Clinical Characteristics of Chronic Obstructive Pulmonary Disease according to Smoking Status

Article information

Tuberc Respir Dis. 2025;88(1):14-25

Publication date (electronic) : 2024 October 30

doi : https://doi.org/10.4046/trd.2024.0060

Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea

Address for correspondence Joo Hun Park, M.D. Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, 206 World cup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea Phone 82-31-219-5116 Fax 82-31-219-5124 E-mail jhpamc@naver.com

Received 2024 April 18; Revised 2024 September 16; Accepted 2024 October 28.

Abstract

Chronic obstructive pulmonary disease (COPD) can be caused by various factors, including lung infections, asthma, air pollution, childhood growth disorders, and genetic factors, though smoking is the predominant risk factor. The main pathological mechanisms in COPD involve small airway disease, emphysema, mucus hypersecretion, and vascular disorders. COPD in non-smokers is characterized by a normal 1-second forced expiratory volume decline, equal sex distribution, younger age of onset, fewer comorbidities, milder airflow obstruction, preserved diffusing capacity of the lungs for carbon monoxide, and radiological features such as more air-trapping and less severe emphysema compared to COPD in smokers. Nevertheless, non-smokers with COPD still experience a high prevalence of acute exacerbations, nearly equal to that of smokers with COPD. Moreover, COPD itself is an independent risk factor for developing lung cancer, regardless of smoking status. Given that COPD coexists with numerous comorbidities, effectively managing these comorbidities is crucial, requiring multifaceted efforts for comprehensive treatment.

Keywords: Chronic Obstructive Pulmonary Disease; Smokers; Non-smokers; Comorbidity

Key Figure

Introduction

Chronic obstructive pulmonary disease (COPD) is a global health issue, becoming one of the major diseases in terms of prevalence, morbidity, and mortality worldwide [1,2]. COPD is defined by a post-bronchodilator 1-second forced expiratory volume (FEV₁)/forced vital capacity (FVC) ratio of less than 0.7 and is characterized by chronic respiratory symptoms such as dyspnea, cough, and sputum production resulting from abnormalities of the airways or emphysematous changes leading to persistent, often progressive airflow obstruction [3,4]. However, COPD is a heterogeneous condition featuring multiple endotypes and phenotypes.

Traditionally, peribronchiolar fibrosis and alveolar wall destruction in emphysema were recognized as two major phenotypes of COPD based on pathological findings [5]. While both pathologies usually result from tobacco exposure in smokers with COPD, non-smokers predominantly exhibit small airway disease with minimal emphysema [5,6]. Additionally, recent recognition of phenotypes like pulmonary hypertension, the frequent exacerbator, the rapid decliner, and Asthma-COPD Overlap Syndrome (ACOS) have significantly impacted the prognostic understanding of COPD [7,8].

Several endotypes based on underlying biological mechanisms have been identified in COPD. Two distinct endotypes, alpha-1 antitrypsin deficiency and telomerase polymorphisms, were identified due to causal genetic factors [5]. The inflammatory endotypes in COPD consist of neutrophilic inflammation unresponsive to corticosteroids and eosinophilic inflammation, which predicts the efficacy of inhaled corticosteroid (ICS) [5]. Hence, the spirometric definition of COPD falls short in reflecting its inherent heterogeneity marked by a variety of pathophysiological processes and differing responses to therapeutic interventions.

Although tobacco smoking is the predominant cause of COPD, up to half of all global cases are attributable to other risk factors besides tobacco exposure [9]. Consequently, this review will explore various aspects of COPD including etiology, endotype, and phenotype, comparing COPD in non-smokers and smokers.

Etiology of COPD

While tobacco smoking is a significant contributor to COPD development, emerging evidence highlights the prevalence, risk factors, and clinical manifestations of COPD among non-smokers (Figure 1) [9-12]. Notably, 25% to 40% of COPD cases arise from non-smoking related factors, with a higher incidence observed in develop-ing countries [9,11]. Although non-impaired smokers may experience significant respiratory morbidity, only 15% to 20% develop COPD [13-16]. A recent study identified the age at which smoking begins as an independent predictor of later-life COPD [16]. Their multivariable analysis indicated that the relative risk for COPD among those who began smoking before age 15 was 1.41 (95% confidence interval, 1.22 to 1.63), compared to those who started smoking later (onset ≥15 years of age) [16]. A recent meta-analysis suggested that secondhand smoke exposure increases the risk of COPD, particularly with exposure duration exceeding 5 years [17].

Fig. 1.

The natural course of COPD based on smoking status. COPD: chronic obstructive pulmonary disease; FEV₁: 1-second forced expiratory volume.

Recently, there has been increasing recognition of the importance of non-smoking-related risk factors in the development of COPD [9]. Besides exposure to smoke, factors such as impaired lung growth during early life, uncontrolled asthma, respiratory infections during childhood, and sequelae of infections like post-tuberculosis lung damage and bronchiectasis contribute to persistent airflow obstruction [18-24]. These factors play a significant role in reduced lung function, culminating in adult-onset COPD [18-23]. Moreover, these findings imply that COPD can begin early in life, challenging the traditional belief that COPD is typically diagnosed after the age of 40 [21,22,25]. Additionally, air pollution, occupational exposures, environmental tobacco exposure, electronic cigarette use, and low-socioeconomic status are contributing factors in developing COPD [9,20-23,26].

Genome-wide association studies (GWAS) on COPD phenotypes have identified moderate genetic heritability for COPD [27,28]. Research within the COPD Gene cohort determined that heritability of FEV₁ was 38.4% in the non-Hispanic white population and 50.9% in the African American population [27].

Alpha-1 antitrypsin deficiency and telomerase reverse transcriptase (TERT) mutation are the only two single genetic variants clearly identified as causative factors in COPD [29]. Alpha-1 antitrypsin deficiency occurs in 1% to 2% of Caucasian patients with COPD [29,30]. A recent study showed that serpin peptidase inhibitor, clade A, member (SERPINA1) variants, which encode alpha-1 antitrypsin, are linked to the cumulative risk of developing alpha-1 antitrypsin deficiency, impaired lung function, and emphysema [31]. Consequently, current guidelines recommend screening for alpha-1 antitrypsin deficiency in all COPD patients [3].

Short telomeres reduce the threshold for cigarette smoke-induced damage and emphysema development in animal models, and mutations in telomerase can predispose individuals to emphysema [32,33]. Recent research indicates that mutations in TERT are significant risk factors for severe emphysema in smokers, with 1% of serious COPD cases involving detrimental mutations in TERT [33]. Furthermore, GWAS has identified several common genetic variants associated with COPD susceptibility, including alpha-nicotinic acetylcholine receptor (CHRNA)/CHRNA5/iron responsive element binding protein 2 (IREB2), hedgehog interacting protein (HHIP), family with sequence similarity 13 member A (FAM13A), G protein-coupled receptor 126 (GPR126), ADAM metallopeptidase domain 19 (ADAM19), advanced glycosylation end-product specific receptor palmitoyl-protein thioesterase 2 (AGER-PPT2), patched 1 (PTCH1), phosphotyrosine interaction domain containing 1 (PID1), 5-hydroxytryptamine receptor 4 (HTR4), integrator complex subunit 12 (INTS12)-C-terminal domain containing (GSTCD)-nephronectin (NPNT), and a region near cytochrome P450 family 2 subfamily A member 6 (CYP2A6) on chromosome 19q [34-38]. Furthermore, epigenetic alterations such as DNA methylation and histone modifications, resulting from gene-environment interactions, could influence the development of COPD [28,39]. Therefore, a thorough investigation of gene-environment interactions over time is essential to understand the pathogenesis of COPD.

Occupational COPD is underdiagnosed due to the clinical challenges of identifying the exposure component [40]. Yet, one research indicates that exposure to vapors, gases, dusts, and fumes significantly contributes to the development of COPD, accounting for a population attributable fraction of 14% from population-based studies [40]. Cohort studies have shown an etiological role for coal dust, gold mine dust, silica, and inorganic dusts such as asbestos and cement in COPD [41-44]. Furthermore, items like cadmium, welding fumes, nitrous fumes, sulphur dioxide, chlorine, and organic dusts in farming, the textile industry, and paper mills have been linked to lung function decline and the development of COPD [45-51].

The recent Lancet Commission report categorized COPD into several types: genetic COPD (alpha-1 antitrypsin deficiency, TERT mutations), COPD related to early-life events (prematurity, childhood asthma), infection-related COPD (childhood infections, tuberculosis-associated COPD, acquired immunodeficiency syndrome [AIDS]-associated COPD), COPD from smoking or vaping (fetal exposure to smoke, secondhand smoke, e-cigarettes, marijuana), and environmental exposure-related COPD (indoor air pollution, ambient air pollution, wildfire smoke, occupational exposure) [30]. The Lancet Commission report provides new insights into the causes of COPD and potential future therapeutic approaches [30]. Following the new classification in the Lancet Commission report, the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) document identified seven etiologies of COPD: (1) genetically determined (COPD-G); (2) abnormal lung development (COPD-D); (3) infections (COPD-I); (4) cigarette smoking and vaping (COPD-C); (5) biomass and pollution exposure (COPD-P); (6) COPD with asthma (COPD-A); and (7) unknown causes (COPD-U) (Table 1) [4].

Table 1.

COPD etiotypes found in the GOLD document and Lancet Commission report [4,30]

Clinical Characteristics of COPD in Nonsmokers Compared to COPD in Smokers

COPD in non-smokers is characterized by a normal FEV₁ decline, equal distribution across sexes, a younger age of onset, fewer comorbidities, milder airflow obstruction, preserved diffusing capacity of the lungs for carbon monoxide (DLCO), and radiological features including more air-trapping and less severe emphysema compared to COPD in smokers (Table 2) [9,52,53]. However, non-smokers with COPD still experience a prevalence of acute exacerbations nearly equal to that of smokers [9,52,53]. Furthermore, COPD itself is an independent risk factor for developing lung cancer, regardless of smoking status [54].

Table 2.

Clinical features of COPD by smoking status [9,52-55]

A radiological analysis from the Korea COPD Subgroup Study (KOCOSS) database indicated that non-smokers with COPD exhibited more severe tuberculosis-destroyed lung and bronchiectasis, while smokers predominantly displayed emphysematous lungs (Table 2) [55]. The Canadian Cohort of Obstructive Lung Disease (CanCOLD) study found that a history of hospitalization in childhood for respiratory illness was prevalent among never-smokers with COPD, while exposure to passive smoke and biomass fuel for heating stood out as significant risk factors for women [53]. Furthermore, it was observed that COPD in both never-smokers and ever-smokers is characterized by increased respiratory symptoms, respiratory exacerbations, and higher residual volume/total lung capacity ratios, but only smokers exhibited reduced DLCO and emphysema on chest computed tomography scans [53]. A study conducted in India also revealed that, in contrast to smokers, COPD in non-smokers is more prevalent in younger individuals, displays a similar male-female ratio, and is primarily characterized by a small airway disease phenotype with less emphysema, preserved DLCO, and a slower rate of lung function decline [56]. Studies in COPD patients aged 20 to 50 years revealed that young or early-stage COPD is associated with significant structural and functional abnormalities, and a substantial proportion of these patients had a respiratory disease family history or were hospitalized before the age of 5 years, suggesting an early-life origin for COPD development [57,58]. However, additional research is necessary to explore the clinical characteristics specific to COPD with early-life origins to further delineate this phenotype.

1. Lung function decline

Fletcher and Peto [59] reported that tobacco smoking is a significant etiological factor causing a decline in pulmonary function, which leads to COPD. They posited that all individuals with COPD achieve a peak in lung function comparable to that observed in healthy individuals [59]. Their findings indicate that the decline in pulmonary function in COPD occurs at an accelerated rate, leading to the onset of symptoms, contrasting with the normal physiological decline in FEV₁, estimated at approximately 25 mL/year [59]. However, recent studies have proposed various mechanisms for lung function deterioration [25,60].

Some studies have indicated that COPD could develop in certain individuals who fail to reach a normal peak in early adulthood, despite a rate of lung function decline within normal limits [25,60]. Contributory factors may include maternal smoking, exposure to air pollution, childhood respiratory infections, and low birth weight [1,25,60]. Therefore, impaired lung growth combined with an accelerated rate of lung function decline is considered a substantial mechanism in COPD development [1].

Lung function decline can be approached from multiple aspects. In COPD staging, lung function declines more rapidly in the moderate stage than in the severe stage, although comprehensive data are still lacking for the mild stage [61-63]. A rapid decline of lung function in COPD has been reported to be associated with several factors including smoking, male gender, acute exacerbation, emphysema, a low FEV₁/FVC ratio, a history of asthma, and the presence of airway reversibility (Table 3) [64-67].

Table 3.

Determinants of lung function decline observed in major trials

Furthermore, recent evidence indicates that air pollution contributes to lung function decline [68]. A cohort study conducted in six metropolitan regions of the United States found that ambient ozone concentrations, but not other pollutants, both initially and during follow-up were significantly associated with a greater decline in FEV₁ over 10 years, while initial ambient concentrations of ozone, particulate matter (PM)2.5, oxides of nitrogen, and black carbon were significantly correlated with larger increases in emphysema severity over 10 years [68]. In contrast, other studies have shown that exposure to ambient PM2.5 is associated with a faster decline in lung function, as well as higher incidence and increased severity of COPD [69,70].

A South African birth cohort study evaluated the short-term exposure effects of nitrogen dioxide (NO₂) and PM₁₀ on lung function during the early developmental stages of childhood. The study found that PM₁₀ leads to acute lung function impairments among infants from low-socioeconomic backgrounds, though the relationship with NO₂ remains less evident [71].

Lung function decline is also associated with occupational dust exposure [72,73]. A study involving two large general population cohorts in Europe found accelerated declines in FEV₁ and the FEV₁/FVC ratio associated with exposure to biological dust, mineral dust, and metals [74]. A population-based Tasmanian Longitudinal Health Study revealed that exposure to aromatic solvents and metals was linked to greater lung function decline [75]. Moreover, recent meta-analyses provide evidence that occupational exposures are associated with FEV₁ decline [73,76]. Additionally, exposures to cotton dust and wood dust can lead to accelerated FEV₁ decline over time [72].

Interestingly, high blood eosinophil counts have been reported to be associated with a decline in lung function [77,78]. Among Korean adults without lung disease, higher blood eosinophil counts are associated with a more rapid decline in lung function, regardless of their smoking status [77]. The CanCOLD study demonstrated that among individuals over 40 years old in the general population, a blood eosinophil count of ≥300 cells/μL is an independent risk factor for accelerated lung function decline and is associated with undetected structural airway abnormalities [78].

Although a recent report suggests that ICS may prevent lung function decline, further research is required to confirm these findings [79].

2. Comorbidities and prognosis

COPD frequently coexists with multiple comorbidities, including ischemic heart disease, heart failure, lung cancer, depression, osteoporosis, anemia, diabetes, sarcopenia, and metabolic syndrome [3]. Besides smoking, various factors such as aging, physical inactivity, and chronic systemic inflammation make patients more susceptible to COPD and its comorbidities [80,81]. Chronic systemic inflammation, due to the overflow of inflammatory mediators, can lead to the development or exacerbation of multiple comorbidities, thus worsening COPD’s prognosis [80,82,83].

COPD in smokers exhibits a higher prevalence of comorbidities, although COPD in never-smokers also presents with numerous comorbidities [9,52]. According to a Danish Population Study, there was a stepwise increase in risk from never-smokers to former and current smokers for hospital admissions due to COPD and pneumonia [52]. On the other hand, only COPD in ever-smokers exhibited a higher risk of cardiovascular comorbidities and all-cause mortality, while never-smokers did not [52]. Furthermore, a population-based cross-sectional study conducted in Korea discovered that osteoporosis and depression are more prevalent in non-smoking COPD patients, highlighting a significant sexual disparity between smokers and non-smokers with COPD [84].

Interestingly, irrespective of smoking status, COPD itself contributes to the development of lung cancer [54]. In patients with COPD, the inhalation of atmospheric carcinogens into the alveoli is problematic for clearance due to airflow limitations [85]. Consequently, these carcinogens can persist and exacerbate lung damage [85]. Pathological changes in COPD, including emphysema and airway obstruction, independently contribute to the development of lung cancer, irrespective of smoking history [86,87]. A meta-analysis has revealed that a 10% reduction in FEV₁ is linked to a 20% increased risk of lung cancer [88].

3. Treatment

Preventive measures such as smoking cessation, avoiding environmental pollutants (both indoor and outdoor), and eliminating occupational exposures are crucial prior to initiating pharmacologic therapy due to the diverse causes of COPD. Recent studies have shown that improvements in air quality correlate with significant positive effects on lung function growth in children and a decrease in mortality, suggesting that reducing air pollution plays a preventive role in COPD [89,90].

Furthermore, specific exposure control and respiratory health surveillance are necessary as preventative measures for COPD related to occupational exposures; longitudinal population-based studies have shown that occupational exposures are associated with a decline in FEV₁ [73,76]. Despite limited evidence on the effectiveness of preventive measures in the workplace, a recent report outlined a preventive intervention strategy: (1) primary prevention based on risk assessment, exposure reduction, workers’ training and education, and use of personal protective equipment; (2) secondary prevention at both primary and specialist levels (respiratory physicians, occupational medicine specialists) to identify at-risk groups and early diagnose occupational COPD; and (3) tertiary prevention, focusing on patients already diagnosed with COPD, aimed at reducing the disease’s severity and consequences [40].

Since most therapeutic trials on COPD have been conducted in ever-smokers, there is limited evidence on treating COPD in never-smokers, except for cases like alpha 1-antitrypsin deficiency. Additionally, concerns about the over-treatment of COPD with an early-life origin using current therapies have been highlighted, given that the pathologies affecting lung growth and development differ from those caused by tobacco-related COPD [4,91]. Therefore, a personalized and tailored approach is essential for managing COPD in non-smokers, recognizing that factors such as environmental pollutants, occupational hazards, or genetic factors may underpin COPD in this group.

Pharmacological intervention in the early stages of COPD could significantly prevent the disease’s progression. A recent randomized controlled trials (RCT) involving tiotropium for mild and moderate COPD, which included 21.1% non-smokers in the tiotropium group and 20.1% non-smokers in the placebo group, showed that tiotropium led to a higher FEV₁ than placebo at 24 months and reduced the annual decline in FEV₁ following bronchodilator usage in COPD (Table 3) [61-63,65,92-94]. However, evidence from randomized clinical trials and real-life studies on the impact of pharmacological treatment in the early stages of COPD remains scarce.

Bronchodilators including long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) are pivotal in managing COPD symptoms and exacerbations. Recent evidence indicates that combined LAMA/LABA therapy is superior to either agent alone in enhancing lung function, reducing dyspnea, improving quality of life, and increasing exercise capacity in COPD patients without raising cardiovascular risks [95]. Consequently, the current GOLD guidelines recommend LAMA/LABA combination as initial therapy for COPD patients with a history of exacerbations (group E) or symptomatic COPD (COPD assessment test ≥10, modified Medical Research Council dyspnea scale grade ≥2) [96]. A trial involving glycopyrronium among LAMAs demonstrated that glycopyrronium treatment significantly enhanced lung function regardless of the patient’s smoking status, with a safety profile consistent between current and former smokers [97]. Furthermore, a study on smoking asthmatics revealed that adding a LAMA to ICS/LABA improved outcomes in small airways [98]. However, a recent trial showed that inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic individuals with a smoking history and preserved lung function, despite previous reports indicating that pre-COPD conditions include symptoms and exacerbations [14,99].

While large RCTs, including the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) and The Effect of Indacaterol—Glycopyrronium Versus Fluticasone– Salmeterol on COPD Exacerbations (FLAME) trials, supported the safe withdrawal of ICS in COPD, recent trials like Informing the Pathway of COPD Treatment (IMPACT) and Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) demonstrated that triple therapy combining ICS, LAMA, and LABA results in reduced COPD exacerbations and hospitalizations, as well as improved survival rates, particularly evident in the IMPACT trial [100-103]. When interpreting recent RCTs, differences in study design should be taken into account. For instance, the IMPACT study featured a higher incidence of frequent exacerbations, defined as ≥2/year (55% vs. 19%), included participants with a previous history of asthma, which were excluded in the FLAME study, and had a more significant percentage of participants on ICS therapy (71.6% vs. 56.3%) during screening [100,101]. Nevertheless, ICS therapy is recommended for COPD subtypes with high blood eosinophil counts and frequent exacerbations, according to the GOLD document based on recent RCTs [100,103]. However, ICS therapy is associated with the risk of respiratory infections, including pneumonia, mycobacterial infections, and oropharyngeal candidiasis [104-108]. Furthermore, tobacco smoking may induce steroid resistance in COPD by diminishing histone deacetylase 2 activity and expression [109].

In addition to phosphodiesterase-4 (PDE-4) inhibitors and macrolides, other medications should be considered in managing COPD exacerbations. A study demonstrated that the PDE-4 inhibitor ‘roflumilast’ enhanced lung function and reduced exacerbations in the chronic bronchitis subtype of COPD among ever-smokers [110]. Experimental evidence supports these findings, showing that roflumilast can improve smoke-induced mucociliary dysfunction by increasing cyclic adenosine monophosphate, enhancing airway surface liquid volume, and stimulating ciliary beat frequency, especially when combined with formoterol [111]. In a randomized trial investigating whether azithromycin reduces the frequency of exacerbations in participants with COPD and a smoking history of at least 10 pack-years, adding azithromycin to standard treatment for 1 year decreased acute exacerbations of COPD despite increased minor hearing loss and nasopharyngeal colonization with azithromycin-resistant organisms [112]. However, azithromycin did not reduce COPD exacerbations in current smokers [113].

Conclusion

In addition to smoking, various factors such as lung infections, asthma, environmental exposure, childhood growth disorders, and genetic elements contribute to COPD. Therefore, further clinical trials are necessary for never-smokers with COPD to enable personalized and targeted approaches based on the underlying etiology, which are crucial for improving outcomes. Additionally, given that COPD often coexists with numerous comorbidities, effective management of these conditions is paramount, necessitating comprehensive and multifaceted efforts in the treatment of COPD.

Notes

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Funding

No funding to declare.

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Lancet Commission report	GOLD document
Type 1: genetically determined	COPD-G: genetically determined
Type 2: early-life events	COPD-D: abnormal lung development
Type 3: infection-related	COPD-I: infection
Type 4: smoking or vaping	COPD-C: cigarette smoking (and vaping)
Type 5: environmental exposure	COPD-P: exposure to biomass and pollution
	COPD-A: COPD and asthma
	COPD-U: unknown cause

	Smokers	Non-smokers
Age of onset	≥40 years	≥30 years
Gender	Predominantly males	Affected equally
Exacerbation frequency	Frequent exacerbations	Frequent exacerbations
Comorbidities	Generally more prevalent	Generally less prevalent
	Reduced asthma rate	Increased asthma rate
Lung cancer	Elevated rate	Persistently high rate
Radiological findings	Increased emphysema	Reduced emphysema
	Decreased air-trapping	Increased air-trapping
	Less tuberculosis-related lung damage	More tuberculosis-related lung damage
	Reduced bronchiectasis	Increased bronchiectasis
Physiological findings	Rapid FEV₁ decline	Typically normal FEV₁ decline
	More severe airflow limitation	Less severe airflow limitation
	Reduced DLCO	Preserved DLCO
	Less small airway obstruction	More small airway obstruction
Therapy	LABA/LAMA combination	Unknown
	ICS for frequent exacerbators with high blood eosinophil count	-

Determinants	Measurement			Outcome
Smoking onset [93]	The relative risk for COPD among smokers who began smoking before 15 years of age compared with those who started smoking at or after 15 years of age			1.41 (95% CI, 1.22–1.63)
Smoking [93,94]	Annual FEV decline in smokers compared to never-smokers or former smokers			Exceeds 10 mL
	FEV₁ decline among smokers			60.3 mL/yr
	FEV₁ decline among former smokers			35.2 mL/yr
PM_2.5 [93]	Each 10 µg/m³ increase (approximately a 1-SD increase) in estimated indoor PM_2.5
	Annual FEV₁ decline in former smokers			10.0 mL (95% CI, 0.2–19.8).
	Annual FEV₁ decline in current smokers			No significant difference
ECLIPSE study [65]	Annual FEV₁ decline
	Current smoking status (yes or no)			21±3.8 mL
	Exacerbations during follow-up (yes or no)			2±0.5 mL
	Bronchodilator reversibility (yes or no)			17±4.2 mL
	Presence of emphysema (yes or no)			13±4.2 mL
Tiotropium in mild and moderate COPD [92]	Annual FEV₁ decline
	FEV₁ before bronchodilator use			p=0.06
	Tiotropium group			38±6 mL
	Placebo group			53±6 mL
	FEV₁ after bronchodilator use			p=0.006
	Tiotropium group			29±5 mL
	Placebo group			51±6 mL
	COPD stage	No. of patients	Age range, yr	Follow-up period, yr	Mean FEV₁ decline, mL/yr
UPLIFT trial [61]	Stage 2	1,355	64±9	4	49
	Stage 3	775	65±8	4	38
	Stage 4	271	63±8	4	23
TORCH trial [62]	Stage 2	535	40–80	3	60
	Stage 3	775	40–80	3	56
	Stage 4	214	40–80	3	34
Alpha-1 antitrypsin deficiency-related emphysema [63]	Stage 1	18	49±9	3	32±19
	Stage 2	26	51±9	3	90±19
	Stage 3	38	53±11	3	52±8
	Stage 4	19	49±9	3	8±9