
==== Front
Respir Res
Respir Res
Respiratory Research
1465-9921
1465-993X
BioMed Central London

39261873
2961
10.1186/s12931-024-02961-5
Review
Tobacco and COPD: presenting the World Health Organization (WHO) Tobacco Knowledge Summary
Lu Wenying 1
Aarsand Rebekka 2
Schotte Kerstin 3
Han Jing 2
Lebedeva Elizaveta 4
Tsoy Elena 5
Maglakelidze Nino 6
Soriano Joan B 57
Bill Werner 8
Halpin David M G 910
Rivera M. Patricia 11
Fong Kwun M 12
Kathuria Hasmeena 1314
Yorgancıoğlu Arzu 15
Gappa Monika 16
Lam David CL 17
Rylance Sarah 2
Sohal Sukhwinder Singh sukhwinder.sohal@utas.edu.au

1
1 https://ror.org/01nfmeh72 grid.1009.8 0000 0004 1936 826X Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag – 1322, Newnham Drive, Launceston, TAS 7248 Australia
2 https://ror.org/01f80g185 grid.3575.4 0000 0001 2163 3745 Department of Digital Health and Innovation, World Health Organization, Geneva, Switzerland
3 https://ror.org/01f80g185 grid.3575.4 0000 0001 2163 3745 Department of Health Promotion, World Health Organization, Geneva, Switzerland
4 https://ror.org/01rz37c55 grid.420226.0 0000 0004 0639 2949 Tobacco Control Unit, Special Initiative on NCDs and Innovation, World Health Organization Regional Office for Europe, Copenhagen, Denmark
5 https://ror.org/01rz37c55 grid.420226.0 0000 0004 0639 2949 Noncommunicable Diseases Management Unit, Special Initiative on NCDs and Innovation, World Health Organization Regional Office for Europe, Copenhagen, Denmark
6 WHO European Regional Office, Strategic Development Adviser - Tbilisi State Medical Academy, Paris, France
7 grid.413448.e 0000 0000 9314 1427 Servicio de Neumología, Hospital Universitario de la Princesa, Facultad de Medicina, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Universidad Autónoma de Madrid, Instituto de Salud Carlos III, Madrid, Spain
8 https://ror.org/00c8n3h65 grid.424882.0 0000 0004 0634 2466 European Respiratory Society, Lausanne, Switzerland
9 https://ror.org/03yghzc09 grid.8391.3 0000 0004 1936 8024 University of Exeter College of Medicine, University of Exeter Medical School, Exeter, UK
10 https://ror.org/03jrh3t05 grid.416118.b Royal Devon and Exeter Hospital, Exeter, UK
11 https://ror.org/022kthw22 grid.16416.34 0000 0004 1936 9174 Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester, New York, USA
12 grid.1003.2 0000 0000 9320 7537 Department of Thoracic Medicine, The Prince Charles Hospital, University of Queensland Thoracic Research Centre, Brisbane, Australia
13 https://ror.org/01y2jtd41 grid.14003.36 0000 0001 2167 3675 Center for Tobacco Research and Intervention, School of Medicine and Public Health, University of Wisconsin, Madison, WI USA
14 grid.28803.31 0000 0001 0701 8607 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI USA
15 https://ror.org/053f2w588 grid.411688.2 0000 0004 0595 6052 Department of Pulmonology, Celal Bayar University Medical Faculty, Manisa, Turkey
16 https://ror.org/036j3hh72 grid.492163.b 0000 0000 8976 5894 Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany
17 https://ror.org/02zhqgq86 grid.194645.b 0000 0001 2174 2757 Department of Medicine, School of Clinical Medicine, University of Hong Kong, Hong Kong SAR, China
11 9 2024
11 9 2024
2024
25 33828 6 2024
25 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
The WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children’s lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry’s aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority.

Keywords

Chronic obstructive pulmonary disease
Smoking
Tobacco control
Smoking cessation
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcWhat 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 [1–3]. 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 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

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 [23–27].

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 [44–46].

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 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

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 [87–91]. 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 [94–96]. 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]

Smoked tobacco products	Any product made or derived from tobacco which generates smoke. Examples include manufactured cigarettes, roll-your-own tobacco, cigars, cigarillos, shisha (also known as waterpipe), kreteks and bidis.	
Second-hand smoke (SHS)	The smoke emitted from the burning end of a cigarette or other tobacco products, usually in combination with the smoke exhaled by the people who smoke.	
Smokeless tobacco	Any product that consists of cut, ground, powdered or other tobacco that is intended to be placed in the oral or nasal cavity. Examples include snuff, chewing tobacco, gutka, mishri and snus.	
Heated tobacco product (HTP)	Tobacco products that produce aerosols containing nicotine and toxic chemicals when tobacco is heated or when a device containing tobacco is heat-activated. These aerosols are inhaled by users during a process of sucking or smoking involving a device. They contain the highly addictive substance nicotine, as well as non-tobacco additives, and are often flavored.	
Electronic nicotine delivery system (ENDS) (also known as e-cigarette)	A device that heats a liquid to create an aerosol that is inhaled by the user, which typically contains nicotine and toxic substances that are harmful to both users and non-users who are exposed to the aerosols second-hand; the liquid is often flavored.	

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, 110–112]. 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]

Brief advice: advice on how to stop using tobacco, usually taking only a few minutes, and given to all tobacco users during a routine consultation or interaction with a healthcare professional.	
Toll-free quit lines: a telephone counselling service that provides proactive and reactive telephone counselling.	
Pharmacological interventions: nicotine replacement therapy, bupropion, varenicline and cytisine should be considered for all tobacco users who want to quit.	
mCessation and chatbots: a two-way messaging system based on the mCessation content library guides tobacco users through a six-month text-message quit support programme. The WHO has also developed chatbots in partnership with social media such as WhatsApp, WeChat, and Viber to give tobacco users the best advice on how to quit smoking.	
WHO Quit Tobacco mobile application: The mobile phone app targets all forms of tobacco, including smokeless tobacco and other newer forms of tobacco products, and helps users identify triggers, set targets, manage cravings, and stay focused on quitting tobacco smoking.	

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]

1. Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health.	
2. People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk.	
3. Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions.	
4. Tobacco smoke also significantly impacts children’s lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations.	
5. The tobacco industry’s aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority.	

Acknowledgements

Not applicable.

Author contributions

WL, RA, RS, SR, SSS conceived, designed the structure of the article, revised, and edited. WL wrote the first draft, made figures, and made revisions. KS, JH, EL, ET, NM, JBS, WB, DMGH, MPR, KMF, HK, AY, MG and DCLL reviewed and edited the manuscript. All authors read and approved the final manuscript.

Funding

Clifford Craig Foundation Launceston General Hospital.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Disclaimer

The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.

Competing interests

S.S. Sohal reports honorarium for lectures from Chiesi, travel support from Chiesi, AstraZeneca and GSK, and research grants from Boehringer Ingelheim and Lung Therapeutics, outside the submitted work; and has served on the small airway advisory board for Chiesi Australia for which an honorarium has been received. All the other authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Chronic obstructive pulmonary disease (COPD). Key facts.: World Health Organization. 2023 [updated 16 March 2023. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd).
2. Fabbri LM Celli BR Agusti A Criner GJ Dransfield MT Divo M COPD and multimorbidity: recognising and addressing a syndemic occurrence Lancet Respir Med 2023 11 11 1020 34 10.1016/S2213-2600(23)00261-8 37696283
Fabbri LM, Celli BR, Agusti A, Criner GJ, Dransfield MT, Divo M, et al. COPD and multimorbidity: recognising and addressing a syndemic occurrence. Lancet Respir Med. 2023;11(11):1020–34.37696283 10.1016/S2213-2600(23)00261-8
3. Global Strategy for Prevention Diagnosis and management of COPD: 2023 report 2023 Fontana Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Prevention. Diagnosis and management of COPD: 2023 report. Fontana: Global Initiative for Chronic Obstructive Lung Disease; 2023.
4. McDonough JE Yuan R Suzuki M Seyednejad N Elliott WM Sanchez PG Small-airway obstruction and Emphysema in Chronic Obstructive Pulmonary Disease N Engl J Med 2011 365 17 1567 75 10.1056/NEJMoa1106955 22029978
McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and Emphysema in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2011;365(17):1567–75.22029978 10.1056/NEJMoa1106955
5. Hogg JC Timens W The pathology of chronic obstructive pulmonary disease Annu Rev Pathol 2009 4 435 59 10.1146/annurev.pathol.4.110807.092145 18954287
Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol. 2009;4:435–59.18954287 10.1146/annurev.pathol.4.110807.092145
6. Eapen MS Hansbro PM Larsson-Callerfelt AK Jolly MK Myers S Sharma P Chronic obstructive Pulmonary Disease and Lung Cancer: underlying pathophysiology and New Therapeutic modalities Drugs 2018 78 16 1717 40 10.1007/s40265-018-1001-8 30392114
Eapen MS, Hansbro PM, Larsson-Callerfelt AK, Jolly MK, Myers S, Sharma P, et al. Chronic obstructive Pulmonary Disease and Lung Cancer: underlying pathophysiology and New Therapeutic modalities. Drugs. 2018;78(16):1717–40.30392114 10.1007/s40265-018-1001-8
7. Atto B Eapen MS Sharma P Frey U Ammit AJ Markos J New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways Clin Sci (Lond) 2019 133 14 1663 703 10.1042/CS20181009 31346069
Atto B, Eapen MS, Sharma P, Frey U, Ammit AJ, Markos J, et al. New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways. Clin Sci (Lond). 2019;133(14):1663–703.31346069 10.1042/CS20181009
8. Park SC Kim DW Park EC Shin CS Rhee CK Kang YA Mortality of patients with chronic obstructive pulmonary disease: a nationwide populationbased cohort study Korean J Intern Med 2019 34 6 1272 8 10.3904/kjim.2017.428 31610634
Park SC, Kim DW, Park EC, Shin CS, Rhee CK, Kang YA, et al. Mortality of patients with chronic obstructive pulmonary disease: a nationwide populationbased cohort study. Korean J Intern Med. 2019;34(6):1272–8.31610634 10.3904/kjim.2017.428
9. Sin DD Anthonisen NR Soriano JB Agusti AG Mortality in COPD: role of comorbidities Eur Respir J 2006 28 6 1245 10.1183/09031936.00133805 17138679
Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;28(6):1245.17138679 10.1183/09031936.00133805
10. Adeloye D Song P Zhu Y Campbell H Sheikh A Rudan I Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis Lancet Respir Med 2022 10 5 447 58 10.1016/S2213-2600(21)00511-7 35279265
Adeloye D, Song P, Zhu Y, Campbell H, Sheikh A, Rudan I, et al. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med. 2022;10(5):447–58.35279265 10.1016/S2213-2600(21)00511-7
11. Safiri S Carson-Chahhoud K Noori M Nejadghaderi SA Sullman MJM Ahmadian Heris J Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990–2019: results from the global burden of Disease Study 2019 BMJ 2022 378 e069679 10.1136/bmj-2021-069679 35896191
Safiri S, Carson-Chahhoud K, Noori M, Nejadghaderi SA, Sullman MJM, Ahmadian Heris J, et al. Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990–2019: results from the global burden of Disease Study 2019. BMJ. 2022;378:e069679.35896191 10.1136/bmj-2021-069679
12. Christenson SA Smith BM Bafadhel M Putcha N Chronic obstructive pulmonary disease Lancet 2022 399 10342 2227 42 10.1016/S0140-6736(22)00470-6 35533707
Christenson SA, Smith BM, Bafadhel M, Putcha N. Chronic obstructive pulmonary disease. Lancet. 2022;399(10342):2227–42.35533707 10.1016/S0140-6736(22)00470-6
13. Borgerding M Klus H Analysis of complex mixtures–cigarette smoke Exp Toxicol Pathol 2005 57 Suppl 1 43 73 10.1016/j.etp.2005.05.010 16092717
Borgerding M, Klus H. Analysis of complex mixtures–cigarette smoke. Exp Toxicol Pathol. 2005;57(Suppl 1):43–73.16092717 10.1016/j.etp.2005.05.010
14. What is in a cigarette? American Lung Association. 2023. https://www.lung.org/quit-smoking/smoking-facts/whats-in-a-cigarette
15. Lugg ST Scott A Parekh D Naidu B Thickett DR Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease Thorax 2022 77 1 94 101 10.1136/thoraxjnl-2020-216296 33986144
Lugg ST, Scott A, Parekh D, Naidu B, Thickett DR. Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease. Thorax. 2022;77(1):94–101.33986144 10.1136/thoraxjnl-2020-216296
16. Maung TZ, Bishop JE, Holt E, Turner AM, Pfrang C. Indoor air Pollution and the health of vulnerable groups: a systematic review focused on Particulate Matter (PM), volatile Organic compounds (VOCs) and their effects on children and people with Pre-existing Lung Disease. Int J Environ Res Public Health. 2022;19(14).
17. Pathak U Gupta NC Suri JC Risk of COPD due to indoor air pollution from biomass cooking fuel: a systematic review and meta-analysis Int J Environ Health Res 2020 30 1 75 88 10.1080/09603123.2019.1575951 30754998
Pathak U, Gupta NC, Suri JC. Risk of COPD due to indoor air pollution from biomass cooking fuel: a systematic review and meta-analysis. Int J Environ Health Res. 2020;30(1):75–88.30754998 10.1080/09603123.2019.1575951
18. Mannino DM Buist AS Global burden of COPD: risk factors, prevalence, and future trends Lancet 2007 370 9589 765 73 10.1016/S0140-6736(07)61380-4 17765526
Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765–73.17765526 10.1016/S0140-6736(07)61380-4
19. Khalequzzaman M Kamijima M Sakai K Hoque BA Nakajima T Indoor air pollution and the health of children in biomass- and fossil-fuel users of Bangladesh: situation in two different seasons Environ Health Prev Med 2010 15 4 236 43 10.1007/s12199-009-0133-6 21432551
Khalequzzaman M, Kamijima M, Sakai K, Hoque BA, Nakajima T. Indoor air pollution and the health of children in biomass- and fossil-fuel users of Bangladesh: situation in two different seasons. Environ Health Prev Med. 2010;15(4):236–43.21432551 10.1007/s12199-009-0133-6
20. Gordon SB Bruce NG Grigg J Hibberd PL Kurmi OP Lam KB Respiratory risks from household air pollution in low and middle income countries Lancet Respir Med 2014 2 10 823 60 10.1016/S2213-2600(14)70168-7 25193349
Gordon SB, Bruce NG, Grigg J, Hibberd PL, Kurmi OP, Lam KB, et al. Respiratory risks from household air pollution in low and middle income countries. Lancet Respir Med. 2014;2(10):823–60.25193349 10.1016/S2213-2600(14)70168-7
21. Anderson DO Ferris BG Jr Role of tobacco smoking in the causation of chronic respiratory disease N Engl J Med 1962 267 787 94 10.1056/NEJM196210182671601 14012834
Anderson DO, Ferris BG Jr. Role of tobacco smoking in the causation of chronic respiratory disease. N Engl J Med. 1962;267:787–94.14012834 10.1056/NEJM196210182671601
22. Nicolaou L Checkley W Differences between cigarette smoking and biomass smoke exposure: an in silico comparative assessment of particulate deposition in the lungs Environ Res 2021 197 111116 10.1016/j.envres.2021.111116 33823195
Nicolaou L, Checkley W. Differences between cigarette smoking and biomass smoke exposure: an in silico comparative assessment of particulate deposition in the lungs. Environ Res. 2021;197:111116.33823195 10.1016/j.envres.2021.111116
23. Martinez FJ Curtis JL Sciurba F Mumford J Giardino ND Weinmann G Sex differences in severe pulmonary emphysema Am J Respir Crit Care Med 2007 176 3 243 52 10.1164/rccm.200606-828OC 17431226
Martinez FJ, Curtis JL, Sciurba F, Mumford J, Giardino ND, Weinmann G, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176(3):243–52.17431226 10.1164/rccm.200606-828OC
24. Downs SH Brandli O Zellweger JP Schindler C Kunzli N Gerbase MW Accelerated decline in lung function in smoking women with airway obstruction: SAPALDIA 2 cohort study Respir Res 2005 6 1 45 10.1186/1465-9921-6-45 15918902
Downs SH, Brandli O, Zellweger JP, Schindler C, Kunzli N, Gerbase MW, et al. Accelerated decline in lung function in smoking women with airway obstruction: SAPALDIA 2 cohort study. Respir Res. 2005;6(1):45.15918902 10.1186/1465-9921-6-45
25. Silverman EK Weiss ST Drazen JM Chapman HA Carey V Campbell EJ Gender-related differences in severe, early-onset chronic obstructive pulmonary disease Am J Respir Crit Care Med 2000 162 6 2152 8 10.1164/ajrccm.162.6.2003112 11112130
Silverman EK, Weiss ST, Drazen JM, Chapman HA, Carey V, Campbell EJ, et al. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162(6):2152–8.11112130 10.1164/ajrccm.162.6.2003112
26. Camp PG Coxson HO Levy RD Pillai SG Anderson W Vestbo J Sex differences in emphysema and airway disease in smokers Chest 2009 136 6 1480 8 10.1378/chest.09-0676 19617404
Camp PG, Coxson HO, Levy RD, Pillai SG, Anderson W, Vestbo J, et al. Sex differences in emphysema and airway disease in smokers. Chest. 2009;136(6):1480–8.19617404 10.1378/chest.09-0676
27. Dransfield MT Davis JJ Gerald LB Bailey WC Racial and gender differences in susceptibility to tobacco smoke among patients with chronic obstructive pulmonary disease Respir Med 2006 100 6 1110 6 10.1016/j.rmed.2005.09.019 16236491
Dransfield MT, Davis JJ, Gerald LB, Bailey WC. Racial and gender differences in susceptibility to tobacco smoke among patients with chronic obstructive pulmonary disease. Respir Med. 2006;100(6):1110–6.16236491 10.1016/j.rmed.2005.09.019
28. Harmful. and potentially harmful constituents in tobacco products and tobacco smoke; established list. US Food and Drug Administration Fed Regist. 2012;77(64):20034–7.
29. Pappas RS Toxic elements in tobacco and in cigarette smoke: inflammation and sensitization Metallomics 2011 3 11 1181 98 10.1039/c1mt00066g 21799956
Pappas RS. Toxic elements in tobacco and in cigarette smoke: inflammation and sensitization. Metallomics. 2011;3(11):1181–98.21799956 10.1039/c1mt00066g
30. Huang MF Lin WL Ma YC A study of reactive oxygen species in mainstream of cigarette Indoor Air 2005 15 2 135 40 10.1111/j.1600-0668.2005.00330.x 15737156
Huang MF, Lin WL, Ma YC. A study of reactive oxygen species in mainstream of cigarette. Indoor Air. 2005;15(2):135–40.15737156 10.1111/j.1600-0668.2005.00330.x
31. Djordjevic MV Doran KA Nicotine content and delivery across tobacco products Handb Exp Pharmacol 2009 192 61 82 10.1007/978-3-540-69248-5_3
Djordjevic MV, Doran KA. Nicotine content and delivery across tobacco products. Handb Exp Pharmacol. 2009;192:61–82.10.1007/978-3-540-69248-5_3
32. Addictiveness and Attractiveness of Tobacco Additives Brussels. 2010 [updated 12 November. https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_031.pdf
33. Rabinoff M Caskey N Rissling A Park C Pharmacological and chemical effects of cigarette additives Am J Public Health 2007 97 11 1981 91 10.2105/AJPH.2005.078014 17666709
Rabinoff M, Caskey N, Rissling A, Park C. Pharmacological and chemical effects of cigarette additives. Am J Public Health. 2007;97(11):1981–91.17666709 10.2105/AJPH.2005.078014
34. Salvi S Tobacco smoking and environmental risk factors for chronic obstructive pulmonary disease Clin Chest Med 2014 35 1 17 27 10.1016/j.ccm.2013.09.011 24507834
Salvi S. Tobacco smoking and environmental risk factors for chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):17–27.24507834 10.1016/j.ccm.2013.09.011
35. Wiegman CH Li F Ryffel B Togbe D Chung KF Oxidative stress in ozone-Induced chronic lung inflammation and Emphysema: a facet of Chronic Obstructive Pulmonary Disease Front Immunol 2020 11 1957 10.3389/fimmu.2020.01957 32983127
Wiegman CH, Li F, Ryffel B, Togbe D, Chung KF. Oxidative stress in ozone-Induced chronic lung inflammation and Emphysema: a facet of Chronic Obstructive Pulmonary Disease. Front Immunol. 2020;11:1957.32983127 10.3389/fimmu.2020.01957
36. Gunen H Tarraf H Nemati A Al Ghobain M Al Mutairi S Aoun Bacha Z Waterpipe tobacco smoking Tuberk Toraks 2016 64 1 94 6 10.5578/tt.13935 27266294
Gunen H, Tarraf H, Nemati A, Al Ghobain M, Al Mutairi S, Aoun Bacha Z. Waterpipe tobacco smoking. Tuberk Toraks. 2016;64(1):94–6.27266294 10.5578/tt.13935
37. She J Yang P Wang Y Qin X Fan J Wang Y Chinese water-pipe smoking and the risk of COPD Chest 2014 146 4 924 31 10.1378/chest.13-1499 24557573
She J, Yang P, Wang Y, Qin X, Fan J, Wang Y, et al. Chinese water-pipe smoking and the risk of COPD. Chest. 2014;146(4):924–31.24557573 10.1378/chest.13-1499
38. Smoking and Tobacco Use. Fast facts and fact sheets 2021. Atlanta (GE)2023 https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm
39. Santoro A Tomino C Prinzi G Lamonaca P Cardaci V Fini M Tobacco Smoking: risk to develop addiction, Chronic Obstructive Pulmonary Disease, and Lung Cancer Recent Pat Anticancer Drug Discov 2019 14 1 39 52 10.2174/1574892814666190102122848 30605063
Santoro A, Tomino C, Prinzi G, Lamonaca P, Cardaci V, Fini M, et al. Tobacco Smoking: risk to develop addiction, Chronic Obstructive Pulmonary Disease, and Lung Cancer. Recent Pat Anticancer Drug Discov. 2019;14(1):39–52.30605063 10.2174/1574892814666190102122848
40. Papke RL The many enigmas of nicotine Adv Pharmacol 2024 99 327 54 10.1016/bs.apha.2023.08.001 38467485
Papke RL. The many enigmas of nicotine. Adv Pharmacol. 2024;99:327–54.38467485 10.1016/bs.apha.2023.08.001
41. Agustí A Hogg JC Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease N Engl J Med 2019 381 13 1248 56 10.1056/NEJMra1900475 31553836
Agustí A, Hogg JC. Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease. N Engl J Med. 2019;381(13):1248–56.31553836 10.1056/NEJMra1900475
42. Brightling C, Greening N. Airway inflammation in COPD: progress to precision medicine. Eur Respir J. 2019;54(2).
43. Eapen MS McAlinden K Tan D Weston S Ward C Muller HK Profiling cellular and inflammatory changes in the airway wall of mild to moderate COPD Respirology 2017 22 6 1125 32 10.1111/resp.13021 28326668
Eapen MS, McAlinden K, Tan D, Weston S, Ward C, Muller HK, et al. Profiling cellular and inflammatory changes in the airway wall of mild to moderate COPD. Respirology. 2017;22(6):1125–32.28326668 10.1111/resp.13021
44. Eapen MS Hansbro PM McAlinden K Kim RY Ward C Hackett TL Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD) Sci Rep 2017 7 1 13392 10.1038/s41598-017-13888-x 29042607
Eapen MS, Hansbro PM, McAlinden K, Kim RY, Ward C, Hackett TL, et al. Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD). Sci Rep. 2017;7(1):13392.29042607 10.1038/s41598-017-13888-x
45. Liu G Haw TJ Starkey MR Philp AM Pavlidis S Nalkurthi C TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase Nat Commun 2023 14 1 7349 10.1038/s41467-023-42913-z 37963864
Liu G, Haw TJ, Starkey MR, Philp AM, Pavlidis S, Nalkurthi C, et al. TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase. Nat Commun. 2023;14(1):7349.37963864 10.1038/s41467-023-42913-z
46. O’Beirne SL Kikkers SA Oromendia C Salit J Rostmai MR Ballman KV Alveolar macrophage immunometabolism and lung function impairment in Smoking and Chronic Obstructive Pulmonary Disease Am J Respir Crit Care Med 2020 201 6 735 9 10.1164/rccm.201908-1683LE 31751151
O’Beirne SL, Kikkers SA, Oromendia C, Salit J, Rostmai MR, Ballman KV, et al. Alveolar macrophage immunometabolism and lung function impairment in Smoking and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2020;201(6):735–9.31751151 10.1164/rccm.201908-1683LE
47. Stoller JK Aboussouan LS α1-antitrypsin deficiency Lancet 2005 365 9478 2225 36 10.1016/S0140-6736(05)66781-5 15978931
Stoller JK, Aboussouan LS. α1-antitrypsin deficiency. Lancet. 2005;365(9478):2225–36.15978931 10.1016/S0140-6736(05)66781-5
48. Shrine N Guyatt AL Erzurumluoglu AM Jackson VE Hobbs BD Melbourne CA New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries Nat Genet 2019 51 3 481 93 10.1038/s41588-018-0321-7 30804560
Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, et al. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat Genet. 2019;51(3):481–93.30804560 10.1038/s41588-018-0321-7
49. Obeidat Me, Hao K Bossé Y Nickle DC Nie Y Postma DS Molecular mechanisms underlying variations in lung function: a systems genetics analysis Lancet Respiratory Med 2015 3 10 782 95 10.1016/S2213-2600(15)00380-X
Obeidat Me, Hao K, Bossé Y, Nickle DC, Nie Y, Postma DS, et al. Molecular mechanisms underlying variations in lung function: a systems genetics analysis. Lancet Respiratory Med. 2015;3(10):782–95.10.1016/S2213-2600(15)00380-X
50. Zhou JJ Cho MH Castaldi PJ Hersh CP Silverman EK Laird NM Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers Am J Respir Crit Care Med 2013 188 8 941 7 10.1164/rccm.201302-0263OC 23972146
Zhou JJ, Cho MH, Castaldi PJ, Hersh CP, Silverman EK, Laird NM. Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. Am J Respir Crit Care Med. 2013;188(8):941–7.23972146 10.1164/rccm.201302-0263OC
51. Barnes PJ Celli BR Systemic manifestations and comorbidities of COPD Eur Respir J 2009 33 5 1165 10.1183/09031936.00128008 19407051
Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165.19407051 10.1183/09031936.00128008
52. André S Conde B Fragoso E Boléo-Tomé JP Areias V Cardoso J COPD and Cardiovascular Disease Pulmonology 2019 25 3 168 76 10.1016/j.pulmoe.2018.09.006 30527374
André S, Conde B, Fragoso E, Boléo-Tomé JP, Areias V, Cardoso J. COPD and Cardiovascular Disease. Pulmonology. 2019;25(3):168–76.30527374 10.1016/j.pulmoe.2018.09.006
53. Bhattarai P, Lu W, Gaikwad AV, Dey S, Chia C, Larby J et al. Arterial remodelling in smokers and in patients with small airway disease and COPD: implications for lung physiology and early origins of pulmonary hypertension. ERJ Open Res. 2022;8(4).
54. Padeletti M Jelic S LeJemtel TH Coexistent chronic obstructive pulmonary disease and heart failure in the elderly Int J Cardiol 2008 125 2 209 15 10.1016/j.ijcard.2007.12.001 18221802
Padeletti M, Jelic S, LeJemtel TH. Coexistent chronic obstructive pulmonary disease and heart failure in the elderly. Int J Cardiol. 2008;125(2):209–15.18221802 10.1016/j.ijcard.2007.12.001
55. Barberà JA Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension Pulm Circ 2013 3 1 160 4 10.4103/2045-8932.109949 23662194
Barberà JA. Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. Pulm Circ. 2013;3(1):160–4.23662194 10.4103/2045-8932.109949
56. Santos S Peinado VI Ramirez J Melgosa T Roca J Rodriguez-Roisin R Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD Eur Respir J 2002 19 4 632 8 10.1183/09031936.02.00245902 11998991
Santos S, Peinado VI, Ramirez J, Melgosa T, Roca J, Rodriguez-Roisin R, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J. 2002;19(4):632–8.11998991 10.1183/09031936.02.00245902
57. Bhattarai P, Lu W, Hardikar A, Dey S, Gaikwad AV, Shahzad AM et al. Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology. ERJ Open Res. 2024;10(1).
58. Chaouat A Naeije R Weitzenblum E Pulmonary hypertension in COPD Eur Respir J 2008 32 5 1371 10.1183/09031936.00015608 18978137
Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371.18978137 10.1183/09031936.00015608
59. Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1).
60. Fiorentino G Esquinas AM Annunziata A Exercise and Chronic Obstructive Pulmonary Disease (COPD) Adv Exp Med Biol 2020 1228 355 68 10.1007/978-981-15-1792-1_24 32342470
Fiorentino G, Esquinas AM, Annunziata A. Exercise and Chronic Obstructive Pulmonary Disease (COPD). Adv Exp Med Biol. 2020;1228:355–68.32342470 10.1007/978-981-15-1792-1_24
61. Henrot P, Dupin I, Schilfarth P, Esteves P, Blervaque L, Zysman M et al. Main pathogenic mechanisms and recent advances in COPD Peripheral skeletal muscle wasting. Int J Mol Sci. 2023;24(7).
62. Osteoporosis prevention Diagnosis, and therapy JAMA 2001 285 6 785 95 10.1001/jama.285.6.785 11176917
Osteoporosis prevention. Diagnosis, and therapy. JAMA. 2001;285(6):785–95.11176917 10.1001/jama.285.6.785
63. Cully JA Graham DP Stanley MA Ferguson CJ Sharafkhaneh A Souchek J Quality of life in patients with Chronic Obstructive Pulmonary Disease and Comorbid anxiety or depression Psychosomatics 2006 47 4 312 9 10.1176/appi.psy.47.4.312 16844889
Cully JA, Graham DP, Stanley MA, Ferguson CJ, Sharafkhaneh A, Souchek J, et al. Quality of life in patients with chronic obstructive pulmonary disease and comorbid anxiety or depression. Psychosomatics. 2006;47(4):312–9.16844889 10.1176/appi.psy.47.4.312
64. Polkey MI Moxham J Attacking the disease spiral in chronic obstructive pulmonary disease Clin Med 2006 6 2 190 6 10.7861/clinmedicine.6-2-190
Polkey MI, Moxham J. Attacking the disease spiral in chronic obstructive pulmonary disease. Clin Med. 2006;6(2):190–6.10.7861/clinmedicine.6-2-190
65. Sin DD Man JP Man SFP The risk of osteoporosis in caucasian men and women with Obstructive Airways Disease Am J Med 2003 114 1 10 4 10.1016/S0002-9343(02)01297-4 12543283
Sin DD, Man JP, Man SFP. The risk of osteoporosis in caucasian men and women with obstructive airways disease. Am J Med. 2003;114(1):10–4.12543283 10.1016/S0002-9343(02)01297-4
66. Li Y Gao H Zhao L Wang J Osteoporosis in COPD patients: risk factors and pulmonary rehabilitation Clin Respir J 2022 16 7 487 96 10.1111/crj.13514 35688435
Li Y, Gao H, Zhao L, Wang J. Osteoporosis in COPD patients: risk factors and pulmonary rehabilitation. Clin Respir J. 2022;16(7):487–96.35688435 10.1111/crj.13514
67. Pompe E Bartstra J Verhaar HJ de Koning HJ van der Aalst CM Oudkerk M Bone density loss on computed tomography at 3-year follow-up in current compared to former male smokers Eur J Radiol 2017 89 177 81 10.1016/j.ejrad.2017.02.011 28267536
Pompe E, Bartstra J, Verhaar HJ, de Koning HJ, van der Aalst CM, Oudkerk M, et al. Bone density loss on computed tomography at 3-year follow-up in current compared to former male smokers. Eur J Radiol. 2017;89:177–81.28267536 10.1016/j.ejrad.2017.02.011
68. Lau RY Guo X A review on current osteoporosis research: with special focus on disuse bone loss J Osteoporos 2011 2011 293808 10.4061/2011/293808 21876833
Lau RY, Guo X. A review on current osteoporosis research: with special focus on disuse bone loss. J Osteoporos. 2011;2011:293808.21876833 10.4061/2011/293808
69. Graat-Verboom L Wouters EF Smeenk FW van den Borne BE Lunde R Spruit MA Current status of research on osteoporosis in COPD: a systematic review Eur Respir J 2009 34 1 209 18 10.1183/09031936.50130408 19567604
Graat-Verboom L, Wouters EF, Smeenk FW, van den Borne BE, Lunde R, Spruit MA. Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J. 2009;34(1):209–18.19567604 10.1183/09031936.50130408
70. Okazaki R Watanabe R Inoue D Osteoporosis Associated with Chronic Obstructive Pulmonary Disease J Bone Metab 2016 23 3 111 20 10.11005/jbm.2016.23.3.111 27622174
Okazaki R, Watanabe R, Inoue D. Osteoporosis Associated with Chronic Obstructive Pulmonary Disease. J Bone Metab. 2016;23(3):111–20.27622174 10.11005/jbm.2016.23.3.111
71. Inoue D Watanabe R Okazaki R COPD and osteoporosis: links, risks, and treatment challenges Int J Chron Obstruct Pulmon Dis 2016 11 637 48 10.2147/COPD.S79638 27099481
Inoue D, Watanabe R, Okazaki R. COPD and osteoporosis: links, risks, and treatment challenges. Int J Chron Obstruct Pulmon Dis. 2016;11:637–48.27099481 10.2147/COPD.S79638
72. Homętowska H, Klekowski J, Świątoniowska-Lonc N, Jankowska-Polańska B, Chabowski M. Fatigue, Depression, and anxiety in patients with COPD, asthma and Asthma-COPD overlap. J Clin Med. 2022;11(24).
73. Kunik ME Roundy K Veazey C Souchek J Richardson P Wray NP Surprisingly high prevalence of anxiety and Depression in Chronic Breathing disorders Chest 2005 127 4 1205 11 15821196
Kunik ME, Roundy K, Veazey C, Souchek J, Richardson P, Wray NP, et al. Surprisingly high prevalence of anxiety and Depression in Chronic Breathing disorders. Chest. 2005;127(4):1205–11.15821196
74. García-Sanz MT González-Barcala FJ COPD is more than just lung function: Let’s not forget depression Arch Bronconeumol 2021 57 8 519 20 10.1016/j.arbr.2021.05.023 34053892
García-Sanz MT, González-Barcala FJ. COPD is more than just lung function: Let’s not forget depression. Arch Bronconeumol. 2021;57(8):519–20.34053892 10.1016/j.arbr.2021.05.023
75. Martínez-Gestoso S García-Sanz MT Carreira JM Salgado FJ Calvo-Álvarez U Doval-Oubiña L Impact of anxiety and depression on the prognosis of copd exacerbations BMC Pulm Med 2022 22 1 169 10.1186/s12890-022-01934-y 35488330
Martínez-Gestoso S, García-Sanz MT, Carreira JM, Salgado FJ, Calvo-Álvarez U, Doval-Oubiña L, et al. Impact of anxiety and depression on the prognosis of copd exacerbations. BMC Pulm Med. 2022;22(1):169.35488330 10.1186/s12890-022-01934-y
76. Willgoss TG Yohannes AM Anxiety disorders in patients with COPD: a systematic review Respir Care 2013 58 5 858 66 10.4187/respcare.01862 22906542
Willgoss TG, Yohannes AM. Anxiety disorders in patients with COPD: a systematic review. Respir Care. 2013;58(5):858–66.22906542 10.4187/respcare.01862
77. Yohannes AM Alexopoulos GS Depression and anxiety in patients with COPD Eur Respir Rev 2014 23 133 345 9 10.1183/09059180.00007813 25176970
Yohannes AM, Alexopoulos GS. Depression and anxiety in patients with COPD. Eur Respir Rev. 2014;23(133):345–9.25176970 10.1183/09059180.00007813
78. Benson VS Müllerová H Vestbo J Wedzicha JA Patel A Hurst JR Associations between gastro-oesophageal reflux, its management and exacerbations of chronic obstructive pulmonary disease Respir Med 2015 109 9 1147 54 10.1016/j.rmed.2015.06.009 26166017
Benson VS, Müllerová H, Vestbo J, Wedzicha JA, Patel A, Hurst JR. Associations between gastro-oesophageal reflux, its management and exacerbations of chronic obstructive pulmonary disease. Respir Med. 2015;109(9):1147–54.26166017 10.1016/j.rmed.2015.06.009
79. Pandolfino JE Kahrilas PJ Smoking and gastro-oesophageal reflux disease Eur J Gastroenterol Hepatol 2000 12 8 837 42 10.1097/00042737-200012080-00002 10958210
Pandolfino JE, Kahrilas PJ. Smoking and gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol. 2000;12(8):837–42.10958210 10.1097/00042737-200012080-00002
80. Lee AL Goldstein RS Gastroesophageal reflux disease in COPD: links and risks Int J Chron Obstruct Pulmon Dis 2015 10 1935 49 10.2147/COPD.S77562 26392769
Lee AL, Goldstein RS. Gastroesophageal reflux disease in COPD: links and risks. Int J Chron Obstruct Pulmon Dis. 2015;10:1935–49.26392769 10.2147/COPD.S77562
81. Ingebrigtsen TS Marott JL Vestbo J Nordestgaard BG Hallas J Lange P Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease Respirology 2015 20 1 101 7 10.1111/resp.12420 25297724
Ingebrigtsen TS, Marott JL, Vestbo J, Nordestgaard BG, Hallas J, Lange P. Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease. Respirology. 2015;20(1):101–7.25297724 10.1111/resp.12420
82. Dore MP Maragkoudakis E Fraley K Pedroni A Tadeu V Realdi G Diet, lifestyle and gender in gastro-esophageal reflux disease Dig Dis Sci 2008 53 8 2027 32 10.1007/s10620-007-0108-7 18030622
Dore MP, Maragkoudakis E, Fraley K, Pedroni A, Tadeu V, Realdi G, et al. Diet, lifestyle and gender in gastro-esophageal reflux disease. Dig Dis Sci. 2008;53(8):2027–32.18030622 10.1007/s10620-007-0108-7
83. Sasaki T Nakayama K Yasuda H Yoshida M Asamura T Ohrui T A Randomized, single-blind study of Lansoprazole for the Prevention of exacerbations of Chronic Obstructive Pulmonary Disease in older patients J Am Geriatr Soc 2009 57 8 1453 7 10.1111/j.1532-5415.2009.02349.x 19515110
Sasaki T, Nakayama K, Yasuda H, Yoshida M, Asamura T, Ohrui T, et al. A Randomized, single-blind study of Lansoprazole for the Prevention of exacerbations of Chronic Obstructive Pulmonary Disease in older patients. J Am Geriatr Soc. 2009;57(8):1453–7.19515110 10.1111/j.1532-5415.2009.02349.x
84. Barnes PJ Burney PG Silverman EK Celli BR Vestbo J Wedzicha JA Chronic obstructive pulmonary disease Nat Rev Dis Primers 2015 1 15076 10.1038/nrdp.2015.76 27189863
Barnes PJ, Burney PG, Silverman EK, Celli BR, Vestbo J, Wedzicha JA, et al. Chronic obstructive pulmonary disease. Nat Rev Dis Primers. 2015;1:15076.27189863 10.1038/nrdp.2015.76
85. de Torres JP Marin JM Casanova C Cote C Carrizo S Cordoba-Lanus E Lung cancer in patients with chronic obstructive pulmonary disease– incidence and predicting factors Am J Respir Crit Care Med 2011 184 8 913 9 10.1164/rccm.201103-0430OC 21799072
de Torres JP, Marin JM, Casanova C, Cote C, Carrizo S, Cordoba-Lanus E, et al. Lung cancer in patients with chronic obstructive pulmonary disease– incidence and predicting factors. Am J Respir Crit Care Med. 2011;184(8):913–9.21799072 10.1164/rccm.201103-0430OC
86. Tahery N Zarea K Cheraghi M Hatamzadeh N Farhadi M Dobaradarn S Chronic obstructive Pulmonary Disease (COPD) and Air Pollution: a review Jundishapur J Chronic Dis Care 2021 10 1 e110273 10.5812/jjcdc.110273
Tahery N, Zarea K, Cheraghi M, Hatamzadeh N, Farhadi M, Dobaradarn S, et al. Chronic obstructive Pulmonary Disease (COPD) and Air Pollution: a review. Jundishapur J Chronic Dis Care. 2021;10(1):e110273.10.5812/jjcdc.110273
87. Lu W, Eapen MS, Hardikar A, Chia C, Robertson I, Singhera GK et al. Epithelial-mesenchymal transition changes in nonsmall cell lung cancer patients with early COPD. ERJ Open Res. 2023;9(6).
88. Gohy ST Hupin C Fregimilicka C Detry BR Bouzin C Gaide Chevronay H Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition Eur Respir J 2015 45 5 1258 72 10.1183/09031936.00135814 25745049
Gohy ST, Hupin C, Fregimilicka C, Detry BR, Bouzin C, Gaide Chevronay H, et al. Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition. Eur Respir J. 2015;45(5):1258–72.25745049 10.1183/09031936.00135814
89. Milara J Peiró T Serrano A Cortijo J Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke Thorax 2013 68 5 410 20 10.1136/thoraxjnl-2012-201761 23299965
Milara J, Peiró T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax. 2013;68(5):410–20.23299965 10.1136/thoraxjnl-2012-201761
90. Karacosta LG Anchang B Ignatiadis N Kimmey SC Benson JA Shrager JB Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution Nat Commun 2019 10 1 5587 10.1038/s41467-019-13441-6 31811131
Karacosta LG, Anchang B, Ignatiadis N, Kimmey SC, Benson JA, Shrager JB, et al. Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution. Nat Commun. 2019;10(1):5587.31811131 10.1038/s41467-019-13441-6
91. Karacosta LG Pancirer D Preiss JS Benson JA Trope W Shrager JB Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry Sci Rep 2023 13 1 21781 10.1038/s41598-023-46458-5 38065965
Karacosta LG, Pancirer D, Preiss JS, Benson JA, Trope W, Shrager JB, et al. Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry. Sci Rep. 2023;13(1):21781.38065965 10.1038/s41598-023-46458-5
92. Sohal SS Soltani A Reid D Ward C Wills KE Muller HK A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study Int J Chron Obstruct Pulmon Dis 2014 9 533 42 10.2147/COPD.S63911 24920891
Sohal SS, Soltani A, Reid D, Ward C, Wills KE, Muller HK, et al. A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study. Int J Chron Obstruct Pulmon Dis. 2014;9:533–42.24920891 10.2147/COPD.S63911
93. Soltani A Walters EH Reid DW Shukla SD Nowrin K Ward C Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD Int J Chron Obstruct Pulmon Dis 2016 11 2359 67 10.2147/COPD.S113176 27703346
Soltani A, Walters EH, Reid DW, Shukla SD, Nowrin K, Ward C, et al. Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:2359–67.27703346 10.2147/COPD.S113176
94. Parimon T Chien JW Bryson CL McDonell MB Udris EM Au DH Inhaled corticosteroids and Risk of Lung Cancer among patients with chronic obstructive Pulmonary Disease Am J Respir Crit Care Med 2007 175 7 712 9 10.1164/rccm.200608-1125OC 17185647
Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and Risk of Lung Cancer among patients with chronic obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2007;175(7):712–9.17185647 10.1164/rccm.200608-1125OC
95. Ge F Feng Y Huo Z Li C Wang R Wen Y Inhaled corticosteroids and risk of lung cancer among chronic obstructive pulmonary disease patients: a comprehensive analysis of nine prospective cohorts Transl Lung Cancer Res 2021 10 3 1266 76 10.21037/tlcr-20-1126 33889508
Ge F, Feng Y, Huo Z, Li C, Wang R, Wen Y, et al. Inhaled corticosteroids and risk of lung cancer among chronic obstructive pulmonary disease patients: a comprehensive analysis of nine prospective cohorts. Transl Lung Cancer Res. 2021;10(3):1266–76.33889508 10.21037/tlcr-20-1126
96. Tareke AA Debebe W Alem A Bayileyegn NS Zerfu TA Ayana AM Inhaled corticosteroids and the risk of Lung Cancer in Chronic Obstructive Pulmonary Disease patients: a systematic review and Meta-analysis Pulm Med 2022 2022 9799858 10.1155/2022/9799858 36046848
Tareke AA, Debebe W, Alem A, Bayileyegn NS, Zerfu TA, Ayana AM. Inhaled corticosteroids and the risk of Lung Cancer in Chronic Obstructive Pulmonary Disease patients: a systematic review and Meta-analysis. Pulm Med. 2022;2022:9799858.36046848 10.1155/2022/9799858
97. Pitre T Kiflen M Ho T Seijo LM Zeraatkar D de Torres JP Inhaled corticosteroids, COPD, and the incidence of lung cancer: a systematic review and dose response meta-analysis BMC Pulm Med 2022 22 1 275 10.1186/s12890-022-02072-1 35843928
Pitre T, Kiflen M, Ho T, Seijo LM, Zeraatkar D, de Torres JP. Inhaled corticosteroids, COPD, and the incidence of lung cancer: a systematic review and dose response meta-analysis. BMC Pulm Med. 2022;22(1):275.35843928 10.1186/s12890-022-02072-1
98. Park JE Lee E Singh D Kim EK Park B Park JH The effect of inhaler prescription on the development of lung cancer in COPD: a nationwide population-based study Respir Res 2024 25 1 229 10.1186/s12931-024-02838-7 38822332
Park JE, Lee E, Singh D, Kim EK, Park B, Park JH. The effect of inhaler prescription on the development of lung cancer in COPD: a nationwide population-based study. Respir Res. 2024;25(1):229.38822332 10.1186/s12931-024-02838-7
99. Diver WR Jacobs EJ Gapstur SM Secondhand smoke exposure in Childhood and Adulthood in Relation to Adult Mortality among Never smokers Am J Prev Med 2018 55 3 345 52 10.1016/j.amepre.2018.05.005 30122215
Diver WR, Jacobs EJ, Gapstur SM. Secondhand smoke exposure in Childhood and Adulthood in Relation to Adult Mortality among Never smokers. Am J Prev Med. 2018;55(3):345–52.30122215 10.1016/j.amepre.2018.05.005
100. Putcha N Barr RG Han MK Woodruff PG Bleecker ER Kanner RE Understanding the impact of second-hand smoke exposure on clinical outcomes in participants with COPD in the SPIROMICS cohort Thorax 2016 71 5 411 10.1136/thoraxjnl-2015-207487 26962015
Putcha N, Barr RG, Han MK, Woodruff PG, Bleecker ER, Kanner RE, et al. Understanding the impact of second-hand smoke exposure on clinical outcomes in participants with COPD in the SPIROMICS cohort. Thorax. 2016;71(5):411.26962015 10.1136/thoraxjnl-2015-207487
101. Yin P Jiang CQ Cheng KK Lam TH Lam KH Miller MR Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank Cohort Study Lancet 2007 370 9589 751 7 10.1016/S0140-6736(07)61378-6 17765524
Yin P, Jiang CQ, Cheng KK, Lam TH, Lam KH, Miller MR, et al. Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank Cohort Study. Lancet. 2007;370(9589):751–7.17765524 10.1016/S0140-6736(07)61378-6
102. Hecht SS Hatsukami DK Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention Nat Rev Cancer 2022 22 3 143 55 10.1038/s41568-021-00423-4 34980891
Hecht SS, Hatsukami DK. Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention. Nat Rev Cancer. 2022;22(3):143–55.34980891 10.1038/s41568-021-00423-4
103. Hatsukami D, Zeller M, Gupta P, Parascandola M, Asma S. Smokeless tobacco and public health: a global perspective. 2014.
104. Kass AP Overbeek DL Chiel LE Boyer EW Casey AMH Case series: adolescent victims of the vaping public health crisis with pulmonary complications Pediatr Pulmonol 2020 55 5 1224 36 10.1002/ppul.24729 32168438
Kass AP, Overbeek DL, Chiel LE, Boyer EW, Casey AMH. Case series: adolescent victims of the vaping public health crisis with pulmonary complications. Pediatr Pulmonol. 2020;55(5):1224–36.32168438 10.1002/ppul.24729
105. McAlinden KD Eapen MS Lu W Sharma P Sohal SS The rise of electronic nicotine delivery systems and the emergence of electronic-cigarette-driven disease Am J Physiol Lung Cell Mol Physiol 2020 319 4 L585 95 10.1152/ajplung.00160.2020 32726146
McAlinden KD, Eapen MS, Lu W, Sharma P, Sohal SS. The rise of electronic nicotine delivery systems and the emergence of electronic-cigarette-driven disease. Am J Physiol Lung Cell Mol Physiol. 2020;319(4):L585–95.32726146 10.1152/ajplung.00160.2020
106. Park JA Crotty Alexander LE Christiani DC Vaping and lung inflammation and Injury Annu Rev Physiol 2022 84 611 29 10.1146/annurev-physiol-061121-040014 34724436
Park JA, Crotty Alexander LE, Christiani DC. Vaping and lung inflammation and Injury. Annu Rev Physiol. 2022;84:611–29.34724436 10.1146/annurev-physiol-061121-040014
107. Bowler RP Hansel NN Jacobson S Graham Barr R Make BJ Han MK Electronic cigarette use in US adults at risk for or with COPD: analysis from two observational cohorts J Gen Intern Med 2017 32 12 1315 22 10.1007/s11606-017-4150-7 28884423
Bowler RP, Hansel NN, Jacobson S, Graham Barr R, Make BJ, Han MK, et al. Electronic cigarette use in US adults at risk for or with COPD: analysis from two observational cohorts. J Gen Intern Med. 2017;32(12):1315–22.28884423 10.1007/s11606-017-4150-7
108. Osei AD Mirbolouk M Orimoloye OA Dzaye O Uddin SMI Benjamin EJ Association between E-Cigarette Use and Chronic Obstructive Pulmonary Disease by Smoking Status: behavioral risk factor Surveillance System 2016 and 2017 Am J Prev Med 2020 58 3 336 42 10.1016/j.amepre.2019.10.014 31902685
Osei AD, Mirbolouk M, Orimoloye OA, Dzaye O, Uddin SMI, Benjamin EJ, et al. Association between E-Cigarette Use and Chronic Obstructive Pulmonary Disease by Smoking Status: behavioral risk factor Surveillance System 2016 and 2017. Am J Prev Med. 2020;58(3):336–42.31902685 10.1016/j.amepre.2019.10.014
109. Perez MF, Atuegwu NC, Mead EL, Oncken C, Mortensen EM. Adult E-Cigarettes use Associated with a self-reported diagnosis of COPD. Int J Environ Res Public Health. 2019; 16(20).
110. Wang JB Olgin JE Nah G Vittinghoff E Cataldo JK Pletcher MJ Cigarette and e-cigarette dual use and risk of cardiopulmonary symptoms in the Health eHeart Study PLoS ONE 2018 13 7 e0198681 10.1371/journal.pone.0198681 30044773
Wang JB, Olgin JE, Nah G, Vittinghoff E, Cataldo JK, Pletcher MJ, et al. Cigarette and e-cigarette dual use and risk of cardiopulmonary symptoms in the Health eHeart Study. PLoS ONE. 2018;13(7):e0198681.30044773 10.1371/journal.pone.0198681
111. Xie Z Ossip DJ Rahman I Li D Use of Electronic cigarettes and Self-reported chronic obstructive Pulmonary Disease diagnosis in adults Nicotine Tob Res 2020 22 7 1155 61 10.1093/ntr/ntz234 31830263
Xie Z, Ossip DJ, Rahman I, Li D. Use of Electronic cigarettes and Self-reported chronic obstructive Pulmonary Disease diagnosis in adults. Nicotine Tob Res. 2020;22(7):1155–61.31830263 10.1093/ntr/ntz234
112. Chen DT, Grigg J, Filippidis FT. European Respiratory Society statement on novel nicotine and tobacco products, their role in tobacco control and harm reduction. Eur Respir J. 2024;63(2).
113. Glantz SA. The cigarette papers. Univ of California; 1996.
114. Glantz SA Heated tobacco products: the example of IQOS Tob Control 2018 27 Suppl 1 s1 10.1136/tobaccocontrol-2018-054601 30352841
Glantz SA. Heated tobacco products: the example of IQOS. Tob Control. 2018;27(Suppl 1):s1.30352841 10.1136/tobaccocontrol-2018-054601
115. Bravo-Gutierrez OA, Falfan-Valencia R, Ramirez-Venegas A, Sansores RH, Ponciano-Rodriguez G, Perez-Rubio G. Lung damage caused by Heated Tobacco Products and Electronic Nicotine Delivery systems: a systematic review. Int J Environ Res Public Health. 2021;18(8).
116. Leigh NJ Tran PL O’Connor RJ Goniewicz ML Cytotoxic effects of heated tobacco products (HTP) on human bronchial epithelial cells Tob Control 2018 27 Suppl 1 s26 9 10.1136/tobaccocontrol-2018-054317 30185530
Leigh NJ, Tran PL, O’Connor RJ, Goniewicz ML. Cytotoxic effects of heated tobacco products (HTP) on human bronchial epithelial cells. Tob Control. 2018;27(Suppl 1):s26–9.30185530 10.1136/tobaccocontrol-2018-054317
117. Sohal SS Eapen MS Naidu GMV Sharma P IQOS exposure impairs human airway cell homeostasis: direct comparison with traditional cigarette and e-cigarette ERJ Open Res 2019 5 1 00159 2018 10.1183/23120541.00159-2018 30775377
Sohal SS, Eapen MS, Naidu GMV, Sharma P. IQOS exposure impairs human airway cell homeostasis: direct comparison with traditional cigarette and e-cigarette. ERJ Open Res. 2019;5(1):00159–2018.30775377 10.1183/23120541.00159-2018
118. Nakama C Tabuchi T Use of heated tobacco products by people with chronic diseases: the 2019 JASTIS study PLoS ONE 2021 16 11 e0260154 10.1371/journal.pone.0260154 34793517
Nakama C, Tabuchi T. Use of heated tobacco products by people with chronic diseases: the 2019 JASTIS study. PLoS ONE. 2021;16(11):e0260154.34793517 10.1371/journal.pone.0260154
119. Glantz SA PMI’s own in vivo clinical data on biomarkers of potential harm in americans show that IQOS is not detectably different from conventional cigarettes Tob Control 2018 27 Suppl 1 s9 10.1136/tobaccocontrol-2018-054413 30131374
Glantz SA. PMI’s own in vivo clinical data on biomarkers of potential harm in americans show that IQOS is not detectably different from conventional cigarettes. Tob Control. 2018;27(Suppl 1):s9.30131374 10.1136/tobaccocontrol-2018-054413
120. Tashkin DP Smoking Cessation in Chronic Obstructive Pulmonary Disease Semin Respir Crit Care Med 2015 36 4 491 507 10.1055/s-0035-1555610 26238637
Tashkin DP. Smoking Cessation in Chronic Obstructive Pulmonary Disease. Semin Respir Crit Care Med. 2015;36(4):491–507.26238637 10.1055/s-0035-1555610
121. Pezzuto A Carico E Effectiveness of smoking cessation in smokers with COPD and nocturnal oxygen desaturation: functional analysis Clin Respir J 2020 14 1 29 34 10.1111/crj.13096 31613417
Pezzuto A, Carico E. Effectiveness of smoking cessation in smokers with COPD and nocturnal oxygen desaturation: functional analysis. Clin Respir J. 2020;14(1):29–34.31613417 10.1111/crj.13096
122. WHO Package of Essential Noncomunicable (PEN). Disease Interventions for Primary Health Care. World Health Organization; 2020.
123. WHO Report on the Global Tobacco Epidemic. 2023: protect people from tobacco smoke. Geneva: World Health Organization; 2023.
124. WHO calls on governments to include smoking cessation in tobacco control strategies. Geneva: World Health Organizition. 2023. https://www.who.int/news/item/06-08-2003-who-calls-on-governments-to-includesmoking-cessation-in-tobacco-control-strategies
125. United States Public Health Service Office of the Surgeon G, National Center for Chronic Disease P Health Promotion Office on S, Health. Publications and reports of the Surgeon General. Smoking Cessation: a report of the Surgeon General 2020 Washington (DC) US Department of Health and Human Services
United States Public Health Service Office of the Surgeon G, National Center for Chronic Disease P. Health Promotion Office on S, Health. Publications and reports of the Surgeon General. Smoking Cessation: a report of the Surgeon General. Washington (DC): US Department of Health and Human Services; 2020.
126. Soriano JB Jenkins C How should good lung health be defined at the population and individual levels? Eur Respir J 2023 62 3 2301166 10.1183/13993003.01166-2023 37690786
Soriano JB, Jenkins C. How should good lung health be defined at the population and individual levels? Eur Respir J. 2023;62(3):2301166.37690786 10.1183/13993003.01166-2023
127. Malone RE Imagining things otherwise: new endgame ideas for tobacco control Tob Control 2010 19 5 349 50 10.1136/tc.2010.039727 20876073
Malone RE. Imagining things otherwise: new endgame ideas for tobacco control. Tob Control. 2010;19(5):349–50.20876073 10.1136/tc.2010.039727
128. Dai X Gakidou E Lopez AD Evolution of the global smoking epidemic over the past half century: strengthening the evidence base for policy action Tob Control 2022 31 2 129 10.1136/tobaccocontrol-2021-056535 35241576
Dai X, Gakidou E, Lopez AD. Evolution of the global smoking epidemic over the past half century: strengthening the evidence base for policy action. Tob Control. 2022;31(2):129.35241576 10.1136/tobaccocontrol-2021-056535
129. WHO global report on trends in prevalence of tobacco use. 2000–2030: World Health Organization; 2024 [updated 16 January 2024. https://www.who.int/publications/i/item/9789240088283
130. Melén E, Faner R, Allinson JP, Bui D, Bush A, Custovic A et al. Lung-function trajectories: relevance and implementation in clinical practice. Lancet. 2024.
131. Lu W, Aarsand R, Rylance S, Schotte K, Han J, Lebedeva E et al. Tobacco and chronic obstructive pulmonary disease (COPD). WHO; 2023 14 November.
132. WHO clinical Treatment guideline for tobacco cessation in adults 2024 Geneva World Health Organization
WHO clinical. Treatment guideline for tobacco cessation in adults. Geneva: World Health Organization; 2024.
