Introduction

Smoking has long been linked to adverse effects on the respiratory system, causing malignant and nonmalignant diseases, exacerbating chronic lung diseases, and increasing the risk for respiratory infections. The observational evidence showing associations with multiple diseases of the respiratory tract is extensive as is the evidence supporting the biological plausibility of smoking as a cause of these associations (U.S. Department of Health and Human Services [USDHHS] 2004, 2010). In addition to finding that smoking caused lung cancer, the 1964 Surgeon General's report also determined that: “Cigarette smoking is the most important of the causes of chronic bronchitis in the United States, and increases the risk of dying from chronic bronchitis and emphysema” (U.S. Department of Health, Education, and Welfare [USDHEW] 1964, p. 31).

This chapter updates previous reviews on smoking and respiratory health, covering chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF)—a form of interstitial lung disease (see Chapter 4, “Advances in Knowledge of the Health Consequences of Smoking: From 1964–2014,” for a detailed description of the conclusions). It also addresses tuberculosis, an infectious disease that has not been previously covered in the reports of the Surgeon General. The understanding of COPD, a leading cause of premature mortality and morbidity, has evolved substantially over the past 5 decades with advances related to its pathogenesis, genetic basis, natural history, and underlying structural changes in the lung. Asthma is the most common chronic disease of childhood and is also very common among adults. This chapter considers the effect of smoking on the incidence and exacerbation of asthma in children and adolescents, and in adults. It also updates the evidence on smoking and IPF, a fibrotic disease of the lung. The emerging evidence on a role for smoking in increasing the risk of developing tuberculosis and for unfavorably affecting its clinical course is examined.

Smokefree policies have now been implemented in many jurisdictions in the United States and other countries (see Chapter 14, “Current Status of Tobacco Control”). This chapter considers the evidence on the benefits of such polices for respiratory illness.

Chronic Obstructive Pulmonary Disease

Perspectives on the epidemiology, genetics, and pathogenesis of COPD have changed profoundly since the 1964 Surgeon General's report (USDHEW 1964). Smoking and chronic respiratory diseases were subsequently covered in numerous reports of the Surgeon General (see Chapter 4 for detailed descriptions of these reports and their conclusions for respiratory illness). This chapter updates previous reviews on COPD, emphasizing how the evidence on smoking and COPD has progressed during the last 50 years and examines how advances in the understanding of the epidemiology, genetics, pathogenesis, and heterogeneity of COPD in relation to smoking will alter disease prevention, management, and prognosis in the future. This chapter does not address the interrelationships among COPD and other common comorbid diseases caused by smoking—cardiovascular diseases and cancer in particular. These comorbidities are strong determinants of outcome for those with COPD (Decramer and Janssens 2013). For each of the primary topics in this chapter, some of the most significant articles were selected to document the progress made over the past 50 years.

Epidemiology of Chronic Obstructive Pulmonary Disease

By the time of publication of the 1964 Surgeon General's report, several key studies had already linked chronic bronchitis to cigarette smoking; and community surveys had characterized the frequency of chronic bronchitis and chronic respiratory symptoms (Short et al. 1939; Stuart-Harris 1954; Higgins 1974; USDHHS 1984). These and other key studies set the stage for the findings of the 1964 report.

COPD, as defined today, was not recognized as a distinct clinical entity in 1964 (Fletcher et al. 1959). Clinicians tended to use the terms “chronic bronchitis” and “emphysema” to refer to the disease constellation now termed COPD; however, the clinical classification lacked specificity and differed across countries. That era preceded the widespread use of spirometry in clinical settings and the availability of computed tomography (CT) to noninvasively determine the presence of emphysema. The time period before, and shortly following, the 1964 report was important in the development of hypotheses related to the pathogenesis of COPD and the role of cigarette smoking in its causation. Two hypotheses were extant: one attributed susceptibility to develop COPD to bronchial hyperresponsiveness, the “Dutch” hypothesis (Orie et al. 1961), and the other to respiratory infections, the “British” hypothesis (Fletcher 1959). The landmark cohort study of London men carried out by Fletcher and Peto (1977) in the 1960s described the progressive decline of lung function with aging and the acceleration of this decline in smokers. In this study, smoking was the dominant determinant of decline beyond that expected from aging alone and infection did not affect the rate of decline.

A key discovery in the early 1960s was the increased risk for COPD associated with α1-antitrypsin deficiency (AAT), a consequence of genetic mutations that increase risk for COPD, particularly in smokers (Eriksson 1965), discussed in more detail below. That discovery identified one genetic factor that increased risk for COPD in smokers and launched substantial research on underlying mechanisms.

Even before the 1964 report, the complexity and overlap of various chronic obstructive lung diseases—chronic bronchitis, asthma, and irreversible obstructive lung disease (primarily emphysema)—were recognized (Fletcher et al. 1959). In its 1995 guidelines, the American Thoracic Society (ATS) proposed a conceptual framework that captured the overlap of the major chronic lung diseases associated with airflow obstruction (Figure 7.1) (ATS 1995). The framework comprises a Venn diagram with overlapping circles indicating chronic bronchitis, emphysema, and asthma, overlaid by a rectangle representing airflow obstruction (Figure 7.1). In this schema, “COPD” comprises persons with chronic bronchitis and/or emphysema, who also have evidence of airflow obstruction (indicated by shading in Figure 7.1). ATS' 1995 definition of COPD referred to chronic airflow obstruction caused by chronic bronchitis or emphysema. The development of guidelines by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2001 changed the approach to the classification of COPD by focusing on the airflow obstruction component (the rectangle in Figure 7.1) rather than symptoms or a clinical diagnosis (Pauwels et al. 2001). GOLD guidelines recommended that lung function be measured after administration of a bronchodilator (to help identify and exclude from the diagnosis of COPD, those people whose primary problem is asthma, although some people with COPD respond to a bronchodilator). The definition of COPD referred to airflow obstruction that is not fully reversible. Thus, since 1964 the concept of permanent airflow obstruction has become central to the identification of COPD, although symptoms and structural changes documented by imaging are considered relevant to clinical management (GOLD 2013).

Figure 7.1

Venn diagram with overlapping circles indicating chronic bronchitis, emphysema, and asthma, overlaid by a rectangle indicating airflow obstruction. Source: American Thoracic Society 1995. Reprinted with permission from American Thoracic Society, © (more...)

Given the changes in clinical approaches and definitions during the past 50 years, the prevalence of COPD cannot be readily tracked. The 1964 report did include the findings of several population-based studies that incorporated lung function measures. A study by Ferris and Anderson (1962) in a New Hampshire town determined that “obstruction” (defined as a forced expiratory volume in 1 second [FEV₁]/forced vital capacity [FVC] ratio of less than 60%) was found in 24.9% of male smokers, 7.3% of male nonsmokers, 17.5% of female smokers, and 9.4% of female nonsmokers. Data from the Ferris and Anderson study were reanalyzed to give population-based estimates of what would now be considered “chronic bronchitis,” defined as bouts of cough and phlegm for 3 weeks for more than 3 winters (Reid et al. 1964). This symptom pattern was reported by 13% of men and 8% of women. In addition, 72% of men and 30% of women in the study community reported current cigarette, pipe, or cigar smoking (Reid et al. 1964).

By 1979, nationally representative estimates of disease burden became available based on data from the National Health Interview Survey (NHIS). Estimates of the prevalence of COPD (which included physician-diagnosed chronic and unqualified bronchitis [International Classification of Diseases (ICD)-9 490–491]; emphysema [ICD-9 492]; asthma [ICD-9 493]; and other chronic obstructive pulmonary diseases and allied conditions [ICD-9 494–496]), for 55–84-year-olds in the United States from 1979–1985, ranged from 9.4% in 1979 to 11.0% in 1985 among men, and 8.8% in 1979 to 11.9% in 1985 among women (Feinleib et al. 1989). For the U.S. adult population 25 years of age and older, estimates of disease burden based on report of a diagnosis of emphysema or chronic bronchitis were between 5.5% and 6.5% during the period 1980–2000 (Mannino et al. 2002). The most recent national data (2011 Behavioral Risk Factor Surveillance System Data) yields a 6.3% overall estimate of the prevalence of self-reported, physician-diagnosed COPD, chronic bronchitis, or emphysema among adults 18 years of age and older (Figure 7.2) (Centers for Disease Control and Prevention [CDC] 2012a). At the time of this survey, the prevalence of smoking among U.S. adults had decreased to 19% of the population (CDC 2012b).

Figure 7.2

Age-adjusteda prevalence of chronic obstructive pulmonary disease (COPD)b among adults—Behavioral Risk Surveillance System, United Statesc, 2011. ^a Age-adjusted to the 2000 U.S. standard population, using 5 age groups: 18–44 years, 45–54 (more...)

These figures are likely underestimates, even considering the most recent estimates. COPD is frequently underdiagnosed clinically (Mannino et al. 2000); consequently, the disease burden is likely to be underestimated when based on data from questionnaire-based surveys. The National Health and Nutrition Examination Survey (NHANES) includes lung function data on U.S. adults 25 years of age and older. During 1971–1975, the estimated prevalence of moderate or worse obstruction (FEV₁/FVC <70% and FEV₁ <80% predicted) was 7.7%, and the estimated prevalence of mild obstruction (FEV₁/FVC <70% and FEV₁ ≥80% predicted) was 7.4%, for a total prevalence of 15.1% (Mannino et al. 2002). By 1988–1994, these estimates had decreased to 6.6% and 6.9%, respectively, with an overall prevalence of 13.5% (Mannino et al. 2002). Spirometry was performed without administration of a bronchodilator so that some of those NHANES participants meeting criteria for obstruction may have had asthma.

Although the prevalence figures do not document a trend of increasing COPD burden since 1964, mortality from COPD has risen progressively in recent decades (Figure 7.3). With regard to the disease now termed COPD, the 1964 Surgeon General's report referred to non-neoplastic respiratory diseases (chronic bronchitis and emphysema, in particular). In 1964, the general category of “other bronchopulmonic diseases” (ICD-7 525–524) was the 10th leading cause of death. In 2010, the category of “chronic lower respiratory diseases” (ICD-10 J40–47), in which COPD predominates, was the third leading cause of death in the United States (National Center for Health Statistics 2012). This figure highlights the steep rise in women and the recent overtaking of men by women in terms of the total number of COPD deaths. While the mortality counts are affected by changes in classification, the trends are nonetheless clear.

Figure 7.3

Deaths due to chronic obstructive pulmonary disease among adult men and women, 1979–2007, United States. Source: Dance 2012. Reprinted with permission from Macmillan Publishers Ltd., © 2012.

A separate “COPD” ICD code was introduced in the early 1970s, and by the mid-1980s this became the main code used for COPD deaths (Feinleib et al. 1989). In 1985, 74,662 deaths were attributed to COPD (Feinleib et al. 1989), a number that increased to 119,054 in 2000 (Mannino et al. 2002) and 133,575 in 2010 (Ford et al. 2013). Between the years 2000–2005, the age-adjusted mortality rate for COPD (standardized to the 2000 U.S. standard population) for adults 25 years of age and older remained stable, between 60 and 65 per 100,000 population.

COPD mortality has increased dramatically over the past several decades. Part of this increase is related to changes in how COPD is characterized and classified, but a substantial part is due to male and female birth cohorts with high smoking rates advancing to ages where death from COPD is more common (older than 70 years of age). Other factors, such as decreasing mortality from other chronic diseases including cardiovascular disease may have contributed. In recent years, the COPD-related mortality rate has stabilized and may show some signs of decreasing in certain age and race-ethnicity groups, reflecting declines in smoking that began several decades ago.

Prevalence by Gender

During the period between NHANES I (1971–1975) and NHANES III (1988–1994), the prevalence of moderate COPD increased in women (from 50.8 to 58.2 per 1,000 population, not a statistically significant change), while the prevalence decreased in men (from 108.1 to 74.3 per 1,000 population, a statistically significant decrease), but male rates remained higher than those for women (Mannino et al. 2002).

Gender-Specific Manifestations of COPD

The 2001 Surgeon General's report noted the extensive pathologic evaluation of the lungs of male and female smokers performed by Thurlbeck and colleagues (1974) showing that male smokers had higher emphysema scores, and a greater prevalence of emphysema, when compared to lung sections from female smokers. In a paper by Martinez and colleagues (2007), an analysis of CT data from the National Emphysema Treatment Trial (NETT) revealed that women had significantly less emphysema, despite similar severity of COPD as measured by the level of FEV₁; on histologic section, the airways of women with COPD had smaller lumens and thicker walls. Although some of these differences may represent baseline gender differences between the lungs of men and women, they may also support differences in how COPD develops and progresses in men versus women.

A series of observations during the past decade indicate that women seem to develop more severe COPD at an earlier age, in comparison with men who smoked the same cumulative number of cigarettes. In the NETT study (Martinez et al. 2007), women reported less pack-years¹ of cigarette smoking, but had similarly severe spirometrically defined COPD as men, raising the question of heightened susceptibility in women to the lung-damaging effects of smoking (Gan et al. 2006). Gan and colleagues observed that beyond 45 years of age, female current smokers had a faster annual decline in FEV₁ compared to male smokers.

Silverman and colleagues (1998) noted a high prevalence of women (almost 80%) in a group with severe, early-onset COPD (FEV₁ <40% of predicted at younger than 53 years of age) recruited for a genetic study. In addition, Sorheim and colleagues (2010) observed that in people with COPD before 60 years of age, women had lower FEV₁ and more severe COPD with lower cigarette smoking exposure. In this study, women had greater reductions in FEV₁ than men in the less than 20 pack-year range; after 25–30 pack-years of smoking, the dose-response relationship was similar to that for men.

The COPDGene study enrolled smokers with and without COPD at 21 clinical centers throughout the United States (ClinicalTrials.gov 2013). Participants were self-classified non-Hispanic Whites and African Americans 45-80 years of age with at least 10 pack-years of lifetime smoking. During the study visit, participants underwent spirometry, before and after inhaled bronchodilator, and completed detailed questionnaires on respiratory disease, medical history, and medications. Foreman and colleagues (2011) analyzed data from the first 2,500 individuals in the COPDGene study. Severe, early-onset COPD participants were predominantly women (66%), with proportionally higher rates in African American smokers; in addition to race and gender, maternal smoking and maternal COPD were also associated with severe, early-onset COPD.

Gender-Specific Morbidity and Mortality

Hospitalization rates for COPD have been approximately equal for men and women since 1995 (Akinbami and Liu 2011). However, during the period 1980–2000, annual death rates from COPD increased in men until about 1995 and then stabilized (Figure 7.4). Among women, death rates during this timeframe tripled and continued to increase. In 2000, 59,936 women died from COPD compared to 59,118 men (Mannino et al. 2002). In a more recent assessment of changes in mortality rates due to COPD (Ford et al. 2012), 5,185 individuals from NHANES I were evaluated at follow-up through 1993 (baseline exam 1971–1975, follow-up 1992–1993), and 10,954 participants from the NHANES III Linked Mortality Study (baseline 1988–1994) were followed up through 2006. Age-adjusted mortality rates among participants with moderate to severe COPD, compared to persons with normal spirometry, were higher in both NHANES I and NHANES III, although there was an overall decrease in mortality rates due to COPD in NHANES III compared to NHANES I. Specifically, in NHANES I and NHANES III, respectively, the age-adjusted mortality rates for COPD were 29.9 and 20.2 per 100,000, compared to the age-adjusted mortality rates of 10.4 and 6.2 in participants with normal spirometry. However, further highlighting previous epidemiologic trends, there was a decrease in the mortality rate among men with moderate or severe COPD (decreased by 17.8%) in contrast to the 3% increase in the mortality rate in women (Figure 7.5) (Ford et al. 2012).

Figure 7.4

Age-adjusted mortality rate from chronic obstructive pulmonary disease among adults 25 years of age or older, by gender, United States, 1968–2010. Source: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (more...)

Figure 7.5

Age-adjusted all-cause mortality rates per 1,000 person-years (95% confidence interval [CI]) for men and women 25–74 years of age in the United States by survey and Global Initiative for Chronic Obstructive Lung Disease classification. Source: (more...)

The most recent and comprehensive assessment of smoking-related mortality in the United States (Thun et al. 2013) evaluated temporal trends in gender-specific smoking-related mortality across three time periods (1959–1965, 1982–1988, 2000–2010) in seven large cohorts (see Chapter 12, “Smoking-Attributable Morbidity, Mortality, and Economic Costs”). In the “contemporary” cohort that encompassed the years 2000–2010, male and female current smokers had similar RRs for mortality from COPD (26.61 for men, 22.35 for women), with this RR for women representing almost a doubling of risk when compared to the 1982–1988 time period (Figure 7.6).

Figure 7.6

Changes in rates of death from chronic obstructive pulmonary disease over time among current women and men smokers in three time periods. Source: Thun et al. 2013. Reprinted with permission from Massachusetts Medical Society, © 2013. Note: Data (more...)

Genetics and Genomics of COPD

The first significant understanding of the role of genetics in the pathogenesis of COPD began with the 1963 discovery of the increased risk of obstructive lung disease associated with AAT (Laurell and Eriksson 1963). The role of genetic factors in COPD and susceptibility to cigarette smoke was reviewed in the 2010 Surgeon General's report (USDHHS 2010). This section focuses on recent advances in genetics and genomics made possible by the rapid advances in technology since the 2010 report.

Rare Genetic Syndromes with COPD

A small percentage of COPD patients (estimated at 1–2%) have severe AAT deficiency, a Mendelian syndrome often presenting as severe, early-onset COPD (Silverman and Sandhaus 2009). The genetic basis for severe AAT deficiency is well-understood; a relatively rare alteration in a single DNA nucleotide base in the SERPINA1 gene sequence causes a single amino acid change in the protein sequence of AAT at amino acid 342. This genetic variant is referred to as the PI*Z allele. Other even less common severe AAT deficiency variants lead to very low expression of the normal M protein (e.g., Mheerlen) or the absence of any AAT protein (e.g., Null alleles). Individuals that inherit two severe deficiency variants—most commonly genotype PI ZZ—are at substantially increased risk for early-onset COPD. Persons with the PI ZZ variant have been described as having lower lobe predominant panlobular emphysema, but a substantial fraction of those affected do not develop an emphysema distribution in this classic pattern (Parr et al. 2004). Severe AAT deficiency is found in approximately 1 in 3,000 Americans, with an increased prevalence in Whites (Silverman et al. 1989). Thus, the genetic variants explain little of the variation in risk for COPD among smokers in the population, but studies in affected individuals have provided important insights into how smoking causes COPD. The discovery of AAT deficiency was a major factor in the formulation of the protease-antiprotease hypothesis for the pathogenesis of COPD (Janoff 1985; USDHHS 2010). This hypothesis relates the development of COPD to an imbalance between the increased proteolytic activity in the lungs of smokers and the diminished activity of the opposing antiproteases, primarily AAT. The primary mechanism for increased COPD risk is likely the reduced plasma levels of circulating AAT in severely deficient persons, which relates to polymerization of the Z protein in the endoplasmic reticulum of hepatocytes (Lomas et al. 1992). However, the Z polymers, which are also detectable within the plasma and in lung tissue samples, appear to have pro-inflammatory activity, which could also contribute to the pathogenesis of COPD in persons with PI ZZ (Mahadeva et al. 2005).

Another SERPINA1 variant, the PI*S allele, leads to a moderate reduction in AAT protein levels; persons that inherit one PI*S allele and one PI*Z allele (PI SZ) are likely at increased risk for COPD (Turino et al. 1996)—although not to the same magnitude of risk as persons with PI ZZ. Whether persons with one normal and one severe deficiency SERPINA1 variant (e.g., PI MZ) are at increased risk for COPD has been a controversial issue for decades. In a meta-analysis published in 2004, Hersh and colleagues found that studies, which compared risk in COPD cases to controls, often showed an increased risk for the PI MZ genotype, while population-based studies did not demonstrate reduced spirometric values in persons with the PI MZ variant. Only a minority of the studies included in this meta-analysis provided results adjusted for cigarette smoking intensity. More recently, Sorheim and colleagues (2010) assessed COPD risk associated with PI MZ risk in the Genetics of Chronic Obstructive Lung Disease (GenKOLS) case-control study in Norway and in the International COPD Genetics Network, a family-based study. Although PI MZ was not associated with significantly increased risk for COPD, persons with the PI MZ variant had a significantly lower FEV₁/FVC ratio in both populations, and an increased risk for CT-defined emphysema was observed in the GenKOLS Study.

Although AAT deficiency is the most widely recognized Mendelian syndrome, which increases risk for COPD, other rare Mendelian syndromes have been studied as well. People with cutis laxa, a very rare syndrome with marked dermatologic manifestations related to skin laxity, can also develop early-onset emphysema due to mutations in several genes, including ELN (Corbett et al. 1994) and FBLN5 (Loeys et al. 2002). Although mutations in these cutis laxa genes do not commonly cause COPD, a rare functional variant in the ELN gene has been reported in several severe early-onset pedigrees (Kelleher et al. 2005; Cho et al. 2009).

Common Genetic Determinants of COPD

Several types of studies have suggested that genetic factors other than AAT deficiency and cutis laxa influence COPD susceptibility. Aggregation of pulmonary function and airflow obstruction was demonstrated beginning in the 1970s in studies in the general population and with twins (Lewitter et al. 1984; Redline et al. 1989). Based on data from familial aggregation analyses, linkage analysis studies were performed using panels of short tandem repeat markers in families from the Boston Early-Onset COPD study for both categorical and quantitative COPD-related phenotypes. These linkage analysis approaches, which have been highly successful in Mendelian syndromes, implicated several genomic regions that may contain susceptibility genes for COPD (Silverman et al. 2002a,b; Palmer et al. 2003). Within these linkage regions, SERPINE2 (DeMeo et al. 2006) and XRCC5 (Hersh et al. 2010) on chromosome 2q and SOX5 (Hersh et al. 2011) on chromosome 12p were suggested as possible COPD susceptibility genes. However, as with many other complex diseases, convincing replication of these linkage-based findings in multiple studies by different investigative groups has thus far been lacking. Therefore, the role of these linkage analysis regions and positional candidate genes remains to be determined.

Similarly, the results of many candidate gene association studies, which compared COPD cases and controls for the distribution of genetic variants within genes, typically selected based on their hypothesized roles in COPD pathogenesis, have been largely inconsistent (Castaldi et al. 2010). By contrast, the application of genome-wide association studies (GWAS) has unequivocally associated common variants in several genetic loci with COPD susceptibility (Table 7.1). Pillai and colleagues (2009) found genome-wide significant associations between COPD and single nucleotide polymorphisms (SNPs that are used as markers across the genome) in the CHRNA3/CHRNA5/IREB2 region on chromosome 15q25. Of interest, DeMeo and colleagues (2009) performed gene expression studies comparing normal and COPD lung tissues and identified SNPs to be tested for association with COPD in several studies. The association analyses identified IREB2 as a COPD susceptibility gene. In a GWAS based in the Framingham Heart Study (Wilk et al. 2009), the HHIP region was associated with FEV₁/FVC ratio, and this same region nearly reached genome-wide significance with COPD susceptibility in the study by Pillai and colleagues (2009). The FAM13A locus has been strongly associated with COPD susceptibility in multiple populations (Cho et al. 2010). In a collaborative GWAS, including four study populations (GenKOLS, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [ECLIPSE], National Emphysema Treatment Trial/Normative Aging study, and COPDGene), a fourth statistically significant link was found for a region on chromosome 19q (Cho et al. 2012).

Table 7.1

Genome-wide association studies of chronic obstructive pulmonary disease (COPD) and COPD-related phenotypes.

Several of these associations for COPD risk have been replicated in other studies. For example, participants with airflow obstruction were identified in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortium studies, and compared to controls with normal spirometry; a genome-wide significant association to the chromosome 15q25 region was found (Wilk et al. 2012). The HHIP and FAM13A associations with COPD have also been replicated in multiple studies (Van Durme et al. 2010; Young et al. 2010a,b; Soler Artigas et al. 2011). Thus, the frustration of inconsistent genetic association results in COPD over the past decade has been replaced by optimism regarding the likely importance of these GWAS-identified loci in COPD susceptibility.

A complicating issue in COPD genetic studies is the overwhelming influence of cigarette smoking on COPD susceptibility. In light of this large effect, most COPD genetics studies have only involved current or former cigarette smokers; however, this approach may have limited detection of gene-by-smoking interactions and hence the identification of those genes determining susceptibility in smokers. In a collaborative study in CHARGE and SpiroMeta of more than 50,000 individuals, genome-wide association analyses of FEV₁ and FEV₁/FVC ratio were performed with joint assessment of main SNP effects and SNP-by-smoking effects. Three novel genome-wide significant regions, on chromosomes 2, 6, and 17, were identified (Hancock et al. 2012).

It is possible that genetic determinants of COPD risk may act through genetic effects which may increase nicotine addiction or smoking intensity. In fact, both the chromosome 15q25 region (which includes genes of several components of the nicotinic acetylcholine receptor, i.e., CHRNA3 and CHRNA5) and the chromosome 19q region (which includes CYP2A6) have been associated with smoking pattern (Thorgeirsson et al. 2010; Tobacco and Genetics Consortium 2010). Additional research will be required to determine whether nicotine addiction is the mechanism that links these genetic loci to COPD susceptibility.

Genetic Determinants of COPD-Related Phenotypes

Studies of quantitative disease-related phenotypes may provide increased power to detect significant associations for genetic determinants for a complex disease. Several large-scale collaborative GWAS (CHARGE and SpiroMeta) have been highly successful at identifying multiple genomic regions that influence lung function levels in population-based samples (Hancock et al. 2010; Repapi et al. 2010). A combined analysis of CHARGE and SpiroMeta has identified 26 genome-wide significant regions associated with spirometric measures (Soler Artigas et al. 2011). Of interest, both the HHIP and FAM13A loci have been associated with lung function values in these general population samples; it is not yet clear how many of the other genomic regions, associated with lung function levels in the general population, also influence COPD susceptibility in smokers (Silverman 2012).

Kong and colleagues (2011) performed GWAS of CT-defined emphysema in three sets of COPD cases (Gen-KOLS, ECLIPSE, and NETT), using both radiologists' assessments of emphysema severity and quantitative densitometric measures of emphysema. Although the quantitative densitometric measurements of emphysema did not demonstrate any genome-wide significant associations, borderline genome-wide significant associations near the BICD1 gene were observed for the endpoint of the radiologists' visual assessment of emphysema severity.

Several GWAS of the rate of FEV₁ decline have been reported. Imboden and colleagues (2012) performed GWAS of FEV₁ decline in a collaborative study of general population participants, including separate analyses in 1,441 persons with asthma and 2,667 in persons who were not asthmatics. However, no significant associations with FEV₁ decline were found across the genome. When Hansel and colleagues (2012) studied FEV₁ decline within 4,048 persons with mild-to-moderate COPD in the Lung Health Study, two genome-wide significant regions were identified, but they were not replicated in other populations. Genetic association analyses in the ECLIPSE and International COPD Genetics Network studies suggested that the CHRNA3/CHRNA5/IREB2, HHIP, and FAM13A COPD GWAS loci influence different aspects of the COPD syndrome (Pillai et al. 2010). For example, the CHRNA3/5 locus was most strongly associated with emphysema, while the HHIP locus was associated with COPD exacerbation frequency.

Gene Expression Studies in COPD

In order to provide insight into the biological pathways involved in COPD pathogenesis, multiple studies have assessed genome-wide gene expression using RNA extracted from lung tissue samples in persons with COPD and controls. Four key lung tissue gene expression studies were compared by Zeskind and colleagues (2008). Ning and colleagues (2004) used both serial analysis of gene expression and microarray analysis in 14 smokers with moderate COPD and 12 smokers with normal spirometry. Golpon and colleagues (2004) studied gene expression using microarrays in 11 COPD cases (6 with AAT deficiency) and 5 controls. Spira and colleagues (2004a) compared lung tissue samples from 18 severe emphysema cases undergoing lung volume reduction surgery to samples from 12 persons with normal spirometry or mild airflow obstruction undergoing resection of a pulmonary nodule. Wang and colleagues (2008) obtained 48 lung tissue samples from persons with a range of spirometric abnormalities, who were undergoing surgical resection of a pulmonary nodule. All four of these studies identified multiple genes that showed significant differential expression between lung tissue samples from persons with COPD and controls, but only minimal overlap in the specific differentially expressed genes was observed across the four studies. This limited degree of replication could be related to several factors, including the small sample sizes of the studies, differences in the analytical approaches, and variation in inclusion and exclusion criteria for participant selection. Nonetheless, Zeskind and colleagues (2008) used pathway analysis to demonstrate that many of the differentially expressed genes observed in these four studies represented similar biological processes. Further evidence for concordance between different lung tissue gene expression studies was provided by Bhattacharya and colleagues (2009). They assessed lung tissue gene expression using both the presence and absence of COPD (15 COPD cases and 18 smoking controls) and quantitative spirometric measures (56 total persons), and found 254 differentially expressed gene biomarkers. A subset of 84 of these gene biomarkers was also assessed in the Spira and colleagues study (2004a), and this subset of biomarkers generated by Bhattacharya and colleagues was able to differentiate COPD cases versus controls in the Spira data set with 97% predictive accuracy.

Wang and colleagues (2008) showed that some of the variability in lung tissue gene expression resulted from variation in the cellular profiles included within the lung tissue sample. One approach to overcome this source of variability is to focus on a particular cell type, and several studies have focused on airway epithelial cells obtained at bronchoscopy. Spira and colleagues (2004b) pioneered this approach, and they identified genes that were differentially expressed within airway epithelial cells in response to smoking. Ammous and colleagues (2008) found substantial variability in gene expression within the small airways of smokers, suggesting that this distal sampling site could provide especially useful information about COPD pathogenesis.

Protein Biomarkers of COPD

The identification of biomarkers of lung destruction and inflammation in COPD has been a major research focus during the past 50 years (Yoon and Sin 2011; Rosenberg and Kalhan 2012). Yoon and Sin (2011) discussed the optimal characteristics of a COPD biomarker, which include having a close relationship to relevant health outcomes, playing an important biological role in disease, and demonstrating modifiability with effective treatment interventions. Since cigarette smoking induces lung inflammation, ideal COPD biomarkers would differentiate smokers with and without COPD.

This section briefly summarizes some of the key evidence related to the potential of several proteins and protein breakdown products as COPD biomarkers. Because COPD often involves destruction of lung parenchyma, development of biomarkers based on breakdown products of lung extracellular matrix components has been pursued. Desmosine and isodesmosine, specific degradation products of elastin, can be measured in the plasma and urine. Small studies have suggested that urinary desmosine levels are increased in response both to current smoking and to COPD (Stone et al. 1995). Clinical trials of AAT augmentation therapy in AAT-deficient persons did not demonstrate consistent effects on urinary desmosine levels (Luisetti et al. 2008). Part of the inconsistency in the results of these interventional trials could be related to technical difficulties in desmosine assays, and more recently developed mass spectrometry approaches may be more reliable (Ma et al. 2003). Mass spectrometry analysis was performed in a total of 390 individuals, including those with stable COPD, individuals with COPD during an exacerbation, and controls with normal spirometry (smokers and nonsmokers) (Huang et al. 2012). Significantly higher desmosine levels were found in blood samples from persons with stable COPD, compared to control smokers or nonsmokers, but urinary desmosine levels were not different when stable COPD cases and controls were compared. During COPD exacerbations, elevated urinary desmosine levels were observed. A more recently characterized degradation product of collagen, proline-glycine-proline, is chemotactic for neutrophils and has been suggested to have higher levels in both serum and induced sputum of persons with COPD than in nonsmoking controls (O'Reilly et al. 2009).

A variety of systemic markers of inflammation have been studied as potential COPD biomarkers. For example, with adjustment for ever smoking status and pack-years of smoking, elevated C-reactive protein (CRP) levels were associated with a significantly increased risk of incident COPD in the Rotterdam Study (van Durme et al. 2009). Of interest, the greatest effect of elevated CRP on COPD risk was observed among former smokers; nonsmokers were not at increased risk if CRP was elevated. Among 34 bloodstream biomarkers assessed in 201 COPD cases and 37 smoking controls from the ECLIPSE study, fibrinogen demonstrated a significantly higher mean level in COPD cases, compared with controls, and was the most reproducible biomarker in blood samples collected 3 months apart (Dickens et al. 2011). However, the relevance of these nonspecific inflammatory markers for COPD pathogenesis, and their response to treatment interventions, remains to be demonstrated.

Proteins synthesized within the lungs may have greater potential to serve as specific COPD biomarkers. Significantly increased serum levels of surfactant protein D (Lomas et al. 2009), decreased serum levels of Clara cell secretory protein 16 (CC16) (Lomas et al. 2008), and increased serum pulmonary and activation-regulated chemokine/chemokine liand-18 (PARC/CCL-18) (Sin et al. 2011) have been found in persons with COPD compared to smokers with normal spirometry. Of interest, treatment of persons with COPD with oral corticosteroids reduced serum surfactant protein D (Lomas et al. 2009) and PARC levels (Sin et al. 2011). In the longitudinal evaluation of lung function in the ECLIPSE study, CC16 levels were associated with both baseline FEV₁ level and change in FEV₁ over 3 years of observation (Vestbo et al. 2011).

Asthma

Asthma is one of the most common chronic respiratory diseases, affecting approximately 5–10% of the U.S. population (Moorman et al. 2007). The disease usually begins during childhood, but can start at any age. Childhood asthma may go into remission and then recur later in life. Asthma is characterized by variable airflow obstruction, which results in the symptoms of wheezing and dyspnea with exertion (National Asthma Education and Prevention Program 2007). In the modern conceptualization of asthma, chronic airway inflammation is the main underlying pathophysiologic abnormality that causes increased constriction of smooth muscles and decreased airway caliber and there can be an overlap between asthma and COPD (Figure 7.1). Chronic changes in the airway, referred to as airway remodeling, can lead to irreversible loss of lung function.

Exposures to allergens and environmental pollutants have long been recognized as factors that can cause or exacerbate asthma, particularly in vulnerable populations (Matsui et al. 2008). Allergic reactions to the antigens of dust mites, cockroaches, and cats have been widely cited as adverse factors in asthma, and both outdoor and indoor exposures to the byproducts of combustion have been linked to poor asthma control (National Heart, Lung, and Blood Institute 2007). This section reviews the accumulating evidence that active cigarette smoking contributes to both the incidence of asthma and its exacerbation.

Conducting epidemiologic studies of the effects of smoking and other environmental factors on asthma is a challenging undertaking. One of these challenges is the nature of asthma itself, which often remits and relapses over time. Indeed, many asthma patients have long periods of symptom-free intervals, only to have the disease return later in life. Consequently, establishing the clear temporal sequence between smoking and the initiation or exacerbation of asthma can be difficult. Moreover, a bias termed the healthy smoker effect may complicate epidemiologic studies of asthma and active smoking (Becklake and Lalloo 1990). This bias occurs when persons who have increased susceptibility to the health effects of smoking quit with relatively greater frequency than less susceptible persons, causing an overrepresentation in the remaining cohort of current smokers of those who are less likely to be affected. The topic of active smoking and asthma in children and adults was reviewed in the 2004 report of the Surgeon General (USDHHS 2004) and is updated in this section.

Tuberculosis

Tuberculosis (TB) was a leading cause of death in the United States at the start of the twentieth century, a time when cigarette smoking was just beginning to become popular among men. Although rates of TB and smoking are both continuing to decline in the United States, the two epidemics continue globally. More than 1.3 billion people worldwide smoke (World Health Organization [WHO] 2010), and estimates indicate that each year sees almost 9 million cases of incident TB and 1.3 million deaths from the disorder (Mathers and Loncar 2006). Moreover, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis (M. tuberculosis) and, therefore, is at risk of active TB disease. Annually, more than 30% of TB cases worldwide are diagnosed in China and India. These two countries account for more than 40% of the world's smokers (WHO 2008).

Smoking has long been considered a potential risk factor for TB mortality (Doll and Hill 1956), but only recently have large case-control and cohort studies shown that strikingly high rates of TB mortality are attributable to smoking (Jha et al. 2008). Several systematic reviews have assembled evidence of the association between smoking and TB (Davies et al. 2006; Bates et al. 2007; Chiang et al. 2007; Lin et al. 2007; Pai et al. 2007; Slama et al. 2007; WHO and International Union Against Tuberculosis and Lung Disease 2007). Each review found that cigarette smoking is associated with an approximate doubling of risk for TB infection, for having clinical evidence of TB disease, and for TB mortality. An analysis from WHO (2010) of the role of risk factors and social determinants in driving the global TB epidemic concluded that in the 22 countries experiencing 80% of the global TB burden, 23% of the cases can be attributed to smoking. The smoking-attributable burden of TB varies with the epidemiologic characteristics of the population, with the high attributable risks for smoking found in China and India, while HIV is the primary driver for the TB burden in sub-Saharan Africa (Lonnroth et al. 2010). To date, the series of Surgeon General's reports has not systematically assessed the association between smoking and TB.

Natural History of Tuberculosis

Figure 7.7 shows the natural history of TB from exposure to the organism and the initial infection through death from the disease. Figure 7.8 offers a closer look at the progression to active TB disease among persons exposed to M. tuberculosis. In brief, TB follows a two-stage process: infection of the host with M. tuberculosis and then the development of active disease (Golub et al. 2013). Infection occurs in an estimated 20–30% of close contacts of people with active disease, and within 2 years, active primary TB develops in 5–10% of those infected (Figure 7.8A) (Comstock et al. 1974; Comstock 1975). However, TB is a unique pathogen in that the first stage of this process can last a lifetime. In what is commonly referred to as latent TB infection, an intact immune system contains the primary infection in a dormant state. Over the course of an infected person's life, the risk that the dormant bacilli will progress to reactivation TB is 5–10% (Comstock et al. 1974; Comstock 1975). People who are immunocompromised have an altered prognosis after infection, with more than 40% experiencing early progression (Figure 7.8B) and the majority reactivating to TB disease later in life if untreated.

Figure 7.7

Natural history of tuberculosis from exposure to mortality. Source: Adapted from Rieder 1995 by the Center for Teaching and Learning with Technology, Johns Hopkins Bloomberg School of Public Health with permission from Springer Science & Business (more...)

Figure 7.8

Progression to active tuberculosis disease among persons exposed to M. tuberculosis. Source: Adapted from Parrish et al. 1998 with permission Elsevier, © 1998. Note: HIV = human immunodeficiency virus. Progression to active tuberculosis disease (more...)

Upon developing active TB disease, a small proportion of persons will spontaneously heal without treatment, but without treatment, the majority will ultimately die. Among persons who are treated for TB, treatment failure and/or recurrent disease are serious risks. Recurrence can result from endogenous reactivation of persistent TB bacilli (relapse) or from exogenous reinfection with a new TB strain.

Evidence Synthesis

Evidence on the relationship between smoking and TB needs to be assessed within the framework offered by the natural history of the infection. Smoking may have an effect at multiple stages of this natural history (Figure 7.7), and thus the evidence should be considered separately for the risks of TB infection, TB disease, recurrent TB disease, and TB mortality (see Table 7.9 for a summary of evidence from three systematic reviews on the association between smoking and three TB outcomes: infection, active disease, and mortality due to TB [van Zyl Smit et al. 2010]). This framework focuses on two questions: (1) Is the risk of incident TB infection higher in smokers than in nonsmokers, and (2) in persons with TB infection, does the course of TB infection differ between smokers and nonsmokers with regard to risk for TB disease, recurrence, and mortality?

Table 7.9

Meta-analysis of the association between smoking and latent tuberculosis (TB) infection, progression to active disease, and mortality from active TB.

TB Infection

The available studies consistently show that smokers are at a greater risk for TB than nonsmokers (RR = 1.2–2.7), but all but one of the studies are cross-sectional in design, leaving the temporality of causation ambiguous. Only the nested case-control study among TST converters found that smoking occurred prior to incident infection (Anderson et al. 1997). The literature has not consistently demonstrated dose-response relationships between TB infection and the number of cigarettes smoked per day or pack-years. Adjusting for alcohol consumption as a potential confounder reduced the strength of the association between tobacco and latent TB infection in a meta-analysis, but the association remained significant (Lin et al. 2007).

Biologic evidence supports the plausibility of increased risk for TB infection among smokers because tobacco smoke has been shown to cause mechanical disruption of ciliary function, alter mucociliary clearance in the airways (Arcavi and Benowitz 2004), and inhibit macrophage responses, thus increasing the likelihood that M. tuberculosis organisms reach the alveoli where TB infection begins (Altet et al. 1996). Although such factors as age, gender, and SES have also been associated with risk of TB infection, smoking has been shown to be an independent risk factor. Exposure to an infectious TB case is necessary for TB infection to occur, but collective evidence suggests that persons exposed to tobacco smoke, either actively or passively, are at greater risk of becoming infected with TB than those who are not exposed to tobacco smoke.

TB Disease

The evidence reviewed in this section implicates smoking as a cause of TB disease. The infectious organism that causes tuberculosis, M. tuberculosis, is, of course, the necessary cause of TB. However, other agents can increase risk for TB by acting to increase the risk for infection or by increasing the risk for disease in those who are infected. Within the framework for causal inference used in the Surgeon General's reports, such additional risk factors that are neither necessary nor sufficient have been interpreted as causal. For example, the 2004 report identified smoking as a causal risk factor for cervical cancer, while acknowledging the necessary role of human papilloma virus (USDHHS 2004). Cohort studies showed that human papilloma virus-infected women who smoked developed cervical intraepithelial neoplasia at a higher rate than nonsmokers. The evidence on smoking and TB is thus interpreted with recognition of the necessary role of M. tuberculosis.

The association between smoking and TB disease is consistent across studies, and findings from several prospective cohort studies confirm previous findings that were largely based on case-control studies. The association is found consistently across different populations and geographic regions, although the most informative studies have been conducted in Asian countries where smoking is common among men and TB disease remains frequent. Most studies have observed dose-response relationships with indicators of the extent of smoking, strongly suggesting that an increased number of cigarettes smoked per day, increased years of smoking, and earlier age at the start of smoking are all associated with increased risk for TB disease.

In interpreting the results of these studies, the main limitation is the incomplete consideration of some potential confounding factors, leaving the possibility of residual confounding. However, prospective cohort studies carried out by Jee and colleagues (2009) and Lin and associates (2009b) have controlled for age, gender, and alcohol use. Aside from smoking, SES has many correlates that are relevant to risk for TB disease, including nutrition, housing, and other exposures. Although various studies have measured SES in different ways, the association between smoking and risk for TB disease persists after adjusting for SES. The body of evidence is greater for pulmonary TB disease than for extrapulmonary TB (Lin et al. 2007). Finally, although research demonstrates a strong association between smoking and TB disease, it is still not clear whether the association reflects an increased risk of infection or of reactivation to active TB disease.

TB Recurrence

Only a few studies present evidence of an association between smoking and risk for recurrent TB disease (Table 7.7S). Unfortunately, when studying recurrent TB, differentiating between relapse due to treatment failure and reactivation of a subsequent infection with M. tuberculosis can be difficult. Studies with short follow-up of patients who have completed treatment—for example, the one by Thomas and colleagues (2005) in South India—suggest that relapse is more likely to occur among smokers than nonsmokers. Studies with longer follow-up are more likely than those with a short follow-up to include both TB cases from relapse and TB cases developing from exogenous reinfection; the former studies report a consistent twofold to threefold increased risk for recurrent TB associated with smoking. Temporality is inherent when investigating recurrent disease, but a dose-response relationship has not been reported. In the Korean cohort study by Jee and colleagues (2009), smoking increased the risk of recurrence by 30% in men but not significantly so in women, and a dose-response relationship with amount smoked was not observed. Overall, the evidence suggests a heightened risk for recurrent TB among smokers.

TB Mortality

The body of evidence for increased risk of mortality among TB patients who smoke has increased considerably over time. Smokers have a greater risk for TB mortality than nonsmokers because of a worsening of the natural history of TB in smokers. Additionally, the impairment of lung function caused by smoking, including the development of COPD, could increase the risk of death from respiratory failure. The several large case-control studies in India and China that have investigated deaths associated with smoking have consistently identified a strong association between smoking and TB mortality, with high attributable risks for smoking. Although most of the mortality evidence comes from studies in India and China, studies from Korea and South Africa provide similar results, suggesting that smoking increases risk for TB mortality across a range of settings in both low- and high-income countries. Two studies found a strong, positive dose-response relationship between number of cigarettes smoked per day and TB mortality (Liu et al. 1998; Lam et al. 2001), but the Korean study did not (Jee et al. 2009). The potential confounders included most commonly in these mortality analyses were age, gender, and education; three of the analyses controlled for alcohol use. Overall, the studies considered in this review consistently show an association between smoking and TB mortality, but the potential limitation among these studies of possible misclassification (in either direction) of TB deaths must be considered.

Idiopathic Pulmonary Fibrosis

The diffuse parenchymal lung diseases are a heterogeneous group of disorders of known and unknown causes with distinct clinicopathologic characteristics. Among these diseases, the evidence on risk associated with cigarette smoking has been variable. For example, cigarette smoking is associated with an increased risk for IPF, desquamative interstitial pneumonia, and interstitial lung disease but with a decreased risk for sarcoidosis and hypersensitivity pneumonitis (Travis et al. 2002; USDHHS 2004). The focus of the present review is on IPF, the most common and also the most severe of the idiopathic interstitial pneumonias (Raghu et al. 2011). This topic was reviewed in the 2004 Surgeon General's report, The Health Consequences of Smoking; at that time, the evidence was determined to be “inadequate to infer the presence or absence of a causal relationship between active smoking and IPF” (USDHHS 2004).

The prevalence of IPF is much lower than that of COPD (USDHHS 2004). The prevalence of IPF is estimated at only 2 to 43 cases per 100,000 persons (Coultas et al. 1994; Raghu et al. 2006, 2011), but IPF is likely underdiagnosed as well. These prevalence estimates reflect not only the low incidence of the disease but also the high case-fatality rate.

Impact of Smokefree Policies on Respiratory Outcomes

The evidence of the impact of smokefree policies within indoor environments on multiple health outcomes is reviewed in this and previous reports. In Chapter 8, “Cardiovascular Diseases” it was concluded that “The evidence is sufficient to infer a causal relationship between the implementation of a smokefree law or policy and a reduction in coronary events among populations under 65 years of age.” Previous Surgeon General's reports have concluded that exposure to secondhand smoke causes cough, phlegm, wheeze, and breathlessness among children; lower respiratory illnesses in infants and children; and the onset of wheeze illnesses and exacerbation of asthma among children and adults.

Despite the limited evidence for causal relationships between exposure to secondhand smoke and the risk for other acute and chronic respiratory diseases in adults, researchers have examined the consequences of the implementation of a smokefree law or policy for the number of hospital admissions for respiratory diseases. Eisner and colleagues (2005, 2009a,b) reported findings suggesting that chronic exposure to secondhand smoke increases the risk of COPD and is associated with exacerbation of respiratory symptoms. Evidence reviewed in the 2010 Surgeon General's report documented the mechanisms by which exposure to the complex chemical mixture of combustion compounds in tobacco smoke causes inflammation and oxidative stress. Flouris and Koutedakis (2011) reported results suggesting that exposure to secondhand smoke can produce adverse inflammatory and respiratory effects within 60 minutes of exposure and that these effects persist for at least 3 hours after the exposure. Earlier work by Flouris and colleagues (2009, 2010) provide additional evidence of the acute and short-term effects of exposure to secondhand smoke on lung functions and immune responses. Additionally, as previous Surgeon General's reports have reviewed (USDHHS 2006), the implementation of smokefree laws improves the respiratory health of bar and restaurant workers (Eisner et al. 1998; Menzies et al. 2006; Ayres et al. 2009; Wilson et al. 2012). Hence, there are biological and observational data suggesting that the implementation of smokefree legislation or policies could result in reduced respiratory symptoms and adverse respiratory events.

A recent review (Tan and Glantz 2012) and other recent papers (Vander Weg et al. 2012; Millett et al. 2013; Sims et al. 2013) found significant declines in hospitalizations for respiratory diseases, following the implementation of a smokefree law or policy. In a meta-analysis of 11 studies of smokefree laws covering workplaces, restaurants, and bars, Tan and Glantz (2012) reported a pooled RR of 0.76 (95% CI, 0.68–0.85) for hospital admissions for respiratory disease following the implementation of a smokefree law or policy, with the strongest effects found for asthma and lung infections (Figure 7.9). The 11 studies evaluate comprehensive smokefree laws covering workplaces, restaurants, and bars in countries (Ireland and Scotland), states (Arizona and Delaware), and the city of Toronto, Canada.

Figure 7.9

Forest plot for hospital admissions for respiratory disease following the implementation of a smokefree law or policy. Source: Adapted from Tan and Glantz 2012 with permission from Wolters Kluwer Health, © 2012. Note: CI = confidence interval; (more...)

Millett and colleagues (2013) found a significant decline in admissions for childhood asthma after the implementation of English smokefree legislation in July 2007 (adjusted risk ratio = 0.91; 95% CI, 0.89–0.93). The effect persisted over the first 3 years after implementation and was observed among children from different age, gender, and SES groups and among those residing in urban and rural locations in England. Sims and colleagues (2013) similarly evaluated the July 2007 English smokefree legislation and found that it was associated with a 4.9% (95% CI, 0.6%–9.0%) decline in emergency admissions for asthma in the adult population. Vander Weg and colleagues (2012) analyzed the patterns of hospital admissions for COPD, among Medicare beneficiaries 65 years of age and older, following the implementation of 938 smokefree laws passed by municipalities, counties, and states between 1991–2008. Adjusting for the trend of an increase in COPD admission rates, this analysis found a significant decline in COPD admission following smoking bans. However, in a smaller study in Rhode Island, Roberts and colleagues (2012) did not observe a decline in asthma admissions following the implementation of their statewide smokefree ordinance.

These results suggest that the relationship between acute and chronic exposure to secondhand smoke and respiratory disease outcomes merits further review and investigation. The lack of assessments of pre- and postexposure in almost all studies has been a limitation.

Evidence Summary

This chapter has reviewed updated evidence on COPD, a disease causally linked to smoking in the 1964 report. Mortality from COPD continues to rise, and smoking remains responsible for the majority of cases. For asthma, another obstructive lung disease, the evidence was found to be sufficient to infer that smoking is a cause of incident asthma in adolescents. The benefits of smoke-free policies have been shown previously for workers with asthma; evidence considered in this report points to a reduction in the admissions for respiratory diseases following implementation of a smokefree policy.

TB was once a leading cause of death in the United States. Now far less frequent in the United States, it remains prominent elsewhere and caused 1.4 million deaths worldwide in 2011 (WHO 2013). Evidence reported over the last decade is sufficient to lead to a conclusion that smoking increases the risk for TB and for dying from TB. For IPF, the evidence was suggestive of a causal association.

Implications

The evidence reviewed in this chapter reaffirms the potential for avoiding a substantial burden of respiratory disease through tobacco control. It reaffirms the possibility of avoiding much of the burden of COPD in the United States and reducing the occurrence of asthma in youth and young adults. Most significantly, the evidence considered here points to an opportunity to reduce the burden of disease and mortality from TB. Smoking has received little attention in relation to TB until recently. Smoking cessation should be integral to the management of the millions of people receiving treatment for this disease worldwide. Few etiological risk factors have been found for IPF; continued research on smoking and IPF is needed, given the potential to prevent another respiratory disease with a high fatality rate.

Chapter Conclusions

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Footnotes

1

Pack-years = the number of years of smoking multiplied by the number of packs of cigarettes smoked per day.