What is COPD?

Chronic obstructive pulmonary disease (COPD) is a progressive and largely irreversible respiratory condition that causes poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs, associated with overall poor lung health [1,2,3]. It affects the airways, lung parenchyma, and pulmonary vasculature as well as having extra-pulmonary effects. COPD mechanisms include mucus hypersecretion (chronic bronchitis), tissue destruction (emphysema), and small airway inflammation with fibrosis. Emphysema usually develops later, and chronic bronchitis is diagnosed if a productive cough persists for at least three months in at least two consecutive years. The main pathological changes are found in the small airways with epithelial remodeling including goblet cell metaplasia, basal cell hyperplasia, leading to thickening of small airway walls and obliteration [4]. The large airways are also affected with remodeling changes, inflammation, squamous metaplasia, and there can be associated bronchiectasis (Fig. 1). Emphysema of the peri-bronchial lung parenchyma can occur more than 10 years after small airway obstruction can be detected, and predominantly in the areas initially affected by air trapping. The pathological changes in the small airways lead to increased airflow resistance, and air trapping [3, 5]. People with COPD are at risk of developing both infections and lung cancer [6, 7]. The 5-year mortality rate for COPD is estimated at 25% [8, 9].

Fig. 1
figure 1

Tobacco smoking and development of Chronic Obstructive Pulmonary Disease (COPD). There were 329 million cases of COPD globally in 2019, with high rates of mortality and morbidity. The leading risk factor for developing COPD is smoking, including early life exposure. The pathogenesis of COPD involves various factors such as airway inflammation, oxidative stress, genetic factors, epithelial-mesenchymal transition (EMT) mediated airway remodeling, and endothelial-mesenchymal transition (EndMT) mediated vascular remodeling. COPD often coexists with other conditions such as lung cancer, cardiovascular diseases, and pulmonary hypertension as common comorbidities

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Development of COPD

COPD is considered a preventable and manageable disease, and it is possible to prevent or reduce its individual and population burden by dealing, among other, with social determinants of health. These social determinants are tobacco and tobacco products, indoor and outdoor pollution, occupational exposures, infections, low education and socioeconomic status, and poverty. COPD is a major global health problem and the third leading cause of death worldwide. In 2019, there were 392 million cases of COPD globally [10], associated with 3.23 million deaths [1] and 74.4 million disability-adjusted life years [11]. Three-quarters of people with COPD live in low- and middle-income countries [1, 10, 11]. Smoking is still the primary, causal risk factor leading to COPD, but environmental exposures, such as exposure to biomass fuel combustion, air pollution, and occupational exposures, and poor lung development (both pre- and post-natal) are increasingly recognized as important causes of COPD [3, 12]. Children’s exposure to tobacco constituents during fetal development, and environmental tobacco smoke exposure are also risk factors associated with poor lung development. Second- and third-hand tobacco smoke exposure are also risk factors for ill-health during childhood, including asthma, respiratory infections, otitis media, sudden infant death syndrome (SIDS), low birth weight and premature birth, cognitive and behavioral problems, and likely an increased cancer risk. It is estimated that approximately 70% of COPD cases in high income countries are caused by tobacco smoking [1], and the burden is growing in low- and middle-income countries. When burned, cigarette smoke contains over seven thousand chemicals, some with toxic and carcinogenic effects [13, 14]. The inhaled complex cigarette smoke particles can adhere to and affect the respiratory tract, and the deposition varies depending on their particles size. Larger particles tend to settle in the upper airways (large airways), while smaller particles are deposited in the lower airways (small airways < 2 mm) and alveoli, leading to chronic inflammation, oxidative stress and damage to the airways and lung parenchymal structures [15]. Substantial evidence indicates that exposure to household air pollution, particularly from indoor sources such as biomass cooking fuel, firewood heating, and candles [16], is also associated with an increased risk of developing COPD [17], especially in low- and middle-income countries [18] where children and women are predominantly exposed [19]. Household air pollution is recognized as a major risk factor for COPD, with chronic respiratory diseases in women being associated with the use of solid fuel for cooking [20]. Moreover, the detrimental effects of household air pollution exposure on lung development during early life are also evident [19, 20].

Up to late-20th century, COPD was considered solely a smoking-related disease [21], and most research focused on the pathological and physiological changes in the airways and lungs caused by smoking. As discussed above, it is now recognized that many patients with COPD are people who never smoked, but there is relatively little data on the pathological changes seen in these patients. There is some evidence that the deposition of the particles produced by cigarette smoking is different to that due to biomass or occupational exposures as these are mostly inhaled nasally where the filtration efficiency is higher, whereas tobacco smoke is inhaled through the mouth at a high flow rate leading to greater deposition in the lower airways and alveoli [22]. In susceptible subjects, cigarette smoke triggers a complex cascade of inflammation, with oxidative stress, accelerated cellular senescence and aberrant repair processes. There is evidence that women, especially after menopause, are more susceptible to the effects of tobacco smoke and develop a different pattern of disease with more severe small airway obstruction and less emphysema [23,24,25,26,27].

Tobacco smoke

Tobacco products and tobacco smoke contain a complex mixture of over 9500 compounds, such as nicotine, tar, and chemicals, many of which have been recognized as hazardous to human health by regulatory agencies [28]. Tobacco smoke is a complex aerosol which includes condensed liquid droplets (the particulate matter (PM) or tar) suspended in a mixture of volatile and semi-volatile compounds and combustion gases (the gas fraction). The gas phase of cigarette smoke include traces of acetaldehyde, methane, hydrogen cyanide, nitric acid, acetone, acrolein, ammonia, methanol, hydrogen sulfide, hydrocarbons, gas phase nitrosamines, carbonyl compounds and toxic metals including sodium, mercury, iron, arsenic, cadmium, and cobalt [29]. Constituents in the particulate phase include carboxylic acids, phenols, water, nicotine, terpenoids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, and catechol. Some toxic effects induced by tobacco smoke, result from direct genetic or epigenetic effects resulting in altered gene functions (for example, cell cycle, DNA repair, and tumor suppressor genes). Many components of tobacco smoke also have the potential to drive the inflammatory response and impaired healing. Depending on the size of the inhaled complex smoke particles, they can be deposited throughout the airway. Larger particles favor the larger and more central airways, while smaller particles are deposited in the smaller peripheral airways and sacs, leading to chronic inflammation, infections, oxidative stress and damage to the airways and gas exchange areas of the lung [15]. Combustion also produces reactive oxidative substances such as superoxide anion (O2−), hypochlorite (ClO−), peroxynitrite (ONOO−), and hydroxyl (•OH) [30] that are not present in the leaf. Nicotine levels vary in different types of tobacco leaves [31]. Additives, chemicals, and flavorings are usually added to increase the palatability, attractiveness, and addictiveness of tobacco products [32, 33]. Combined with other substances, such additives can become toxic during combustion of these products [33, 34]. These contribute to oxidative stress and damage epithelial cells by inducing peroxidation of lipids and other cell membrane constituents, activate oxidative-sensitive cellular pathways, and induce DNA damage [35]. Other forms of smoked tobacco products, for example, hookah or water-pipe, burn tobacco leaves with other additives [36, 37]. These forms of smoking are at least as detrimental to lung health as smoking cigarettes and should not be considered as a safe alternatives of cigarette smoking [38]. Moreover, nicotine, a highly addictive substance, is deposited in the lung and rapidly absorbed, stimulating the central nervous system, and causing increase in heart rate and blood pressure [39, 40].

Airway inflammation

The immune response to inhaled tobacco smoke leads to the recruitment of inflammatory cells, such as neutrophils, lymphocytes and alveolar macrophages [41]. COPD is a heterogeneous condition, with between-individual variation in the nature and severity of airway inflammation [42] and the inflammatory cell profile also varies in large and small airways and with severity of COPD, hence careful appraisal is needed [43]. Both neutrophil-associated COPD with T1 and T17 type immune responses and eosinophil-associated T2-mediated immunity are found in different patients, as well as autoimmunity in more severe disease [42]. Studies have also shown increase in M1/M2 macrophages and mast cells in people who smoke and patients with COPD [44,45,46].

Genetic factors

Genetic factors also play a role in the development of COPD and may accelerate a decline in lung function. The well-known genetic factor related to COPD is the deficiency of serine protease α1-antitrypsin (AATD), a hereditary disorder, which increases the risk of 1–3% of individuals developing COPD, especially in those who smoke [47]. Genetic variants could strongly predict COPD in independent populations, and these variants are higher in those who smoke [48]. In addition, the enrichment of lung developmental pathways was observed in lung function-associated genetic variants, which altered lung gene expression [49]. The study also showed that although the heritability of lung function and COPD was estimated to be between 38 and 50%, individual genetic variants only account for a small fraction of the overall risk associated with COPD [50].

Tobacco smoking, COPD and multimorbidity

People with COPD also have a higher risk for other health problems, both because of shared risk factors and due to the systemic effects of COPD [3, 51]. Multimorbidity can impact negatively on symptoms, quality of life, complication rates, disease management and life expectancy [2]. The most common multi-morbid conditions include coronary artery disease, atrial fibrillation, congestive heart failure, skeletal muscle wasting, metabolic syndromes including diabetes mellitus, osteoporosis, depression, anxiety, gastro-esophageal reflux disease (GERD) and lung cancer [3]. Nearly half of all COPD patients have three or more other long-term conditions, underscoring the importance of a holistic person-centered approach to the overall management of COPD [51]. (Fig. 2)

Fig. 2
figure 2

Chronic obstructive pulmonary disease (COPD) and multimorbidity, and the management strategies. The most common comorbidities in COPD include cardiovascular diseases, lung cancer, gastro-oesophageal reflux disease (GERD), skeletal muscle wasting, osteoporosis, depression and anxiety, which normally affect COPD progression and management. Most COPD patients have three or more comorbidities. Multidisciplinary management strategies, including smoking cessation, weight management, dietary changes, exercise training, medication and psychological counselling, are essential for COPD patients with multimorbidity

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Cardiovascular diseases

Individuals with COPD often share cardiovascular risk factors, such as smoking, sedentary lifestyle, and hypertension [52]. Chronic inflammation in COPD can also contribute to atherosclerosis and vascular thrombosis [51]. Impaired lung function or oxygen exchange can increase strain on the heart in people with COPD. Cardiovascular diseases can have a negative impact on individuals with COPD, causing pulmonary hypertension (PH) [53]. In addition, coronary artery disease or heart failure can compromise lung function by reducing oxygen supply to the lungs [54]. The co-existence of COPD and cardiovascular diseases is associated with worse outcomes, increased hospitalization, higher death rates and reduced quality of life. PH has also been associated with COPD and cardiovascular abnormalities. Patients with COPD showed noticeable alteration in the pulmonary vasculature, characterized by vascular remodeling primarily affecting small size vessels, such as muscular walls of arteries and arterioles [55, 56]. The process of endothelial to mesenchymal transition might be central to this pathology [57]. Severe COPD can contribute to the development of PH due to several factors. These include chronic inflammation, loss of lung tissue elasticity, destruction of small blood vessels in the lungs, and hypoxemia [58]. Similarly, PH can also worsen COPD symptoms and prognosis. The increased pressure in the pulmonary arteries puts additional strain on the right side of the heart, leading to right heart failure [59]. This can further compromise lung function and exacerbate COPD symptoms.

Skeletal muscle wasting

Inactivity is common among COPD patients and significantly contributes to many systemic issues of COPD [60], especially during exacerbations [61]. Research indicate that inactivity independently increases the risk of skeletal muscle wasting, osteoporosis [62], type 2 diabetes, cardiovascular disease and depression [63]. Among these, skeletal muscle wasting is a critical consequence of inactivity and around 20% of COPD patients suffer from severe skeletal muscle wasting, which leads to considerable morbidity and mortality [61]. Skeletal muscle wasting can initiate a “downward disease spiral”, where muscle weakness and inefficient metabolism at low exercise intensity further decrease exercise capacity [64].

Osteoporosis

Osteoporosis is one of the most prevalent comorbidities in COPD, especially the severe airflow obstruction had the greatest risk of osteoporosis [65, 66]. Smoking is a common risk factor for both COPD and osteoporosis. Long-term smoking can result in reduction of bone density [67], degeneration of bone microstructure, and increased bone fragility [66]. Inactivity is another main risk factor osteoporosis in COPD. Due to respiratory failure and shortness of breath after activity in patients with COPD, reduced physical exercise ability becomes an important cause of bone mass loss [68]. Other factors, such as low body composition measures, pulmonary dysfunction, and inflammation, are associated with osteoporosis and COPD [69, 70]. Effective treatments with COPD-associated osteoporosis are unknown, and a specific treatment guideline is needed for better management of these patients [71].

Depression and anxiety

Patients with COPD are commonly experienced mental health conditions, such as depression and anxiety, more than the general population [72, 73]. Depression and anxiety have a significant negative impact on COPD prognosis by reducing physical activity, worsening dyspnea, increasing the frequency of exacerbations, and increase the burden of healthcare services [74]. Depression and anxiety also further interfere with other risk factors such as smoking and worsen patients’ quality of life [75]. In particular, anxiety is linked to poor quality of life regarding mental and physical health outcomes in COPD patients [76]. Routine assessment for depression and anxiety are crucial and should become a standard practice in managing COPD [77]. Early detection and comprehensive treatment of depression and anxiety in COPD patients are essential for improving their overall quality of life and health outcomes.

Gastro-oesophageal reflux disease (GERD)

GERD is another commonly observed comorbidity in patients with COPD and can significantly impact the disease’s progression and management [78]. Smoking is a known risk factor for GERD in general population [79] and COPD [80]. GERD is associated with an increase frequency of COPD exacerbations [81]. The reflux of stomach contents can irritate the airways and lungs, and further worsen respiratory symptoms such as coughing and shortness of breath and diminishing the quality of life for COPD patients [80]. Modification of lifestyle, including dietary changes [82], weight management, smoking cessation and appropriate medications to reduce stomach acid production can alleviate GERD symptoms [78, 83], improving quality of life in COPD patients.

Lung cancer

Individuals with COPD have a four-to-six-fold higher risk of developing lung cancer compared with the general population [84]. COPD and lung cancer share the same risk factors, such as exposure to tobacco smoke and indoor/outdoor air pollution [85, 86]. COPD and lung cancer often have overlapping symptoms, such as chronic cough, shortness of breath and chest discomfort. This can make it challenging to differentiate between the two conditions based on symptoms alone. Along with inflammation, epithelial to mesenchymal transition have been reported in people who smoke and patients with COPD, which may be one of the shared mechanisms leading to lung cancer in these patients [87,88,89,90,91]. High dose inhaled corticosteroids ameliorate epithelial to mesenchymal transition and improve vascular changes [92, 93]. Inhaled corticosteroids have been shown to reduce risk of lung cancer [94,95,96]. However, effects of inhaled corticosteroids against lung cancer in COPD remains controversial [97, 98].

Second-hand smoke and COPD

Exposure to second-hand smoke is a significant risk factor for the onset and progression of COPD. Exposure to second-hand smoke in both childhood and adulthood have been linked to an increased risk for COPD-related mortality [99]. Inhalation of second-hand smoke can adversely affect the respiratory system, particularly for individuals already affected by asthma, infections, or allergies. Prolonged exposure to second-hand smoke can cause airway inflammation, broncho-constriction, airway obstruction and lung tissue damage, increase the likelihood of developing COPD, worsen existing COPD symptoms and accelerate lung function decline [100, 101]. Second-hand smoke also increases the risk of developing lung cancer. Tobacco smoke exposure in utero may lead to preterm birth and increase the risk of respiratory diseases such as asthma and COPD in the offspring.

Smokeless tobacco and COPD

There is no direct evidence to date that smokeless tobacco (such as chewing tobacco or snuff) can lead to the development of COPD. Although smokeless tobacco does not involve inhaling smoke into the lungs, it still exposes users to high level of nicotine and harmful chemicals and toxins that can cause oropharyngeal cancer, which could affect the lungs [102]. The use of smokeless tobacco can lead to chronic irritation and inflammation in the airways [103], contributing to the development of respiratory conditions such as large airway inflammation or bronchitis. We have defined different tobacco products in Table 1.

Table 1 Tobacco definitions [131]
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New and emerging nicotine-delivery systems and other tobacco products and COPD

Electronic nicotine delivery systems (ENDS)

Serious health concerns regarding the use of electronic cigarettes (e-cigarettes) have been raised, particularly related to their use by adolescents and young adults [104, 105]. Early studies have shown a correlation between the use of e-cigarettes and lung injury [12, 106], with e-cigarette users showing increased respiratory symptoms, an elevated risk of developing airway disease and a decline in lung function [107]. However, to date, there is no direct evidence that use of electronic smoking devices leads to the development of COPD. However, based on the literature review, it is postulated that use of e-cigarettes could lead to lung health issues and be a risk factor for development of COPD among those who have never smoked. Osei et al. reported that current e-cigarette users have a 75% higher risk of developing COPD compared with those who have never used e-cigarettes [108]. Daily e-cigarette users and former tobacco cigarette users who currently use e-cigarettes are at a higher risk of developing COPD compared with individuals who have never smoked conventional cigarettes or never used e-cigarettes [109]. In addition, individuals who smoke conventional cigarettes and use e-cigarettes (“dual use”) showed the highest likelihood of developing COPD compared with those who have never smoked conventional cigarettes or used e-cigarettes [108, 110,111,112]. These findings suggested that the use of e-cigarettes may potentially promote pathophysiological processes similar to those seen in COPD. Hence e-cigarettes should not be promoted as a tool for smoking cessation [110, 111]. Additional research is needed to examine the long-term risk of developing COPD among users of e-cigarette products, considering the heterogenous composition of e-cigarette products.

Heated tobacco products

Heated tobacco products (HTPs) emit toxic chemicals, including nicotine, when tobacco is heated or when a device containing tobacco is heated, and these are inhaled by the user. The tobacco industry markets these products as a “less harmful alternative” to conventional cigarettes [113, 114]. Currently, the existing evidence is insufficient to support the reduced exposure claims for HTPs, and existing evidence is also insufficient to support either the reduced risk or reduced harm claims for HTPs [115]. HTPs have recently gained popularity and are available in about 70 countries [114]. Research studies have shown that exposure to HTP emissions can be just as harmful to human lung cells as exposure to smoke from conventional cigarettes. It can cause a persistent allergic response, smoke- or environmental-triggered inflammation that leads to airway scarring, which are the principal causes of airflow limitation in COPD [116, 117]. There was a high prevalence of dual use of HTPs with conventional cigarettes among COPD patients (up to 33%), which did not reduce the harm for these patients [118] or the prevalence of smoking-related chronic diseases [119].

Impact of selected tobacco control interventions on COPD

There is no safe way to use tobacco. Tobacco control plays an important role in public health and chronic disease management. People should be supported to stop using tobacco in all forms, including e-cigarettes and HTPs. Smoking cessation has a great impact on reducing the health risks associated with smoking. It is a crucial intervention for all people who smoke and have COPD, as it can slow the decline in lung function and the progression of COPD [3], improve respiratory symptoms and reduce mortality in patients with COPD compared with those who continue to smoke [120]. Smoking cessation also benefits COPD patients who have nocturnal sleep disorders [121]. Health-care professionals should increase patients’ awareness of the hazards of smoking and provide smoking cessation advice to enhance their self-efficacy in quitting [122, 123]. The WHO urges governments to include smoking cessation and treatment services as part of tobacco control programmes [124], also recommended in the United States Surgeon General’s 2020 report on smoking cessation [125].

Population-level interventions to address tobacco use

Population-level interventions to combat tobacco-linked COPD morbidity and mortality are essential. WHO has well-established tools for implementing tobacco control measures. To support countries in implementing the WHO Framework Convention on Tobacco Control (FCTC), WHO introduced the MPOWER package in 2008 and reported on progress in a biennial report on the global tobacco epidemic [123]. MPOWER contained a set of six tobacco control demand reduction measures corresponding to one or more articles in the WHO FCTC. These are, (1) Monitoring tobacco use and prevention policies; (2) Protecting people from tobacco smoke; (3) Offering help to quit tobacco use; (4) Warning about the dangers of tobacco; (5) Enforcing bans on tobacco advertising, promotion, and sponsorship; (6) Raising taxes on tobacco (MPOWER). The WHO Package of Essential Noncommunicable (PEN) Disease Interventions for primary health care includes a module on the management of COPD. PEN emphasizes the need to inform people with COPD about the risks of smoking and indoor air pollution and the need to stop smoking [122]. The updated “best buys” and other recommended interventions for the prevention and control of noncommunicable diseases were adopted by the 76th World Health Assembly in 2023. These include six cost-effective interventions to reduce tobacco exposure and two on the management of COPD. The WHO recommends the following population-level and pharmacological interventions to ensure access to comprehensive cessation support (Table 2).

Table 2 WHO recommended the following population-level and pharmacological interventions to ensure access to comprehensive cessation support [131, 132]
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Emerging concerns and future directions

The primary strategy to reduce the burden of COPD is to address all risk factors, especially exposure to all forms of tobacco smoke throughout life, to promote respiratory health and overall well-being [126]. Lungs have not evolved to safely inhale tobacco smoke. Bold action is required by individuals, health practitioners and policymakers to create a tobacco-free world. In particular, the Tobacco Endgame targets to have a generation free of tobacco by 2030, banning sales in those born from 2012 and later [127]. Although smoking rates have fallen globally but still smoking is likely to remain a leading cause of preventable death throughout this century unless smoking cessation efforts can significantly and rapidly reduce the number of people who smoke, particularly in the developing countries [128]. The risk of developing COPD is present throughout life, and exposure to risk factors can be particularly harmful during lung growth and development (in utero, in childhood and in adolescence). Tobacco use among children, adolescents and young people is of particular concern. It is important to note in this context that worldwide, at least 37 million young people aged 13–15 years (9.7%) use some form of tobacco product [129]. In fact, it is now well known, that COPD may start in childhood, when genetic and environmental factors may lead to reduced lung growth; and repeated insults/exposures may add to the negative effects [130]. These vulnerable groups are being actively targeted by the tobacco industry with campaigns promoting nicotine and tobacco products, including e-cigarettes, HTPs and nicotine pouches. The emergence of a tobacco epidemic among populations already vulnerable to COPD through adverse early life events and exposure to indoor and outdoor air pollution is catastrophic for already overstretched health systems, which are ill-equipped to manage chronic conditions. Protecting these groups from the dangers of tobacco use through effective tobacco control legislation, including total product ban, it is not just a matter of public health, but also an ethical obligation. It is also crucial to expose the tobacco industry’s tactics and equip the general public with knowledge and tools to combat the influence of the tobacco industry. Moreover, it is imperative that all tobacco users, particularly those living in low-to-middle income countries, have access to comprehensive cessation support aligned with WHO recommendations. This support should encompass brief advice from healthcare professionals, availability of toll-free quit lines, access to treatment for tobacco dependence, and digital cessation tools. Table 3 summarizes the five key messages from the WHO Tobacco Knowledge Summary [131] shared with the wider population.

Table 3 Five key messages from the WHO Tobacco Knowledge Summary (TKS) [131]
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