpha-1 Antitrypsin Deficiency should be contemplated in individuals presenting with early-onset COPD or those with a familial predisposition to the condition.

Electrocardiography (ECG) and echocardiography are diagnostic tests used to evaluate the presence of comorbidities such as corpulmonale, in which alterations in the pulmonary system lead to structural changes in the right heart.

7. COPD management

7.1 Smoking cessation

Smoking cessation: The act of quitting smoking is often recognized as the most impactful intervention in the therapy of COPD.

Behavioral counseling and pharmacology, such as the utilization of nicotine replacement therapy or prescription drugs, are frequently seen essential in the treatment process.

7.2 Pharmaceutical substances

Bronchodilators are a class of medications that are used to treat specific respiratory symptoms of COPD.

Short-acting bronchodilators, such as albuterol, are commonly utilized for immediate relief, in emergency situations, from some specific symptoms such as shortness of breath, wheezing, coughing and chest tightness.

Long-acting bronchodilators, such as long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), are commonly used as maintenance therapy. LABAs work by stimulating beta-2 adrenergic receptors in the smooth muscles of the airways. The activation of beta-2 adrenergic receptors causes relaxation of the smooth muscles surrounding the airways, leading to bronchodilation. This relaxation opens up the airways, making it easier for the individual to breathe. LABAs have a prolonged duration of action, providing bronchodilation that can last for approximately 12 hours, making them suitable for use as maintenance therapy.

LAMAs work by blocking the action of acetylcholine at muscarinic receptors in the airway smooth muscles. When acetylcholine binds to muscarinic receptors, it causes the airway smooth muscles to contract, leading to bronchoconstriction. LAMAs block these receptors, preventing acetylcholine from exerting its constricting effect, thereby promoting bronchodilation and improving airflow. LAMAs also have a prolonged duration of action, typically lasting 12 to 24 hours, which makes them also suitable for use as a maintenance therapy option.

Individuals who have frequent exacerbations or who exhibit an eosinophilic phenotype are advised to contemplate the utilization of inhaled corticosteroids (ICS). ICS are anti-inflammatory medications that can help reduce airway inflammation, including eosinophilic inflammation, and therefore, they can help control symptoms and reduce the frequency of asthma exacerbations.

The eosinophilic phenotype often refers to a specific pattern of airway inflammation characterized by an elevated number of eosinophils in the airway tissue and/or in sputum (mucus coughed up from the lungs). Eosinophils are a type of white blood cell, a part of the immune system. They play a role in the body’s response to various infections and are also involved in allergic and inflammatory responses. Eosinophils are particularly associated with conditions involving inflammation of the airways, such as asthma. This type of inflammation is often seen in individuals who have allergic asthma, which is triggered by allergens, such as pollen or dust mites.

Eosinophilic airway inflammation can contribute to the symptoms and exacerbations of asthma, as eosinophils release substances that can cause bronchoconstriction (narrowing of the airways) and increase airway reactivity.

Eosinophil levels can be measured in different ways such as Blood test, sputum analysis and bronchoalveolar lavage (BAL).

Phosphodiesterase-4 (PDE-4) is an enzyme that plays a crucial role in the regulation of intracellular processes. Inhibitors may be employed as an adjunctive therapy in cases of severe COPD.

Antibiotics are indicated for exacerbations characterized by heightened sputum purulence.

7.3 Exercise

Pulmonary rehabilitation is a comprehensive program that aims to improve the overall well-being and functional capacity of individuals with chronic respiratory conditions.

Comprehensive interventions encompassing exercise training (such as pulmonary rehabilitation programs, physical therapy, and a home exercise plan), educational components (such as disease management education, breathing technique, and medication management), and nutritional assistance (such as dietary counseling and weight management) have been shown to enhance both the quality of life and exercise tolerance.

7.4 Oxygen therapy

Oxygen therapy is a medical intervention that involves the administration of supplemental oxygen to individuals with respiratory conditions or those experiencing low oxygen levels in order to improve their oxygen saturation and overall respiratory function.

The intervention was conducted on individuals exhibiting severe hypoxemia, characterized by a partial pressure of arterial oxygen (PaO₂) below 55 mm Hg or arterial oxygen saturation (SaO₂) below 88%.

7.5 Surgical interventions

Surgical interventions are medical procedures that use invasive techniques to treat or manage various health conditions. These interventions typically need the skills of trained surgeons, operating rooms equipped with specialized instruments, and the use of anesthesia to ensure the patient’s comfort and safety during the procedure.

Lung Volume Reduction Surgery (LVRS) should be considered for a subset of patients who present with severe emphysema. The primary purpose of this procedure is to correct overinflated lungs and thus improve quality of life for individuals with advanced emphysema. While LVRS can be beneficial for many patients with severe emphysema, it is an invasive surgical procedure and carries certain risks, such as operative risk, pneumonia, air leaks, and pulmonary function decline and recovery challenges. It is therefore, necessary to take into consideration patient selection, pre-operative assessment, and post-operative management as crucial aspects of ensuring the success and safety of this procedure for those with severe emphysema.

Lung transplantation serves as a viable therapeutic option for those in the advanced stages of COPD. Due to some limitations such as donor organ availability, eligibility criteria, surgical risks, immunosuppression, rejection and complications, post-transplant care, cost and accessibility, and the complex nature of lung transplantation, it is considered as a treatment of last resort for individuals with advanced COPD.

Vaccinations are a crucial aspect of public health interventions aimed at preventing the spread of infectious disease.

The administration of influenza and pneumococcal vaccinations is effective in reducing the occurrence of exacerbations [55].

7.6 The management of exacerbations

While many of the above interventions are applied to treat COPD over the long term and to prevent the condition from worsening, patients with severe COPD have periodic exacerbations that require more acute treatment. In respiratory exacerbation, such as an acute exacerbation of COPD or asthma, several physiological changes occur in the airways, such as:

Airway Inflammation: Exacerbations are often triggered by increased inflammation in the airways. Inflammation leads to swelling and narrowing of the air passages, making it harder to breathe.

Increased Mucus Production: An overproduction of mucus in the airways can further obstruct airflow.

Bronchoconstriction: The smooth muscles surrounding the airways constrict, leading to narrowed air passages, which exacerbates the feeling of breathlessness.

Decreased Oxygen Exchange: These factors cause the exchange of oxygen and carbon dioxide in the lungs to become less efficient, leading to low oxygen levels (hypoxia) and high carbon dioxide levels (hypercapnia) in the blood.

The administration of bronchodilators, corticosteroids, and antibiotics is employed on an as-needed basis. The choice of treatment, whether it is bronchodilators, corticosteroids, antibiotics, or a combination of these therapies, depends on the underlying cause of the exacerbation.

Bronchodilators: Bronchodilators, like short-acting beta-agonists (SABAs) or LABAs, work to relax the smooth muscles around the airways, thereby alleviating bronchoconstriction and improving airflow. They are particularly effective when bronchoconstriction is a primary cause of the exacerbation, as seen in asthma or COPD.

Corticosteroids: Corticosteroids, such as oral or inhaled forms, are anti-inflammatory medications. They help reduce airway inflammation and swelling. They are useful when inflammation plays a significant role in the exacerbation, such as in asthma or some cases of COPD exacerbations.

Antibiotics: Antibiotics are used when a bacterial infection is suspected or confirmed. In some exacerbations, a respiratory infection, such as pneumonia, can be a triggering factor. If a bacterial infection is present, antibiotics are prescribed to treat the infection. However, they are not effective for viral infections.

Indications: Signs of a bacterial infection, such as increased sputum production, green or yellow mucus, fever, and changes in the appearance of chest X-rays, may lead to the use of antibiotics.

Non-invasive ventilation (NIV) is a therapeutic approach employed in instances of respiratory failure, and it differs from simple oxygen therapy and invasive ventilation (intubation) in several key ways:

7.6.1 Delivery method

NIV: NIV is delivered using a mask or other interface that covers the nose and/or mouth, or in some cases, a nasal mask. It assists with breathing by providing a combination of pressurized air or a mixture of oxygen and air. NIV is often administered using devices like bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) machines.

Simple Oxygen Therapy: Oxygen therapy involves delivering supplemental oxygen through various devices, such as nasal cannulas, face masks, or oxygen concentrators. It does not provide pressure support to assist with ventilation.

Invasive Therapy (Intubation): Invasive ventilation involves the placement of an endotracheal tube through the mouth or nose into the trachea, or a tracheostomy tube directly into the windpipe. It provides mechanical support for breathing by taking over the work of the patient’s respiratory muscles.

7.6.2 Degree of intervention

NIV: NIV is considered a non-invasive and intermediate level of respiratory support. It does not require inserting a tube into the airway, making it less invasive compared to intubation.

Simple Oxygen Therapy: Oxygen therapy is the least invasive form of respiratory support. It simply provides additional oxygen to the patient without altering the patient’s breathing pattern.

Invasive Therapy (Intubation): Intubation is highly invasive, as it involves the insertion of a tube directly into the patient’s airway to take over their breathing completely.

7.6.3 Patient comfort and cooperation

NIV: NIV is typically well-tolerated by conscious and cooperative patients. They can talk, eat, and remove the mask when necessary. It is often used for patients with respiratory distress but who are still conscious and can protect their airway.

Simple Oxygen Therapy: Oxygen therapy is generally well-tolerated and does not interfere with a patient’s ability to eat, talk, or move about.

Invasive Therapy (Intubation): Intubated patients are not able to talk, eat, or drink because the tube bypasses the vocal cords. Intubation requires sedation or even full anesthesia, and it is typically used for patients who are unable to protect their airway or breathe effectively on their own.

7.6.4 Indications

NIV: NIV is often used in conditions like acute exacerbations of COPD, congestive heart failure, or other forms of respiratory failure, where patients can still maintain some level of respiratory effort.

Simple Oxygen Therapy: Simple oxygen therapy is primarily used to correct hypoxemia (low blood oxygen levels) and is applicable in a wide range of respiratory conditions.

Invasive Therapy (Intubation): Intubation is reserved for patients with severe respiratory failure, inability to protect their airway, or who require complete control of their breathing, such as during surgery or when in a state of unconsciousness.

7.7 Interaction of different therapies

7.7.1 Combining therapies

Bronchodilators and Corticosteroids: It is common to use short-acting bronchodilators alongside inhaled corticosteroids (ICS) in the treatment of asthma and COPD. The bronchodilators provide immediate relief, while corticosteroids address underlying inflammation when used together in the form of a combination inhaler (e.g., LABA/ICS).

Bronchodilators and Non-Invasive Ventilation (NIV): During acute exacerbations of COPD or asthma, bronchodilators can be administered alongside NIV to help open airways and alleviate respiratory distress.

7.7.2 Patient-centered approaches

Individualized Treatment Plans: The choice of treatment often depends on the patient’s specific symptoms, underlying condition, and severity of the exacerbation. For example, in COPD, some patients may benefit from inhaled bronchodilators alone for mild exacerbations, while others with significant inflammation may require corticosteroids in addition to bronchodilators.

Comorbidity Considerations: Patients with comorbid conditions may require tailored treatment approaches. For instance, a patient with COPD and heart failure may need therapies targeting both conditions simultaneously.

Response to Treatment: Patient response to treatments can vary. Some individuals may respond well to a particular therapy, while others may require a combination of interventions to manage their symptoms effectively.

7.7.3 Contraindications and cautions

Invasive Ventilation and Oral Corticosteroids: In some cases, when intubation and invasive ventilation are required, the use of oral corticosteroids might be reduced or stopped, as they can increase the risk of infections and complications.

Antibiotics and Viral Infections: Antibiotics are ineffective against viral infections. Using antibiotics when not indicated (e.g., in the common cold or uncomplicated upper respiratory infections) can lead to antibiotic resistance.

7.7.4 Escalation and de-escalation

Treatment Plans: The treatment plan may need to be adjusted based on how a patient’s condition evolves. For instance, starting with non-invasive therapies like bronchodilators and corticosteroids and escalating to NIV or intubation if the condition deteriorates.

Prevention and Maintenance: Long-term management of chronic conditions often involves daily medications to prevent exacerbations. These can include inhaled corticosteroids, long-acting bronchodilators, and lifestyle modifications, alongside rescue medications for acute symptom relief.

8. Concluding remark

COPD represents a significant global health concern, warranting attention and concerted efforts on an international scale. Collaborative endeavors across nations have the potential to propel advancements in COPD research. The act of exchanging data, resources, and expertise has the potential to enhance the comprehension of COPD within various populations and facilitate the creation of interventions that are universally efficacious. Therefore, the advancement of research on COPD is crucial in order to boost patient outcomes and improve the overall quality of life for individuals affected by this incapacitating ailment. Future research should adopt the principles of precision medicine, harness the potential of artificial intelligence (AI) and big data, investigate innovative therapeutic approaches, and give precedence to the provision of patient-centered care. By acknowledging the diverse nature of COPD and customizing therapies to suit the specific requirements of each individual, researchers can make substantial advancements in combating this ailment, thereby enhancing the well-being of COPD patients on a global scale.