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Public Health Consequences of E-Cigarettes (2018)

Chapter: 11 Respiratory Diseases

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11 Respiratory Diseases Smoking of combustible tobacco products is the number one cause of chronic obstructive pulmonary disease (COPD) worldwide. Although the proportion of smokers has decreased over the past 25 years, approximately 1.1 billion people continue to smoke as of 2015 (Rabe and Watz, 2017). COPD leads to more than 3 million deaths per year worldwide, with only ischemic heart disease and cerebrovascular disease causing more deaths. Individuals who smoke also have an increased risk of sleep apnea and asthma exacerbations (Jayes et al., 2016). Respiratory complications from smoking can be further confounded by the increase in cardiovascular disease in individuals who smoke (Rabe and Watz, 2017). In addition to the adverse respiratory health effects caused by smoking combustible tobacco products, secondhand smoke (SHS) exposure has been reported to be associated with significant respiratory morbidities in non-users (Jayes et al., 2016). Tobacco smoke exposure (TSE) has been shown to increase the severity of asthma exacerbations in children exposed to SHS (Merianos et al., 2016). Exposure to tobacco smoke in utero has been associated with abnormalities in lung development and small airway dysfunction in school-age children, manifested by reductions in forced expiratory volume in 1 second (FEV1) and forced expiratory flow 25-75 percent (FEF25-75 percent) (den Dekker et al., 2015; Duijts et al., 2012; Hayatbakhsh et al., 2009). A study in China found that school-age children exposed to SHS had increased cough and decreased lung function compared with children not exposed to SHS (He et al., 2011) and a study from Finland found that children of mothers who smoked combustible tobacco cigarettes during pregnancy were more likely to have increased airway resistance than children of mothers who did not smoke (Kalliola et al., 2013). Postnatal exposure to tobacco smoke also has been associated with an increased risk of wheeze and upper and lower respiratory tract illnesses in exposed children compared with unexposed children (Jayes et al., 2016). Currently there is a lack of information regarding the short- and long-term effects of e-cigarettes on the respiratory system. This is due in part to the relative newness of the delivery system, the vast assortment of devices being used, and the variety of nicotine concentrations and flavorings that are currently available. Nevertheless, exposure of the lungs to various components of the e-cigarette aerosol could potentially damage the respiratory system or worsen preexisting lung disease through a variety of mechanisms (see Figure 11-1). For example, nicotine-containing e-cigarette aerosols have the potential to adversely impact several host defense mechanisms in the lungs. In a murine model, 7 nicotinic acetylcholine receptors ( 7nAChRs) were shown to regulate cystic fibrosis transmembrane conductance regulator 11-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

11-2 PUBLI HEALTH CONSEQU IC H UENCES OF E-CIGARET TTES FIGURE 11-1 Concep ptual framewo of plausib pathways, including me ork ble echanisms an intermediar nd ry outcomes, by which ex xposure to e-c cigarettes influ uences respir ratory disease e. NOTE: ACH = acetylc A choline recept tors; CFTR = cystic fibrosi transmemb is brane conducttance regulato or. (CFTR) activity in th airways. Exposure to nicotine dow a he E wnregulated 7nAChR a activity, which in turn impa aired CFTR function, ca ausing impair mucocil iary clearanc (MCC) (M red ce Maouche et al., 2013). In humans, CF n FTR dysfunc ction has bee shown to be associate with the d en ed development of t COPD an asthma hy nd yperresponsi iveness (Saint-Criq and Gray, 2017) Exposure t nicotine in ). to n tobacco smoke and e-cigarette ae s e erosols also has been rep h ported to imp cough (D pair Dicpinigaitiss, 2017; Dicpinigaitis et al., 2006; Sitkauskiene and Dicpin e S e nigaitis, 2010 Furtherm 0). more, nicotine has e been shown to downr regulate Th1 immune re 1 esponses to li ipopolysacch haride (Yanagita et al., 2012), coonsistent wit an immun th nomodulatory effect of n y nicotine on viral and bact terial clearan nce. In ndependent of nicotine, exposure to particulates and flavorin in e-ciga o e ngs arette aerosols could als potentially impair lung function. The presence of ultrafine particles ha been so y g T e e as measured in the aerosols of e-cig d garettes (Lau et al., 2017), and par ube rticulates in t submicro the on range hav the potential to damag airways and lung par ve ge a renchyma. A noted in C As Chapter 3, the e health ris from exp sks posure to parrticles will depend on the nature, not simply th size. d eir heir Neverthe eless, certain ultrafine pa n articles, whic encompas particle si ch ss izes less than 100 nm, ca n an cause DN damage, induce pro-inflammator cytokine e NA ry expression, a adversel affect the and ly immune system throu the prod ugh duction of fre oxygen ra ee adicals (Li et al., 2016). In addition, t inhalation of ultrafine particles has been repo n h orted to incre ease rate of aasthma exac cerbations (L et Li al., 2016) Flavorings in e-cigarettes may also alter cellul redox bal ). s o lar lances in the airways by e y PR REPUBLICA ATION COP UNCO PY: ORRECTED PROOFS D

RESPIRATORY DISEASES 11-3 increasing pro-inflammatory cytokines (Lerner et al., 2015), and high temperatures generated by e-cigarette devices may cause formation of formaldehyde, leading to toxic effects on the lungs (Geiss et al., 2015). In established smokers who are trying to quit or reduce combustible tobacco use, e-cigarettes may be less deleterious to the respiratory system when compared with exposure to combustible tobacco smoke (see Chapter 18). However, initiation of e-cigarette use by a person who has never smoked may cause harm to the respiratory system compared with never using e-cigarettes, particularly if initiation of e-cigarettes occurs at a young age. Therefore, understanding the health effects of e-cigarettes is dependent on the context of age, current and prior use of combustible tobacco products, and whether the user has preexisting lung conditions such as asthma and COPD. In addition, there is a need to examine the short- and long-term effects of secondhand and thirdhand e-cigarette aerosols on the respiratory health of non-users, who may inhale or come in contact with exhaled mainstream aerosol, which can settle on hard surfaces. Infants and preschool children who live with e-cigarette users may be at higher risk for secondary exposures because this age group spends much of their time in the residence of the smoker. Finally, exposure of the dual user to both combustible tobacco products and e-cigarette aerosols may cause unique health risks to the respiratory system. CHARACTERIZATION OF DISEASE ENDPOINTS AND INTERMEDIATE OUTCOMES In studying the effects of e-cigarette use on respiratory disease endpoints, an important question is whether or not e-cigarette use by itself can lead to the development of chronic respiratory conditions such as asthma and chronic obstructive lung disease or if e-cigarette use can worsen preexisting lung conditions compared with people who do not smoke. Additionally, researchers should determine if substitution of e-cigarettes for combustible tobacco use lessens the development of chronic respiratory conditions or lessens progression of preexisting lung conditions compared with people who continue to smoke. Because these respiratory disease endpoints may take years or even decades to realize, it becomes necessary to measure intermediate outcomes that may predict a disease state. The intermediate outcomes most relevant to the clinician include measurements of lung function and lung structure. The most common measurements of lung function include forced vital capacity (FVC), FEV1, FEV1/FVC ratio and FEF25-75 percent, with the latter three most useful in detecting presence and progression of obstructive lung diseases, such as asthma and COPD. These measurements are easily obtainable using spirometry. Body plethysmography can be used to detect an increase in residual volume, which can correlate with worsening airflow obstruction. In addition, impulse oscillometry can be used to detect changes in large and small airway resistance, and may be more sensitive than spirometry in detecting reversibility of airway obstruction in people with COPD (Saadeh et al., 2015). Structural changes in the lung such as the development of emphysematous changes or mucus plugging can be determined using computed tomography (CT) of the chest. Ultra-low dose CT (Messerli et al., 2017) and more recently, MRI of the chest, has been shown to be an alternative modality to conventional chest CT in assessing COPD changes (Saadeh et al., 2015; Washko et al., 2012). Finally, standardized respiratory questionnaires can be helpful in evaluating outcomes, however instrument responsiveness may differ among questionnaires (Puhan et al., 2006). Research on other intermediate outcomes on respiratory health should include the effect of e-cigarette aerosols, with and without nicotine, on cough reflex sensitivity, PREPUBLICATION COPY: UNCORRECTED PROOFS

11-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES urge to cough, and nasal MCC because cough and MCC are integral defense mechanisms that help clear pathogens and environmental pollutants from the lungs and sinuses (Chatwin et al., 2003; Lee et al., 2017; Tarrant et al., 2017). Quantification of inflammatory cell numbers from bronchoalveolar lavage (BAL) (Levanen et al., 2016; Siew et al., 2017) and measurement of pro-inflammatory cytokines from bronchial biopsies (Shields et al., 2017) could be used as intermediate respiratory endpoints to assess inflammation in the lower respiratory tract inflammation caused by e-cigarette use. In addition, combustible tobacco smoke has been shown to alter microbiome diversity; therefore, examination of sputum, nasal, and pharyngeal microbiome diversity (Diao et al., 2017) may also help predict the impact of e-cigarette use on respiratory health. Other intermediate outcomes that could be used as markers of respiratory health include self-reported wheeze, bronchitis, shortness of breath, mucus production, other respiratory symptoms, and quality of life measurements. OPTIMAL STUDY DESIGN Since the potential health effects of e-cigarettes on the respiratory system are not completely understood, randomized controlled trials (RCTs) would not be appropriate at this time. Alternatively, prospective cohort studies that assess respiratory health outcomes in e-cigarettes users compared with combustible tobacco users and dual users could help determine the risks and benefits of using e-cigarettes. In addition, RCTs testing the efficacy of e-cigarette substitution as a method of smoking cessation in smokers unable to quit using nicotine replacement therapy (NRT) could concurrently measure lung function, lung structure, lung symptoms, and quality of life in individuals substituting e-cigarettes for combustible tobacco products. These additional studies could provide valuable information regarding the respiratory health effects of e-cigarette substitution on established smokers and help determine if switching completely or partly to e-cigarettes from combustible tobacco products in people with preexisting lung disease, can alter progression or stability of lung disease. Prospective cohort studies in adolescents and young adult e-cigarette users without a history of combustible tobacco product use should be performed to determine the likelihood of e-cigarette leading to the development of chronic respiratory symptoms or decline in lung function. Furthermore, since asthma is a common respiratory disease of childhood, it is also important to determine in adolescents and young adults with asthma are at increased risk for asthma exacerbations and a more rapid decline in lung function when using e-cigarettes. Consideration of potential confounding factors, such as dual tobacco or cannabinoid use, exposure to secondhand smoke and prior history of tobacco use could introduce bias into the comparisons across exposure groups and needs to be considered. Rigorous, objective assessment of the spectrum of endpoints, including lung function, respiratory symptoms, and cardiovascular and other co-morbidities would also be essential to these studies. QUESTIONS ADDRESSED BY THE LITERATURE Due to the relatively recent widespread acceptance of e-cigarettes, there is a lack of understanding regarding the positive and negative effects of e-cigarettes on respiratory health. This is due in part to the paucity of long-term observational studies in adolescent/young adult never-smokers who initiate e-cigarette use and observational studies and RCTs in adult smokers PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-5 who switch to e-cigarettes for smoking cessation. Human studies are also needed that examine how exhaled mainstream aerosols affect the respiratory system of non-users when inhaled. As previously noted, exposure to these aerosols may disproportionately impact infants and children in the homes of indoor e-cigarette users because the very young often spend the majority of their time in this environment. However, since e-cigarettes, unlike combustible tobacco products, lack substantial side-stream emissions, it is unclear how detrimental exposure to second-hand e-cigarette emissions is to the non-user. Further investigations into the effects of e-cigarette aerosols on the lung defense mechanisms such as cough, MCC, and the innate and adaptive immune system are needed. In addition, a better understanding of the impact of particle size on the development of DNA damage in respiratory cells is needed as is the relationship between flavorings and development of reactive oxygen species. CLINICAL AND EPIDEMIOLOGICAL STUDIES IN HUMANS Effects on Users of Combustible Tobacco Products The literature search identified 17 studies that examined respiratory or pulmonary outcomes in people using e-cigarettes (see Table 11-1). Subjects in these studies include adult users of combustible products who switch to e-cigarettes completely or become dual users and include subjects with or without preexisting respiratory disease. Outcomes in the studies include standard measures of function ranging from self-reported symptoms of cough to asthma to exhaled carbon monoxide or nitric oxide. Six of these studies were from the same study group (Campagna et al., 2016; Cibella et al., 2016; Polosa et al., 2014a,b, 2016a,b). Three of these studies were observational studies in which the subject population included smokers not intending to quit. These subjects were invited to switch to first generation e-cigarettes (Campagna et al., 2016; Cibella et al., 2016; Polosa et al., 2014b). Cibella and colleagues reported significant improvement in self-reported respiratory symptoms of cough/phlegm at 52 weeks in smokers who switched completely to e-cigarettes (18 of 130 subjects) and a significant increase in FEF25-75 percent, but not in FEV1 or FVC. No difference in lung function was found in dual users at 52 weeks (Cibella et al., 2016). In a similar study population of smokers not intending to quit, Campagna found significant decreases in the fractional concentration of carbon monoxide in exhaled breath (FeCO) in smokers who switched completely to e-cigarettes (18 of 134 subjects) and significant increases in the fractional concentration of nitric oxide in exhaled breath (FeNO) at 52 weeks (Campagna et al., 2016). Polosa and colleagues reported on 40 smokers not intending to quit, 17 of whom were lost to follow-up, and found that when invited to use e-cigarettes 5 of the 40 switched completely to e-cigarettes at 24 months (Polosa et al., 2014b). In two studies from Polosa and colleagues (2014a, 2016a), they identified retrospectively 18 mild to moderate asthmatic smokers who switched to e-cigarettes (either single or dual users). They reported an improvement in FEV1, performance in the methacholine challenge test, and asthma control questionnaire but no change in asthma exacerbations when these subjects were followed prospectively over a 12-month period (Polosa et al., 2014a, 2016a). In a similar study design, Polosa and colleagues (2016b) identified patients with COPD from medical records who switched to e-cigarettes (single or dual users) and reported that they had significantly fewer COPD exacerbations. D’Ruiz and colleagues (2017) reported on pulmonary function tests in PREPUBLICATION COPY: UNCORRECTED PROOFS

11-6 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES smokers who were switched to e-cigarettes for 5 days and found no significant difference in lung function between the groups. These studies suggest that smokers with preexisting lung conditions such as asthma and COPD may experience some benefits from switching to e-cigarettes. As reported in the Polosa studies (Polosa et al., 2016a,b), such benefits may include an increase in FEV1, improved performance in a methacholine challenge test and in asthma control, and a decrease in COPD exacerbations. However, a limitation of these studies is that they were performed in a small number of subjects selected retrospectively. In addition, a reasonably highquality randomized control trial was negative: Cravo and colleagues (2016) reported in a clinical study that recruited subjects from two centers in the United Kingdom, no difference in lung function in subjects who switched to e-cigarettes. Their study had two cohorts. In both cohorts, smokers were randomized to either change to e-cigarettes containing 2 percent nicotine (with or without menthol flavoring) or to continue smoking. The authors reported no significant changes in pulmonary function tests after 12 weeks between the two groups. In this study, smokers with respiratory conditions were excluded from the study and subjects in the e-cigarette randomized arm, although encouraged not to use combustible tobacco cigarettes, did often report dual use (Cravo et al., 2016). Taken together the majority of studies in the literature examining respiratory outcomes of e-cigarette use and their benefit on respiratory function in current smokers come from the same region of Italy, which limits generalizability of their results. In addition, with the exception of the study by Cravo and colleagues (2016), the sample sizes were generally small and subjects were selected retrospectively. Acute Exposures Two studies focused on the short-term effects of e-cigarettes on exhaled breath measurements (FeCO and FeNO) and pulmonary function tests. The first study examined the effects of nicotine-free e-cigarettes on lung function and exhaled breath measurements. Ferrari and colleagues (2015) recruited 10 smokers and 10 non-smokers and found no significant decline in lung function after 5 minutes in the subjects using nicotine-free e-cigarettes by contrast to subjects who smoked combustible tobacco cigarettes. Vardavas and colleagues recruited healthy smokers and found that after 5 minutes of using a nicotine-containing e-cigarette, airway flow resistance increased and FeNO decreased from baseline (Vardavas et al., 2012). Although the mechanisms underlying the lower FeNO in e-cigarette users are unclear, smokers also have been shown to have low FeNO levels compared with non-smokers (Malinovschi et al., 2012; Torén et al., 2006). This suggests that the mechanisms that cause lower FeNO in e-cigarette user are similar to those which causes lower FeNO levels in smokers. Although higher FeNO levels have been demonstrated in people with eosinophilic-induced asthma and considered a marker of airway inflammation (Malinovschi et al., 2012), studies of subjects with other respiratory conditions including cystic fibrosis have reported lower FeNO levels possibly associated with impaired CFTR function (Korten et al., 2018). Cough and Mucociliary Clearance Airway exposure to nicotine has also been implemented as a causal factor in inhibiting cough and MCC defenses (Dicpinigaitis et al., 2016a; Laube et al., 2017; Maouche et al., 2013). Specifically, nicotine may modulate perceptual and motor responses to irritant cough stimulants (capsaicin), inhibiting the urge to cough (Davenport et al., 2009). Three studies reported on the PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-7 effects of e-cigarettes on cough and nasal MCC (Dicpinigaitis, 2017; Dicpinigaitis et al., 2016a,b; Kumral et al., 2016). In a randomized single-blind clinical trial, Kumral and colleagues (2016) measured Sino-Nasal Outcome Test (SNOT-22) scores and nasal MCC of subjects recruited from a smoking cessation clinic in which they were assigned to either e-cigarettes or non-e-cigarette cessation therapy. At 3 months, subjects assigned to the e-cigarette group had significantly worse sino-nasal symptoms and nasal MCC than subjects assigned to the non-e-cigarette group (Kumral et al., 2016). Two studies from Dicpinigaitis and colleagues (2016a,b) recruited healthy adult non-smokers. Subjects were challenged with capsaicin at baseline and then at 15 minutes and 24 hours after a short exposure to nicotine-containing or non-nicotine-containing e-cigarettes. They found that urge to cough as measured by capsaicin challenge was depressed at 15 minutes following nicotine-containing e-cigarettes, but not nicotine free e-cigarettes. At 24 hours after nicotine-containing e-cigarette use, cough reflex sensitivity returned to baseline (Dicpinigaitis et al., 2016b). Dicpinigaitis and colleagues (2016a) also reported that nicotine-containing e-cigarettes caused a decrease in cough reflex sensitivity (C5), analyzed using mixed-effects modeling, at 15 minutes, after nicotine-containing e-cigarette use but not in nicotine free e-cigarettes. Dicpinigaitis (2017) again highlighted the role of nicotine causing centrally mediated suppression of cough in a study in which he reported suppression of cough at 15 minutes after capsaicin challenge in both combustible tobacco users and users of nicotine-containing e-cigarettes. Following cessation of combustible tobacco cigarette smoking, this centrally mediated cough reflex returned (Dicpinigaitis, 2017). Respiratory Symptoms in Adolescents Four studies examined respiratory symptoms in adolescents using or who have used e-cigarettes. Using self-reported questionnaires from participants in the Southern California Children’s Health Study, McConnell and colleagues (2017) found a significant association between increased rates of chronic bronchitis symptoms among past, but not current, e-cigarette users over the previous 12 months. Cho and Paik (2016), using a web-based questionnaire in a population of high school students from South Korea, found that students who used e-cigarettes were more likely to have a self-reported doctor diagnosis of asthma and were more likely to have been absent from school due to severe asthma symptoms. Using an anonymous questionnaire in Chinese adolescents in Hong Kong, Wang and colleagues (2016) reported a higher rate of respiratory symptoms in those who used e-cigarettes regardless of previous or current history of smoking and observed that adolescents who used e-cigarettes had more days absent from school because of asthma. Choi and Bernat (2016) examined the prevalence of ever and past 30-day use of e-cigarettes in adolescents, using the 2012 Florida Youth Tobacco Survey. They reported an association between past 30-day e-cigarette use and having an asthma exacerbation in adolescents with asthma. Interestingly, adolescents with asthma in this study were more likely to have used in e-cigarettes ever and in the past 30 days compared with adolescents not diagnosed with asthma. IN VIVO ANIMAL STUDIES AND IN VITRO MECHANISTIC STUDIES Animal studies in combination with in vitro studies have provided some unique insights into the potential health effects associated with e-cigarette use. Larcombe and colleagues (2017) exposed 4-week-old female BALB/c mice to 8 weeks of either tobacco smoke or propylene PREPUBLICATION COPY: UNCORRECTED PROOFS

11-8 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES glycol (PG) or glycerin e-cigarette solutions with and without nicotine. They found that mice exposed to tobacco smoke had increased pulmonary inflammation and changes in pulmonary function, including methacholine hyperresponsiveness. Although inflammation was not increased in the e-cigarette exposed mice, pulmonary function abnormalities were found. A limitation to the study is that they excluded male mice from analysis. Garcia-Arcos and colleagues (2016) examined the effects of aerosolized nicotine-free and nicotine-containing e-cigarette fluid via inhalation in mice and normal human airway epithelial cells. Exposure in mice was for 1 hour per day for 4 months. Human bronchial epithelial (HBE) cells were cultured at an air–liquid interface with exposure to e-cigarette aerosols or nicotine solutions. Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD, including increased airway hyperreactivity, distal airspace enlargement, mucin production, and cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters, suggesting effects were nicotine dependent in the mouse lung. These effects were also nicotine dependent in human airway cells in culture, further suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Exposure of HBE cells to nicotine-containing e-cigarette fluids also demonstrated impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator, and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. The major concerns for this study include the matter of aerosolization and the dose delivered to animals by inhalation compared with human use, as well as the dose delivered to cells in culture versus actual exposure conditions in vivo (Garcia-Arcos et al., 2016). Acute exposure to e-cigarettes compared with combustible tobacco cigarette smoke has been studied by Husari and colleagues (2016). Mice were exposed for 6h/d to air, e-cigarette or combustible tobacco cigarette smoke for 3 days with higher particulate levels for e-cigarettes compared with combustible tobacco cigarette smoke. Human alveolar cells (A549) in culture were also exposed to various concentrations of e-cigarette aerosol and combustible tobacco cigarette smoke extracts. The authors found a significant increase in interleukin-1 (IL-1) beta with exposure to e-cigarette, while combustible tobacco cigarette smoke resulted in significant increases in IL-1 beta, IL-6, TNF-alpha expression, and oxidative stress. TUNEL staining demonstrated significant cell death in combustible tobacco cigarette smoke, but not with exposure to e-cigarettes. Concerns for this study includes the manner of exposure delivery to animals and the relevance of the A549 cell test results to the assessment of human implications for health (Husari et al., 2016). Lim and Kim (2014) examined e-cigarette cartridge solution and its potential to aggravate allergen-induced airway inflammation and hyperresponsiveness in BALB/c mice. These investigators used diluted e-cigarette cartridge solution, which was delivered to mice by intratracheal instillation two times a week for 10 weeks. The mice had been previously sensitized to ovalbumin (OVA) by intratracheal, intraperitoneal, and aerosol allergen challenge. E-cigarette exposure increased infiltration of inflammatory cells, including eosinophils into airways; enhanced the asthmatic AI and airway hyperresponsiveness; and stimulated cytokine production of IL-4, IL-5, and IL-13, as well as OVA-specific IgE production. These data suggest e-cigarette solutions can exacerbate allergy-induced asthma symptoms. This study is limited by its use of intratracheal instillation of dilute e-cigarette solution rather than true delivery of e-cigarette exposure by inhalation. PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-9 Hwang and colleagues (2016) examined the effects of e-cigarette inhalation on immune function. Mouse inhalation of e-cigarette aerosols were done 1 hour daily for 4 weeks, leading to alterations in inflammatory markers within the airways and elevation of an acute-phase reactant in serum. Exposure of human epithelial cells at the air–liquid interface to aerosols from an e-cigarette device resulted in dose-dependent cell death; in mice, reduced antimicrobial activity against SA in epithelial cells, alveolar macrophages, and neutrophils were observed. The authors concluded that inhalation of e-cigarette aerosols alters immunomodulatory cytokines in the airways of mice and increases markers of inflammation in BAL and serum, thus enhancing the virulence of Staphylococcus aureus. Although observations of e-cigarette impact are similar in mice and cells in culture, the actual mechanisms based on dose are difficult to ascertain (Hwang et al., 2016). Additional studies by Sussan and colleagues (2015) also questioned how e-cigarettes may impair antibacterial and antiviral defenses in mice. They found e-cigarette aerosol exposure for 2 weeks produced a significant increase in oxidative stress and moderate macrophage-mediated inflammation, and significantly impaired pulmonary bacterial clearance, compared with air-exposed mice, following an intranasal infection with Streptococcus pneumonia. For mice infected with influenza A virus, e-cigarette exposure was associated with increased lung viral titers and enhanced virus-induced illness and mortality. These findings demonstrate that e-cigarettes may impair the immune response and enhance susceptibility to bacterial and viral infections (Sussan et al., 2015). Laube and colleagues (2017) exposed 10-week-old male mice to e-cigarette aerosol containing PG alone or PG in combination with nicotine for 20 minutes per day for either 1 or 3 weeks. Following exposure, mice were examined for MCC using technectium-labeled sulfur colloid with clearance of the colloid determined using an X-SPECT gamma camera. The research showed that daily exposure for 3 weeks to PG and nicotine slowed MCC compared with exposure to PG alone. This finding supports the potential biological plausibility for the previous study by Sussan and colleagues (2015), which also used mice and showed impaired bacterial clearance in the lungs of mice. Together, these studies provide evidence that exposure to e-cigarette aerosols during adolescence and early adulthood is not harmless to the lungs and can result in significant impairments in lung function even in the absence of lung inflammation. Toxicity, oxidative stress, and inflammatory response in mice and human airway epithelial cells were examined by Lerner and colleagues (2015). E-cigarette exposure in C57BL/6J mice increased pro-inflammatory cytokines, while diminishing glutathione levels in the lungs, critical in maintaining a balance of cellular redox in the lungs. E-cigarette aerosol exposure of human airway epithelial cells (H292) in an air–liquid interface system resulted in increased secretion of inflammatory cytokines IL-6 and IL-8. Delivery of unaerosolized e-liquids was also found to be oxidative dependent on flavor additives. They found flavors containing sweet or fruit flavors to be stronger oxidizers than tobacco flavors. Thus, exposure to e-cigarette aerosols/juices produces measurable oxidative and inflammatory responses in lung cells and tissues that might lead to unrealized health consequences. Concerns for this study are minimal, but include the methods of delivery to cells in culture and the extrapolation of in vitro results to humans. E-cigarette exposure has been found to have potential implications on the larynx as well. Salturk and colleagues (2015) found that exposure of Wistar albino rats to e-cigarette aerosol for 1 hour per day for 4 weeks caused hyperplasia and metaplasia of the laryngeal mucosa of rats, but this finding was not statistically significant. This study, although interesting, is inconclusive PREPUBLICATION COPY: UNCORRECTED PROOFS

11-10 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES as to the relevance of how possible health effects to the larynx should be considered in e-cigarette use. Laube and colleagues (2017) examined MCC changes in C57BL/6 mice after 3 weeks of daily exposure and found that young adult male mice exposed to PG alone had significantly higher MCC than mice exposed to nicotine/PG aerosol. This study suggested that chronic exposure to nicotine-containing e-cigarette aerosols can impair airway MCC. A 90-day inhalation study in rats, followed by a 42-day recovery period, was conducted by Werley and colleagues (2016). Exposure was done with low-, mid-, and high-dose levels of aerosols composed of vehicle (glycerin and propylene glycol mixture); vehicle and 2.0 percent nicotine; or vehicle, 2.0 percent nicotine, and flavor mixture. Daily targeted aerosol total particulate matter (TPM) doses of 3.2, 9.6, and 32.0 mg/kg/day were achieved by exposure to 1 mg/L aerosol for 16, 48, and 160 min, respectively. Treatment-related effects following 90 days of exposure included changes in body weight, food consumption, and respiratory rate. Also observed were dose-related decreases in thymus and spleen weights, and increased BALF lactate dehydrogenase, total protein, alveolar macrophages, neutrophils, and lung weights. This study in rats provides some insight for establishing a threshold level based on body-weight decreases at the mid-dose level for each formulation, equivalent to a daily TPM exposure dose of approximately 9.6 mg/kg/day. Histopathology changes appear to be isolated to the nasal mucosa. Concerns for this study include how to extrapolate these findings to human exposure and the relevance of the e-cigarette device used and non-respiratory parameters used for comparison. Further, lung weights and body weights are crude measures of effect. One study reported that neonatal exposure to aerosol from nicotine-containing e-cigarettes was associated with diminished alveolar cell proliferation and impairment in postnatal lung growth (McGrath-Morrow et al., 2015). SYNTHESIS AND CONCLUSIONS The human observational studies examining the effect of switching to e-cigarettes (single or dual use) provide support for a finding of beneficial health effects relative to continued use of combustible tobacco products, with most favoring that conclusion. These studies were judged to be of fair quality. A major limitation of them, however, is that they are primarily from a single study group. In addition, the one randomized control trial was negative, finding no improvement in lung function after 12 weeks in subjects who switched to e-cigarettes compared with people who continued to smoke combustible tobacco cigarettes (Cravo et al., 2016). Therefore, the committee concludes that there is limited evidence supporting improvements in lung function in smokers who switch to e-cigarettes. Studies examining the long-term effects of e-cigarettes on the development of chronic respiratory symptoms are completely lacking due to the newness of the product. It is of importance to know whether chronic e-cigarette use by itself can cause COPD and if substitution of e-cigarettes for combustible tobacco products can prevent or slow the development of COPD in smokers who quit or reduced use of combustible tobacco products. At this time, there is a lack of well-designed epidemiological studies examining either question. Studies examining the short-term effects of e-cigarettes indicate that nicotine-containing e-cigarettes, but not nicotine-free e-cigarettes, can have short-term adverse effect on lung defense mechanisms, including MCC, urge to cough, and cough sensitivity. These studies are of fair quality. They include subjects with and without a history of smoking and there are few-to-no PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-11 credible opposing findings. These studies provide moderate evidence supporting short-term adverse effect of nicotine-containing e-cigarettes on lung defense mechanisms. The committee identified four studies examining the effects of e-cigarette use on adolescent respiratory health—all are cross-sectional and use self-reported questionnaires. They include large groups of adolescents from three countries and reach similar results, thus providing moderate evidence of an association between respiratory symptoms in adolescents and e-cigarette use. In non-users who are exposed to secondhand smoke and in healthy adolescents and young adult users, common respiratory endpoints can include an increase in asthma symptoms and severity and a higher prevalence of upper and greater lower respiratory tract symptoms and infections (Liu et al., 2016; Shargorodsky, 2016; Shargorodsky et al., 2015; Wilson et al., 2013). Currently, there is a lack of rigorously designed epidemiologic studies examining the relationship between chronic e-cigarette use in adolescents and young adults and increased prevalence of respiratory symptoms and respiratory illnesses. There are also no epidemiologic studies reporting on the respiratory effects of exposure to exhaled mainstream smoke from an e-cigarette user on a non-user. The animal studies that have examined the effects of e-cigarettes on respiratory outcomes have used different e-cigarette devices, pumps, solutions, and exposures, limiting the ability to compare results among studies. Confounding factors such as aerosol temperature and particle size have not been taken into account. These methodological differences among studies can result in differences in particle deposition in the lung and differences in systemic absorption of particles, nicotine, and toxins, resulting in different respiratory outcomes. In addition, not all studies evaluating the effects of nicotine aerosols on lung inflammation, MCC, and lung immune responses have included biomarkers of systemic nicotine absorption, which would help to standardize exposures in animal studies. The utility of studies using whole-body exposures in animal studies when examining health effects of e-cigarette aerosols is limited because this type of exposure may overestimate or underestimate an exposure in the human condition. Furthermore, in vitro cell studies would be more informative and representative of the human condition if aerosols rather than liquid e-cigarette solutions are used and if primary and not immortalized cell lines are used. Despite these limitations, the animal and in vitro studies described provide additional evidence of adverse effects of e-cigarette exposure on the respiratory system and do not change the committee’s conclusions regarding the evidence of human health effects. There is coherence across studies in humans, animals, and in vitro systems regarding the effect of e-cigarette exposure and respiratory symptoms. This adverse effect on respiratory symptoms is likely associated with an increase in cellular inflammation and oxidative stress and decreased cough reflexes and MCC. The observation that past e-cigarette use was associated with an increase in chronic bronchitic symptoms in adolescents and an increase in school absenteeism from asthma symptoms in current e-cigarette user is potentially concerning since a more rapid decline in lung function in later life has been linked to asthma and chronic bronchitis in early life (Bernal et al., 1989; Vestbo and Lange, 2016). In addition, there is limited evidence to indicate that e-cigarette substitution for tobacco product use in established smokers is associated with a decrease in cellular oxidative stress and improved respiratory symptoms and lung function. Conclusion 11-1. There is no available evidence whether or not e-cigarettes cause respiratory diseases in humans. PREPUBLICATION COPY: UNCORRECTED PROOFS

11-12 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Conclusion 11-2. There is limited evidence for improvement in lung function and respiratory symptoms among adult smokers with asthma who switch to e-cigarettes completely or in part (dual use). Conclusion 11-3. There is limited evidence for reduction of COPD exacerbations among adult smokers with COPD who switch to e-cigarettes completely or in part (dual use). Conclusion 11-4. There is moderate evidence for increased cough and wheeze in adolescents who use e-cigarettes and an association with e-cigarette use and an increase in asthma exacerbations. Conclusion 11-5. There is limited evidence of adverse effects of e-cigarette exposure on the respiratory system from animal and in vitro studies. VULNERABLE/SUSCEPTIBLE POPULATIONS Chronic Obstructive Pulmonary Disease Despite a number of studies, the results are unclear about whether use of e-cigarettes as a substitute for combustible tobacco use in people with COPD may be beneficial, neutral, or harmful. Harm may occur if e-cigarette use prevents the smoker from quitting entirely and instead prolongs the use of combustible tobacco products through dual use. Harm may also occur in an individual with COPD if single use of an e-cigarette as a substitute for combustible tobacco cigarettes causes additional airway inflammation in already damaged lungs. No studies have examined whether e-cigarette use alone can cause lower respiratory tract (LRT) inflammation in healthy adults or increase or decrease existing LRT inflammation in adults with COPD. If the use of e-cigarettes in a smoker with COPD can reduce use of combustible tobacco products and can decrease lung inflammation secondary to the reduction of exposure to toxicants found in combustible tobacco smoke but not e-cigarettes, this could be beneficial to the patients with COPD. In addition, individuals with COPD who failed or who are resistant to conventional NRT or other cessation strategies may be more willing to use e-cigarettes to quit smoking. Asthma and Other Respiratory Diseases of Childhood Asthma is one of the most common chronic respiratory diseases in the United States and is prevalent in young children and adolescents. In recent years since the introduction of e-cigarettes in the United States, substantial numbers of adolescents have tried and have used e-cigarettes (Backinger, 2017; HHS, 2016; Jamal et al., 2017; Kann et al., 2016; Miech et al., 2017). Recent longitudinal studies have shown that children with asthma may have an accelerated decline in lung function as they age (Martinez, 2016). Smoking and other environmental exposures, including air pollution, can increase severity of asthma symptoms and these exposures have been associated with a more rapid decline in lung function in children (Gautier and Charpin, 2017; Schultz et al., 2017; Vanker et al., 2017). An area that remains unclear is if e-cigarette use can cause neutrophilic inflammation, similar to that which can be found in the asthmatic smoker and smoker with COPD (Andelid et al., 2015; Siew et al., 2017). If so, then e-cigarette use in people with asthma may further exacerbate lower airway PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-13 inflammation regardless of whether their asthma phenotype is predominately allergic or neutrophilic in origin. As discussed above, adolescents with asthma—a disease characterized by reversible airway obstruction—who use e-cigarettes may be more likely to have an increase in respiratory symptoms and exacerbations compared with adolescent non-users, as indicated by one cross-sectional study (Cho and Paik, 2016). Cystic Fibrosis Children and adolescents with other respiratory diseases who use e-cigarettes may also be at increased risk for worsening of respiratory symptoms. Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are respiratory diseases also characterized by lower respiratory tract neutrophilic inflammation. In the United States, the carrier frequency of CF mutations is 1/36, with whites having a carrier rate of 1/27 and African Americans with a carrier rate of 1/79 (Zvereff et al., 2014). It is unclear whether adolescents with CF or PCD would be more likely to try e-cigarettes if they perceive them to be less harmful than combustible tobacco cigarettes. Nicotine alone has been shown to cause dysregulation of the CFTR chloride channel in the airways in animal studies, causing impaired airway MCC (Maouche et al., 2013). Another study found an association between secondhand smoke exposure in children with CF and lower FEV1 and weight percentile (Ong et al., 2017). Nicotine exposure from e-cigarette use could potentially cause a higher rate of respiratory symptoms in CF carriers if nicotine causes dysregulation of CFTR in the airways. Preterm Infants Exposure to nicotine in utero may have long-lasting negative effects on lung function in vulnerable populations such as preterm infants. Recently, maternal smoking during pregnancy has been associated with the development of bronchopulmonary dysplasia and later respiratory morbidities in preterm infants (Morrow et al., 2017). No studies have been done examining the respiratory health effects of e-cigarettes on the preterm infants of mothers who used e-cigarettes during pregnancy. PREPUBLICATION COPY: UNCORRECTED PROOFS

11-14 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 11-1 Clinical and Epidemiological Studies in Humans Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results Effects in Users of Combustible Tobacco Products Campagna n = 134 3 arm, “Categoria” EC Those (1) FeNO in ppb Demographic (1) FeNO showed significant changes over the 2016a double-blind, (model “401”). participants from 10-second characteristics, time: at baseline (BL), FeNO was (ppb, medians controlled, E-cigarette kit receiving exhalation; smoking and interquartile range) 6.6 (4.3-8.4), 5.9 (5.0-7.8) randomized, with either e-cig with (2) eCO in ppm reduction, and and 5.5 (4.5-6.9) for failures, reducers and quitters clinical trial; “Original” (2.4 % 0% nicotine from a single quit rates were (as per continuous classification at week 52), longitudinal. nicotine—Group expiratory not respectively. At week 52, it was 7.0 (5.5-9.9), 7.9 75% return rate A), or “Categoria” breath; significantly (6.0-10.8) and 17.7 (13.3-18.9), respectively. at week 12, (1.8 % nicotine— (3) adverse different Repeated-measures ANOVA showed that effect 70.3% at week Group B), or event symptom among study of smoking phenotype was significant (p < 24, and 61% at “Original” score for groups 0.0001). No significant difference in FeNO week 52. No without nicotine different eight changes from baseline was observed in quitters difference in (“sweet tobacco” symptoms who stopped using EC [+11.8 (7.4-13.4) ppb, characteristics aroma—Group C) medians and interquartile range] compared with between those cartridges quitters who were still using EC [+14.3 who remain (9.9-15.3)] at any study time points; (2) and drop out, Significant within-subject effect (i.e., time, p < except gender 0.0001) was found for changes in eCO. Exhaled (males were CO was (ppm, medians and interquartile range) 71% among 21 (14-29), 20 (15-26) and 17 (12-20) at BL for those lost to failures, reducers and quitters (as per continuous follow-up). No classification at week 52), respectively. The same difference in figures at week 52 were 20 (14-30), 13 (6-19), drop-out rate and 3 (1-4). Repeated-measures ANOVA showed between three a significant between-subject effect (i.e., smoking experimental phenotype, p < 0.0001). Linear regression groups. analysis showed that changes in FeNO were significantly correlated (p < 0.0001) to those in eCO at all time points; (3) High prevalence of respiratory symptoms was reported at baseline PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-15 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results and virtually disappeared very quickly in both quitters and reducers. Among failures and reducers, the slopes were flat or not significant. Significant and steeper slopes (positive for eCO and negative for FeNO) were found among quitters. Differences among slopes were significant for both eCO and FeNO (p < 0.0001, ANCOVA). Polosa n = 16 Review of Varied N/A (1) Juniper’s Not stated; (1) At F/up 1 there were significant improvements 2016ab medical Asthma Control Missing in ACQ scores; at F/up 2 and F/up 3 significant longitudinal Questionnaire measurements improvements were observed on ACQ scores, and medical (ACQ) score, were not all lung function parameters including records spirometry for included in the methacholine PC20. Improvements at 12 months FEV1, FVC, analyses were still present at 24 months. Similar and improvements were also observed in the dual FEF25-75%, users. At F/up 1, there were significant Bronchial improvements in ACQ scores and FEF25-75%. provocation At F/up 2 and F/up 3 significant improvements tests assessing from baseline (except for FVC at F/up 3) were airway observed on ACQ scores, lung function hyperresponsive parameters, and methacholine PC20. ness (AHR) for Deterioration in objective and subjective asthma methacholine outcomes noted in the 2 patients who relapsed to PC20; exclusive tobacco smoking. The normal (2) number of FEV1/FVC of 79.5% at 12 months (F/up 2) exacerbations decreased to 71.0% at 24 months (F/up 3). Their from previous methacholine PC20 was reduced 3-fold from 2.95 visit; mg/ml to 1.05 mg/ml and their ACQ score (3) eCO increased substantially from 1.45 to 2.3; (2) No monitoring and significant differences in number of respiratory self-reported exacerbations throughout the study. Average cigarette number of exacerbations at baseline of 1.13 not PREPUBLICATION COPY: UNCORRECTED PROOFS

11-16 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results consumption; being significantly different from 0.93 (4) E-cigarette exacerbations at F/up 1, 0.87 exacerbations at smoking F/up 2, and 0.81 exacerbations at F/up 3 patterns respectively. Of note, exacerbation rate increased from 0 at 12 months (F/up 2) to 2 at 24 months (F/up 3) in the 2 patients who relapsed to exclusive tobacco smoking; (3) Marked reduction in combustible tobacco cigarette use amongst EC users, the mean cigarette/day consumption of 21.9 at baseline decreasing to 2.3 at F/up 1, 1.9 at F/up 2, and 1.5 at F/up 3 respectively. Substantial reduction in combustible tobacco cigarette use also observed in dual users; their mean cigarette/day consumption at baseline decreasing from 20.7 to 5.3 at F/up 1, 3.7 at F/up 2, and 3.5 at F/up 3, respectively. 10 out of 16 asthmatics were still exclusively using EC at 24 months and not smoking combustible tobacco cigarettes throughout the study (single users); (4) Duration of regular EC use ranged from 20 to 26 months, with 10 patients using them for at least 2 years. All participants were using standard refillable ECs by the end the study. The preferred nicotine strength of their e-liquid was 9 mg/ml and 18 mg/ml, which was consumed by 62.5% and 18.8% of EC users respectively. Most of the participants preferred tobacco flavors over other flavors. Cibella 2016c Varied, 3 arm, “Categoria” EC Participants (1) Subjective Demographic 1) Cough/phlegm was significantly more frequent depending double-blind, (model “401”). receiving respiratory characteristics, at BL among those resulting quitters (64%) with on controlled, E-cigarette kit e-cigarette problems smoking respect to Reducers (55%) and Failures (36%). outcome randomized, with either with 0% (frequency of reduction, and No reported wheezing or chest tightness. High PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-17 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results (generally clinical trial; “Original” (2.4 % nicotine (n cough/phlegm, quit rates were prevalence of cough/phlegm and shortness of 103+) longitudinal. nicotine—Group varied wheezing, not breath (SoB) reported at BL: frequency of 75% return rate A), or “Categoria” depending on shortness of significantly cough/phlegm decreased at each follow-up visit at week 12, (1.8 % nicotine— outcome) breath, or different with respect to BL regardless of subjects’ 70.3% at week Group B), or difficulty among study smoking phenotypes classification. SoB showed a 24, and 61% at “Original” breathing); groups similar behavior. Symptoms of cough/phlegm and week 52. No without nicotine (2) Spirometry SoB disappeared completely in quitters during the difference in (“sweet tobacco” metrics (FEV1, study. Significant effect of smoking phenotype on characteristics aroma—Group C) forced vital the reduction in cough/phlegm and SoB with between those cartridges capacity (FVC), time. Of note, changes in respiratory symptoms who remain and maximum from BL were greater for both reducers and and drop out, midexpiratory quitters with respect to failures (p < 0.0001). The except gender flow presence/ absence of respiratory symptoms at all (males were (FEF25-75%) time-points (BL, week-12, week-24 and week-52) 71% among and FEV1/FVC was not associated with significant differences in those lost to ratio). any of evaluated spirometric variables; (2) follow-up). No Significant within-subject effect was found for difference in changes in FEV1, FVC and FEF25-75% over the drop-out rate time (at BL, and at week-12, week-24 and between three week-52, p < 0.0001). No effect of smoking experimental phenotype classification was evident for FEV1, groups. FVC and FEV1/FVC. Effect of smoking phenotype classification was evident on FEF25-75% that significantly (p = 0.034) increased over the time among Quitters. FEF25-75% was (means ± S.D.) 80.6 ± 18.2, 78.3 ± 19.3 and 85.7 ± 15.6 at BL for Failures, Reducers and Quitters (as per continuous classification at week-52) respectively. The same figures at week-52 were 83.1 ± 18.4, 87.0 ± 20.0 and 100.8 ± 14.6 (p < 0.0001) PREPUBLICATION COPY: UNCORRECTED PROOFS

11-18 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results Cravo 2016d n = 419 Randomized, EC with combustible Primary Not stated No clinically significant findings in: vital signs, parallel group rechargeable tobacco outcomes: AEs, electrocardiogram, lung function tests and clinical study; battery, atomizer, cigarette vital signs, standard clinical laboratory parameters. combustible capsule with (CC) 12-lead ECG, tobacco e-liquid; 2% smokers lung function AEs reported: more frequent during the first week cigarette (CC) nicotine; subjects tests, and then reduced. 1,515 reported AEs, 495 related smokers in CC arm used hematology, to nicotine withdrawal symptoms. Most frequent: switched to EC own usual brand clinical headache, sore throat, desire to smoke, and cough. for 12 weeks biochemistry, 6% judged as probably or definitely related to the urinalysis EC. Additional observations: up to 33.8% decrease in level of urine nicotine equivalents, and decreases in the level of benzene, acrolein and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone. D’Ruiz n = 105 Randomized, 3 closed system Complete Pulmonary Not stated Use of the e-cigarettes for 5 days: did not lead to 2017e open-label, blu™ tobacco and function (FVC, negative respiratory health outcomes or serious forced-switch e-cigarette nicotine FEV1, and AEs. parallel arm products: product exhaled CO and study rechargeable cessation NO); safety and Pulmonary function tests: small but not (exclusive tobacco flavor, tolerability significant improvements in FVC and FEV1 e-cigarette use rechargeable measurements in most use groups. Statistically group, dual use cherry flavor and significant benefits associated with smoking group, disposable cherry reduction were also noted in exhaled CO and NO cessation flavor; all levels. group) contained 24 mg/mL (2.4%) nicotine Polosa n = 18 Review of Varied N/A (1) Lung Not stated; No significant differences in the parameters of 2014af medical function Missing lung function, BHR or ACQ scores between the PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-19 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results longitudinal (FEF25-75%), measurements pre-baseline and baseline visits (except for a small medical bronchial were not change in FEF25-75%); (1) Compared with records hyperresponsive included in the baseline, at 6 months there were significant ness (BHR), and analyses improvements in FEF25-75% and ACQ scores; at Asthma Control 12 months significant improvements were Questionnaire observed on all asthma outcomes measures. At 12 (ACQ) scores; months both dual and single users had (2) Combustible considerable improvements compared with tobacco baseline in all parameters (except for FVC in cigarette use; single users); (2) There was a reduction in (3) combustible tobacco cigarette use amongst all exacerbations; e-cigarette users from a mean combustible (4) Safety and tobacco cigarette/day use of 21.9 at baseline tolerability decreasing to 1.7 at follow-up visit 2 (p < 0.001). Similar reduction in combustible tobacco cigarette smoking was observed in dual users as well (22.4 at baseline to 3.9 at follow-up visit 2; p < 0.001). Importantly, 10 asthmatics gave up combustible tobacco cigarette use in favor of the e-cigarette (single users); (3) Prior to e-cigarette use in the 18 patients the average number of exacerbations was 1.06 (at pre-baseline) and 1.17 (at baseline). Over the period of observation none of the subjects in the cohort reviewed had a hospital or intensive care unit admission; (4) No severe adverse reactions or acute exacerbation of asthma symptoms were reported during period of observation with e-cigarette use. Polosa n = 40 Observational Categoria None 1) > 50% Not stated (1) Sustained 50% reduction in the number of 2014bg prospective e-cigarette, reduction in cigs/day at 24 months was shown in 11/40 study “original” flavor, number of subjects, with a median of 24 cigs/day decreasing PREPUBLICATION COPY: UNCORRECTED PROOFS

11-20 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results following a 7.4 mg nicotine cigarettes from significantly to 4 cigs/day (p = 0.003); (2) Of cohort of cartridges (no baseline and these 11 tobacco smoke reducers, 6 could be smokers in a more than 4 corresponding classified as sustained heavy reducers at 24 naturalistic cartridges per day) eCO level months. They had a median consumption of 27.5 setting after a (reducers); (2) > cig/day at baseline, decreasing significantly to 4 24-week 80 reduction in cig/day by 24 months (p = 0.012); (3) There were intervention number of 5/40 quitters by the end of the study; (4) Mean of phase during cigarettes from 1.82 (±1.44) cartridges/day was used at 6 months. which baseline, with At 24-months, some e-cigarette users were not participants corresponding using the product (and stayed quit), some relapsed were issued eCO (heavy back to tobacco smoking and 4 upgraded their with Categoria reducers); (3) entry level e-cigarette to better performing e-Cigarettes. abstinence from intermediate products using e-liquid nicotine from Used a smoking with refill bottles (all categorized as heavy reducers); “Categoria” corresponding (5) At 6 months, mouth irritation, throat irritation, e-Cigarette 6 eCO (quitters). and dry cough were reported, respectively by months and Failure to meet 14.8, 7.4, and 11.1% of the participants. Dry followed any of those mouth, dizziness, headache and nausea were prospectively benchmarks was infrequent. Overall, these symptoms remained for 2 years. defined as stable during the whole duration of the After an initial smoking observation phase, with the exception of dizziness 6-month cessation and nausea, which disappeared by 24-month study intervention failure; (4) visit. phase using the Product usage; e-Cigarette, (5) Adverse participants smoking-related attended two events or follow-up symptoms. visits, at 18 and 24 months. PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-21 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results Polosa n = 48 Reviewed Not stated; varied Age- and (1) changes in Not stated; no (1) Significant reduction in combustible tobacco 2016bh clinical notes sex-matched smoking significant cigarette consumption in COPD EC users. of COPD COPD behavior and differences in Complete abstinence from tobacco smoking in patients patients who EC use; (2) baseline 13/24 (54.2%) of COPD EC users. Dual usage attending smoked COPD characteristics was reported by 11/24 (45.8%) COPD EC users. clinics; 2 combustible exacerbations; between EC Significant reduction in combustible tobacco follow-up tobacco (3) Lung and control cigarette consumption in dual users. More than visits (12, 24 cigarettes but Function groups 75% reduction from baseline in cigarette/day months after not Assessments consumption reported by all COPD EC dual users baseline). e-cigarettes and COPD at both follow-up visits; (2) Significant reduction Analyses staging; (4) in annual COPD exacerbations within the COPD include data CAT scores and EC user group but not in control group. from the 3 6MWD Significant reduction in COPD exacerbations visits. observed in dual users, but only at 24 months. In the single users there was significant reduction in exacerbations at both follow-ups; (3) Compared with baseline there were no significant differences in the post-bronchodilator FEV1, FVC and %FEV1/FVC between study groups. Significant difference in the rate of FEV1 decline at the 24-month follow-up visit in COPD ECs users than in the control group. A few COPD patients in the EC study group downstaged from GOLD Stage 4 to GOLD Stage 3 and 2; (4) COPD symptoms, as assessed using the CAT, at both follow-up visits decreased statistically and clinically significantly in the EC group, but no change in control group. Over the 24 months observation period, the median 6MWD improved more than 60 m in the EC user group compared with just over a median of 3 m in the control group. PREPUBLICATION COPY: UNCORRECTED PROOFS

11-22 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results Acute Exposures Ferrari 2015i n = 20 Laboratory-bas The nicotine free Crossover (1) Exhaled Not stated (1) No significant changes of FeNO were ed, randomized (NF) e-cigarette design (Both nitric oxide (except that observed in the 2 groups. (2) Baseline FeCO crossover used in this study: smokers and (FeNO); (2) smoking habit values were significantly higher in smokers than design ELIPS C Series non-smokers Fractional and cross-over in nonsmokers. The combustible tobacco cigarette (steel shell, were concentration of design were significantly increased FeCO values; this effect microprocessor randomized carbon considered as was significant in both groups of subjects. powered by a to smoke monoxide factors in the E-cigarette did not have any significant effects on battery, a filter both the NF (FeCO); (3) ANOVA) FeCO. The increase of FeCO values observed and a removable e-cigarette Forced vital after smoking the combustible tobacco cigarette cartridge); and a lung capacity was significantly different from the effect of the nicotine-free commercial (FVC); (4) e-cigarette. (3) Smoking a combustible tobacco liquid with combustible Forced cigarette significantly decreased the FEV1/FVC hazelnut flavor tobacco expiratory in non-smokers. (4) Both types of cigarettes (“Natur Smoke cigarette ad volume (FEV1); significantly decreased FEV1 values in smokers aroma Nocciola libitum for 5 (5) Forced while the decreases in non-smokers were not Antistress 0 min in 2 expiratory flow significant; thus FEV1 decreased significantly in mg/ml nicotina”). different (FEF); (6) Peak the overall population after smoking a The commercial sessions expiratory flow combustible tobacco cigarette while the effect of combustible according to (PEF) the e-cigarette did not reach a statistically tobacco cigarette a cross-over significant level. (5) The combustible tobacco (Marlboro® Red) design cigarette significantly decreased FEF25, FEF50 contained nicotine and FEF75 in the overall population, particularly 0.8 mg. due to the significant reductions of FEF25 in smokers and FEF75 in non-smokers while the reduction of FEF50 did not reach the significant levels in either smokers or non-smokers. The only significant effect of the e-cigarette was a reduction of FEF25 in smokers. Comparing the effects of combustible tobacco and e-cigarette smoking, only a significantly greater reduction of FEF50 was found after combustible tobacco PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-23 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results cigarette smoking in non-smokers. Higher values of FEF75 were found after smoking an e-cigarette than after smoking a combustible tobacco cigarette, whereas the inverse was the case in smokers. (6) The combustible tobacco cigarette significantly decreased PEF values in the overall population due to effect in the smokers. The changes in FEV1, FVC, FEV1/FVC, and PEF between the two types of cigarettes were not significantly different in either smokers or non-smokers or in the overall population. Vardavas n = 30 Laboratory-bas NOBACCO Control (1) Exhaled Adjustments (1) FeNO in the experimental group decreased by 2012j ed, intervention e-cigarettes, black group Nitric Oxide for the group 16% after the use of an e-cigarette, but not in design. 2 line. Medium subjects were FeNO, ppb; (2) (control versus control group. (2) Pulmonary function assessed groups: cartridge, 11 mg asked to use Dynamic Lung experimental) via spirometry did not change in either group. (3) experimental nicotine. The the Volumes; (3) and the relative Airway impedance at Z5Hz increased in the group (n = 30) subjects in the e-cigarette ad Total baseline experimental group by 0.033 kPa/(L/s), whereas and control experimental lib for 5 Respiratory measurement no differences were noted among control group group (n = 10). group were minutes, but Resistance (pre versus participants. Lung resistance in the experimental Control group instructed to use without the post). After group also increased at R5Hz, R10Hz, and R20Hz randomly the e-cigarette ad e-cigarette controlling for by an average of 0.031 kPa/(L/s), 0.029 kPa/(L/s), selected from lib for 5 min as cartridge baseline and 0.030 kPa/ (L/s), respectively. Peripheral experimental they would included (not responses in pulmonary resistance also increased significantly group to usually smoke. blinded). linear from 0.22 kPa/(L/s) to 0.25 kPa/(L/s). participate in regression, an extra results are session at a strengthened separate time. compared with The role of the simple using an bivariate e-cigarette was associations. assessed PREPUBLICATION COPY: UNCORRECTED PROOFS

11-24 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results through: (1) comparing the changes noted among control group participants with changes noted among experimental group participants after the intervention (intragroup comparison); and (2) comparing pre versus post respiratory function among experimental group participants (intergroup comparison). Cough and Mucociliary Clearance Dicpinigaitis n = 30 pre-post cough 30 puffs from a No control (1) Cough reflex Not stated (1) After e-cigarette exposure, cough reflex 2016ak test (before disposable group sensitivity (C5), sensitivity was significantly diminished compared e-cigarette e-cigarette (blu, (instead, measured by the with baseline. This effect was transient. Mean log exposure, and Classic Tobacco pre-post number of C5 at baseline was 0.50 ± 0.09 (SEM); 15 min after) flavor; analysis) coughs after electronic cigarette exposure it was 0.79 ± PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-25 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results approximately 1.5 following a 0.11; and 24 h subsequently it was 0.55 ± 0.10. to 1.8 mg nicotine capsaicin Difference between log C5 at baseline and challenge; post-e-cigarette exposure was significant as was (2) Secondary the difference between post-e-cigarette use and 24 analysis with h later. 23 of 30 subjects demonstrated an non-nicotine inhibition of cough reflex sensitivity after e-cigarette in 8 e-cigarette exposure; 5 subjects had no change, subjects who and 2 subjects had a one-doubling concentration demonstrated decrease in C5. Twenty-six of the 30 subjects large degrees of coughed to some degree. The median number of inhibition of coughs for the study group was 15.5 [range cough reflex 0-114] coughs. No correlation between the sensitivity number of coughs induced by e-cigarette inhalation and subsequent change in cough reflex sensitivity. (2) No inhibition of cough reflex sensitivity observed after exposure to the non-nicotine-containing e-cig, by contrast to the change in C5 after use of the nicotine containing e-cig. Significantly less coughing observed after 30 puffs of the non-nicotine-containing e-cigarette compared with the nicotine-containing product. Dicpinigaitis n = 17 pre-post cough 30 puffs from a No control (1) Cough reflex Not stated 17 subjects had a demonstrable Cu and formed 2016bl test (before disposable group sensitivity (C5), the subject population; (1) after e-cigarette e-cigarette e-cigarette (blu, (instead, measured by the exposure, C5, and (2) the Cu were significantly exposure, and Classic Tobacco pre-post number of diminished compared with baseline. Mean log C5 after) flavor; analysis) coughs at baseline was 0.60 ± 0.11 (SEM) and 0.92 ± approximately 1.5 following a 0.16, 15 minutes after e-cigarette exposure. Mean to 1.8 mg nicotine capsaicin log Cu was 0.035 ± 0.08 at baseline and 0.21 ± challenge; (2) 0.12, 15 minutes after e-cigarette exposure. The Urge to cough difference between log C5 at baseline and 15 (Cu) minutes post e-cigarette exposure was significant as was the difference in log Cu. This effect was PREPUBLICATION COPY: UNCORRECTED PROOFS

11-26 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results transient. 14 of the 17 subjects coughed to some degree in response to inhalation. The median total number of coughs for the study group was 9 with a range of 0-30 coughs. Kumral n = 98 prospective Participants Non-EC (1) Sino-Nasal Not stated (1) SNOT 22 scores were insignificant between 2016m randomized selected brand of smokers (n = Outcome Test groups before the cessation of cigarette smoking; single-blind device and flavor 40) were the (SNOT-22) for there was a significant difference between the clinical trial of the cartridge. smokers who subjective groups at the third month measurements. 11-12 mg/ml quit smoking symptoms; (2) Comparison of SNOT 22 results of groups at the liquid for all ECs. without the Saccharin beginning of the study and after 3 months aid of transit test to revealed statistically significantly lower scores medical evaluate nasal after the 3 months; (2) MCC measurements were therapy or a MCC function. insignificant between groups before the cessation device, of cigarette smoking; there was a significant although difference between the groups at the third month they were measurements. Comparison of MCC results of provided group 2 at the beginning of the study and after 3 cognitive months revealed statistically significantly lower behavioral scores after the 3 months. Group 1 did not show treatment. any significant difference after 3 months. Respiratory Symptoms in Adolescents Cho and Paik n = Cross-sectional EC use assessed “Current (1) Asthma 7 variables (1) Prevalence rates of asthmatics in “current EC 2016n 35,904 survey study by “Have you e-cig users” based on were included users,” “former EC users,” and “never EC users,” ever used an EC are compared student’s in the model: were 3.9%, 2.2% and 1.7%, respectively. in your life?” with “former self-reported gender, city Comparing “current EC” users with “never EC” (yes/no). e-cig users” doctor’s size, users, the unadjusted OR for asthma was 2.36. Answering no: and “never diagnoses of multi-cultural Comparing “current EC” users with “never EC” “never user.” e-cig users” asthma; (2) family status, users, the adjusted OR for gender only was 2.09, Answering yes: as well as severe asthma overweight and the adjusted OR for CC smoking only was asked a follow-up those who based on days status, second 1.73. The CC smoking was the highest factor question “Have had used of missing hand smoking which affected the effect of EC on asthma. you used ECs in combustible school due to at home, atopic Gender was the second factor. For all other PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-27 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results the past 30 days?” tobacco symptoms dermatitis factors, the changes-in-estimate of the effect of (yes/no). cigarettes history, allergic EC on asthma were comparable to that of the Answering yes: (CC). rhinitis history. unadjusted model. (2) Within the “never CC” “current user” and A variable for group, the OR for “more than 4 day absence from answering no: CC smoking school due to asthma symptoms” was 18.59 in “former user.” was added. Model A, 13.21 in Model B, and 15.42 in Model Cigarette smoking Next, we C. Differences not significant for the “former CC” assessed by performed group and “current CC” group. Within the “never question “Have multiple CC” group, the OR for “1-3 day absence from you ever smoked, logistic school due to asthma symptoms” was 6.81 in even one puff in regression Model A, 5.67 in Model B, and 5.04 in Model C. your life?” (yes/ analyses for Within the “current CC” group, the OR for “1-3 no). Answering each potential day absence from school due to asthma no: “never confounder. symptoms” was 2.48 in Model A, 2.46 in Model smoker.” B, and 2.23 in Model C. Differences not Answering yes: significant for the “former CC” group. asked a follow-up question “In the past 30 days, how many days did you smoke?” Answering “one or more days”: “current smoker,” answering “none:” “former smoker.” Choi and n= Cross-sectional E-cigarettes N/A (1) Asthma Analyses were The weighted prevalence of ever e-cigarette use Bernat 2016o 36,085 survey described to status weighted to was 8.2% (8.0% among students in metropolitan students as (determined by account for counties and 11.0% in nonmetropolitan/rural “battery-operated asking if cluster counties). Students in metropolitan counties who devices that look, currently had sampling and reported currently having asthma were feel, and taste like asthma [never were stratified significantly more likely to have ever used PREPUBLICATION COPY: UNCORRECTED PROOFS

11-28 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results a tobacco diagnosed, by county-level e-cigarettes compared with those never diagnosed cigarette;” currently has metropolitan with asthma. The prevalence of ever e-cigarette students asked asthma, does status. use in students with current asthma was about e-cigarette not currently Additional significantly higher among students in use (asked if had have asthma, associations non-metropolitan/rural counties (18.2%) ever tried using unsure] and if adjusted for compared with those students with current asthma e-cigarette had an asthma demographic in metropolitan areas (9.9%). [yes/no] and if attack in last 12 variables, had used months living with The weighted prevalence of past 30-day e-cigarette in past [yes/no]); (2) combustible e-cigarette use was 3.3% (3.2% in students in 30 days [yes/no]) e-cigarette use; tobacco metropolitan counties and 4.8% in students in (3) cigarette nonmetropolitan/rural counties). The prevalence susceptibility to smokers, days of past 30-day e-cigarette use in students with combustible smoked in the current asthma was significantly higher among tobacco past 30 days, students in non-metropolitan/rural counties cigarette positive social (9.5%) compared with those students with current smoking (asked norms toward asthma in metropolitan areas (5.1%). about number of smoking, and days smoked in exposure to Among students with current asthma who had past 30 days; if secondhand never smoked combustible tobacco cigarettes, said never tried, combustible ever e-cigarette use was associated with higher assessed for tobacco odds of being susceptible to combustible tobacco susceptibility to cigarette cigarette smoking (AOR = 3.96) compared with combustible smoking. those who never used e-cigarettes. Past 30-day tobacco use of e-cigarettes was associated with an asthma cigarette attack in the last 12 months (AOR = 1.78) among smoking) those with current asthma. McConnell n = 2086 Cross-sectional Students asked the N/A (1) Chronic Asthma was 502 participants (24.0%) who had ever used 2017p survey with age at which first bronchitis based on e-cigarettes; 301 (14.4%) were past and 201 past data tried cigarettes or symptoms student’s (9.6%) current users. Among current users, 107 included. e-cigarettes and (daily cough for self-report of (53.3%) used e-cigarettes on 1-2 days monthly Logistic number of days 3 months, ever having and 94 (46.8%) on 3 or more days. Among past PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-29 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results regression used used the product congestion or had asthma. and current e-cigarette users, 132 (44.2%) and 81 to evaluate the in the past 30 phlegm other Parent-complet (40.5%), respectively, were never cigarette users) association of days. Participants than when ed Compared with Hispanic White participants, bronchitic who had “never accompanied by questionnaire non-Hispanic White youth were more likely to symptoms and tried” a product a cold, or assessed have bronchitic symptoms or wheeze. Parental current wheeze were classified as bronchitis in the sociodemograp education greater than high school was associated with e-cigarette “never users.” previous 12 hic with greater risk of both outcomes. SHS exposure use. Dummy Those who had months); (2) characteristic. in the home was associated with increased risk of variables were used a product, wheeze assessed Confounding bronchitic symptoms but not of wheeze. Current created to but not in the last based on a assessed by and non-current use of cigarettes was associated assess effects 30 days, were report of including with greater risk of each outcome. Bronchitic of past and classified as “past wheezing or covariates in symptoms were associated with both past [OR current use, users.” whistling in the model. Models 1.85] and current use of e-cigarettes [OR 2.02]. compared with Participants who chest during the were adjusted They were attenuated by additional adjustment for never use, and had used a previous 12 for lifetime lifetime number of cigarettes smoked and SHS of frequency of product on at least months. number of exposure in the home [OR 1.71, for past and 1.41 use among one of the past 30 Analysis based cigarettes. In for current use]. We examined interactions of current users. days were on subjects with sensitivity e-cigarette use with gender; ethnicity (Hispanic The linear classified as complete analyses, and non-Hispanic white); asthma; and with a dog trend in effects “current users” of information on associations of or cat in the home, none of which was statistically of frequency of that product. e-cigarette use. e-cigarettes significant. The risk of bronchitic symptoms current Frequency of with bronchitic increased with number of days used in the e-cigarette use current e-cigarette symptoms and previous 30 days, (OR 1.66 for 1-2 days and OR assessed across use was wheeze were 2.52 for 3 or more days), compared with never 3 categories of categorized as 1-2 adjusted for e-cigarette users. This association with e-cigarette use (never days or 3 or more these same use frequency was not confounded by users, 1-2 and days. Students conditions in demographic characteristics, but was attenuated 3 or more days reported number 2010 and were by additional adjustment for SHS exposure and in the previous of cigarettes restricted to lifetime number of cigarettes smoked (OR 1.37 30 days). smoked in the children for 1-2 days and OR 1.64 for 3 or more days of previous month without use) and the trend was no longer significant. 2) and the lifetime symptoms in Wheeze was associated with current [OR 1.86] PREPUBLICATION COPY: UNCORRECTED PROOFS

11-30 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results number of 2010. 23 but not with past use of e-cigarettes [OR 1.02]. cigarettes smoked. interaction The effect of current e-cigarette use was not Lifetime number terms of confounded by sociodemographic characteristics of cigarettes e-cigarette use but was markedly attenuated by adjustment for smoked was with a dog or SHS exposure and lifetime number of cigarettes categorized as 0 cat at home smoked [OR 1.24], and after adjustment the (never smokers), were examined association of past use of e-cigarettes with wheeze > 0-10, 11-99 and for this became negative [OR 0.70]. The magnitude of > 99 cigarettes. outcome. For effect estimates for e-cigarette exposure in each outcome, analyses restricted to never smokers were similar the interactions to those found in the entire population after of gender, adjustment for sociodemographic characteristics, ethnicity smoking history and SHS exposure. (Hispanic and Non-Hispanic white) and asthma (in separate models) with e-cigarette use were also evaluated by calculating a likelihood ratio test for models with and without the interaction across categories of e-cigarette use. In all models, PREPUBLICATION COPY: UNCORRECTED PROOFS

RESPIRATORY DISEASES 11-31 Operationally Confounders or Sample E-Cigarette Control Defined Factors Study Size Study Design Product Conditions Outcomes Adjusted For Results missing data were assumed to occur at random. Wang 2016q n = Cross-sectional Not stated; varied N/A (1) E-cigarette Adjusted odds (1) Only 1.1% of all students, 0.1% of 45,128 Survey (current use; (2) ratios (AORs) never-smokers, 5.8% of ever-smokers, 2.0% of and past Respiratory of respiratory experimenters, 9.6% of ex-smokers, and 9.6% of smoking status, Symptoms symptoms due current smokers had used e-cigarettes in the past e-cigarette to e-cigarette 30 days; (2) Respiratory symptoms were reported smoking status, use calculated by 18.8% of all students, 17.7% of respiratory using logistic never-smokers, 25.8% of ever-smokers, 21.7% of symptoms, regression for experimenters, 27.2% of ex-smokers, and 34.3% demographic all students and of current smokers. E-cigarette use was characteristics, by smoking significantly associated with respiratory secondhand status, symptoms (AOR, 1.28). The corresponding AORs smoke adjusting for were 2.06 in never-smokers, 1.39 in exposure) sociodemo- ever-smokers, and 1.40 in ex-smokers. Positive graphic but nonsignificant associations were observed in characteristics, experimenters and current smokers. secondhand tobacco smoke exposure, school clustering effects, and smoking status. NOTES: ACQ = asthma control questionnaire; AE = adverse event; AHR = airway hyperresponsiveness; ANCOVA = analysis of covariance; ANOVA = analysis of variance; AOR = adjusted odds ratios; BHR = bronchial hyperresponsiveness; BL = baseline; CAT = COPD Assessment Test; CC = combustible tobacco cigarette; CO = carbon monoxide; COPD = chronic obstructive pulmonary disease; Cu = urge to cough; C5 = cough reflex sensitivity; EC: e-cigarette; eCO = exhaled carbon monoxide; ECG = echocardiogram; FeCO = forced expiratory carbon monoxide; FeNO = forced expiratory nitric oxide; FEF25-75% = forced expiratory flow at 25-75 percent of the pulmonary volume; FEV1 = forced expiratory volume; FVC = forced vital capacity; F/up: follow-up; GOLD Stages 1-4 = Global Initiative for Chronic Obstructive Lung Disease Stages of COPD (1 = mild, 2 = PREPUBLICATION COPY: UNCORRECTED PROOFS

11-32 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES moderate; 3 = severe; 4 = very severe); MCC = mucociliary clearance; NF = nicotine free; NO = nitric oxide; PEF = peak expiratory flow; SNOT-22 = Sino-Nasal Outcome Test; SoB = shortness of breath; 6MWD = 6-minute walk distance. SOURCES: a Campagna et al., 2016. b Polosa et al., 2016a. c Cibella et al., 2016. d Cravo et al., 2016. e D’Ruiz et al., 2017. f Polosa et al., 2014a. g Polosa et al., 2014b. h Polosa et al., 2016b. i Ferrari et al., 2015. j Vardavas et al., 2012. k Dicpinigaitis et al., 2016a. l Dicpinigaitis et al., 2016b. m Kumral et al., 2016. n Cho and Paik, 2016. o Choi and Bernat, 2016. p McConnell et al., 2017. q Wang et al., 2016. PREPUBLICATION COPY: UNCORRECTED PROOFS

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RESPIRATORY DISEASES 11-35 Jayes, L., P. L. Haslam, C. G. Gratziou, P. Powell, J. Britton, C. Vardavas, C. Jimenez-Ruiz, J. Leonardi-Bee, and S. Tobacco Control Committee of the European Respiratory. 2016. Smokehaz: Systematic reviews and meta-analyses of the effects of smoking on respiratory health. Chest 150(1):164-179. Kalliola, S., A. S. Pelkonen, L. P. Malmberg, S. Sarna, M. Hamalainen, I. Mononen, and M. J. Makela. 2013. Maternal smoking affects lung function and airway inflammation in young children with multiple-trigger wheeze. Journal of Allergy and Clinical Immunology 131(3):730-735. Kann, L., T. McManus, W. A. Harris, S. L. Shanklin, K. H. Flint, J. Hawkins, B. Queen, R. Lowry, E. O. Olsen, D. Chyen, L. Whittle, J. Thornton, C. Lim, Y. Yamakawa, N. Brener, and S. Zaza. 2016. Youth risk behavior surveillance—United States, 2015. Morbidity and Mortality Weekly Report 65(6):1-174. Korten, I., M. Liechti, F. Singer, G. Hafen, I. Rochat, P. Anagnostopoulou, D. Müller-Suter, J. Usemann, A. Moeller, U. Frey, P. Latzin, and C. Casaulta. 2018. Lower exhaled nitric oxide in infants with cystic fibrosis compared to healthy controls. Journal of Cystic Fibrosis 17(1):105-108. Kumral, T. L., Z. Salturk, G. Yildirim, Y. Uyar, G. Berkiten, Y. Atar, and M. Inan. 2016. How does electronic cigarette smoking affect sinonasal symptoms and nasal mucociliary clearance? B-ENT 12(1):17-21. Larcombe, A. N., M. A. Janka, B. J. Mullins, L. J. Berry, A. Bredin, and P. J. Franklin. 2017. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. American Journal of Physiology—Lung Cellular and Molecular Physiology 313(1):L67-79. Laube, B. L., N. Afshar-Mohajer, K. Koehler, G. Chen, P. Lazarus, J. M. Collaco, and S. A. McGrath-Morrow. 2017. Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an e-cigarette on mucociliary clearance in a murine model. Inhalation Toxicology 29(5):197-205. Lee, A. L., B. M. Button, and E. L. Tannenbaum. 2017. Airway-clearance techniques in children and adolescents with chronic suppurative lung disease and bronchiectasis. Frontiers of Pediatrics 5:2. Lerner, C. A., I. K. Sundar, H. Yao, J. Gerloff, D. J. Ossip, S. McIntosh, R. Robinson, and I. Rahman. 2015. Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PLoS ONE 10(2):e0116732. Levanen, B., P. Glader, B. Dahlen, B. Billing, I. Qvarfordt, L. Palmberg, K. Larsson, and A. Linden. 2016. Impact of tobacco smoking on cytokine signaling via interleukin-17a in the peripheral airways. International Journal of Chronic Obstructive Pulmonary Disease 11:2109-2116. Li, N., S. Georas, N. Alexis, P. Fritz, T. Xia, M. A. Williams, E. Horner, and A. Nel. 2016. A work group report on ultrafine particles (American Academy of Allergy, Asthma & Immunology): Why ambient ultrafine and engineered nanoparticles should receive special attention for possible adverse health outcomes in human subjects. Journal of Allergy and Clinical Immunology 138(2):386-396. Lim, H. B., and S. H. Kim. 2014. Inhalation of e-cigarette cartridge solution aggravates allergen-induced airway inflammation and hyper-responsiveness in mice. Toxicological Research 30(1):13-18. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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