Electronic cigarettes: One size does not fit all

Accepted Manuscript Electronic Cigarettes: One Size Does Not Fit All Amika K. Sood, MD, Matthew J. Kesic, PhD, Michelle L. Hernandez, MD PII:

S0091-6749(18)30321-X

DOI:

10.1016/j.jaci.2018.02.029

Reference:

YMAI 13337

To appear in:

Journal of Allergy and Clinical Immunology

Received Date: 27 October 2017 Revised Date:

8 February 2018

Accepted Date: 21 February 2018

Please cite this article as: Sood AK, Kesic MJ, Hernandez ML, Electronic Cigarettes: One Size Does Not Fit All, Journal of Allergy and Clinical Immunology (2018), doi: 10.1016/j.jaci.2018.02.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

1

Electronic Cigarettes: One Size Does Not Fit All

2

Amika K. Sood, MD1, Matthew J. Kesic, PhD1, Michelle L. Hernandez, MD1 1

Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina at

3 Address for correspondence:

5

Amika K. Sood, MD

6

Center for Environmental Medicine, Asthma and Lung Biology

7

University of North Carolina at Chapel Hill

8

104 Mason Farm Road, CB #7310

9

Chapel Hill, NC 27599-7310

11

919-962-4421 (fax)

12

[email protected]

13

M AN U

919-966-2936 (office)

TE D

10

SC

4

RI PT

Chapel Hill

Sources of support: AKS is supported by 5T32AI007062-39. MLH is supported by the AAAAI

15

Foundation & NHLBI135235.

17 18 19 20 21 22 23 24 25

Conflicts of Interest: The authors have nothing to disclose.

AC C

16

EP

14

ACCEPTED MANUSCRIPT

Abstract (Word Count: 189)

27

Electronic cigarettes (EC) have been rapidly growing in popularity among youth and adults in

28

the US over the last decade. This increasing prevalence is partially driven by the ability to

29

customize devices, flavors, and nicotine content and the general notion that EC are harmless,

30

particularly in comparison to conventional cigarettes (CC). In vitro and in vivo murine models

31

have demonstrated a number of harmful biological effects of e-liquids (EL) and their aerosols.

32

However, limited clinical data exists on whether these effects translate into detrimental long-

33

term outcomes in humans. The short-term harmful respiratory effects of EC use demonstrated

34

in non-smokers argue against their use. Slightly more favorable data, though, exists for the

35

respiratory benefits of substituting CC with EC and the short-term efficacy of EC as smoking

36

cessation tools. Nonetheless, available research is severely limited in regards to long-term

37

outcomes and by study designs fraught with bias, pointing to the need for additional research

38

efforts with well-designed longitudinal studies to guide FDA regulatory efforts. The hurdle

39

presented by diverse device designs and EL permutations, which contribute to inconsistency of

40

available data, also highlights the need for legislative standardization of EC.

43 44 45 46 47 48

SC

M AN U

TE D

EP

42

AC C

41

RI PT

26

ACCEPTED MANUSCRIPT

Key Words

50

electronic cigarette, e-cigarette, ENDS, e-liquid, aerosol, cytotoxicity, inflammation, barrier

51

dysfunction, microbial defense, smoking cessation, respiratory effects

52

Abbreviations

53

electronic cigarettes (EC), electronic nicotine delivery systems (ENDS), conventional cigarettes

54

(CC), chronic obstructive lung disease (COPD), e-liquid (EL), interleukin (IL), mucin glycoprotein

55

5AC (MUC5AC), normal human bronchial epithelial (NHBE), toll-like receptors (TLRs), fractional

56

excretion of nitric oxide (FeNO), fractional excretion of carbon monoxide (FeCO), pulmonary

57

function tests (PFTs)

M AN U

SC

RI PT

49

58 59

63 64 65 66 67 68 69

EP

62

AC C

61

TE D

60

ACCEPTED MANUSCRIPT

Introduction (Word Count: 4675)

71

Electronic cigarettes (EC), also known as electronic nicotine delivery systems (ENDS), are the

72

most popular new tobacco products to have emerged over the last decade and are becoming

73

widely adopted in the United States and abroad among a vast age distribution and among

74

chronic smokers and nonsmokers. This has prompted an impassioned debate regarding the

75

safety of these battery-operated devices, especially considering the assumption by the lay

76

public that EC are harmless or less harmful than conventional cigarettes (CC)(1, 2). In fact, in

77

December 2016, the Surgeon General’s report concluded that the use of EC, particularly among

78

youth and young adults, represents an emerging public health concern(3). However, EC

79

advocates cite a lack of evidence against the harmfulness of EC aerosols and argue that these

80

devices offer safer alternatives to CC, appealing to the theory of “harm reduction”(4). U.S.

81

physicians are also divided in their recommendations to patients regarding the use of EC

82

despite the topic being frequently broached during clinical care(5, 6). Given that smoking is

83

widely-known as a leading cause of increased morbidity and mortality due to neoplastic,

84

vascular, and respiratory diseases, including chronic obstructive lung disease (COPD) and

85

asthma(7), the FDA has now extended its tobacco regulatory power to include EC. However, the

86

research on EC use to guide these regulatory policies is currently limited but rapidly growing.

87

We review here the available body of evidence on the safety of EC as it relates to respiratory

88

health and their efficacy as smoking cessation tools.

89

Epidemiological data on prevalence of e-cigarette use

90

Since their emergence to the U.S. market in 2007, EC are being used, both experimentally and

91

regularly, in increasing rates by both youths and adults, though estimates of use vary among

92

surveys(8-10). Representative, cross-sectional surveys of U.S. adults between 2010 and 2013

93

noted a rise in the proportion of individuals who reported having ever tried EC from 1.8% to

94

13%. Additionally, current use of EC, defined as use on “some days” or every day, increased

AC C

EP

TE D

M AN U

SC

RI PT

70

ACCEPTED MANUSCRIPT

from 0.3% to 6.8%. Current use among young adults aged 18-24 surpassed that of older age

96

groups. Caucasians and individuals with lower levels of education were also more likely to use

97

EC. Although current CC smokers were most likely to concurrently use EC, one-third of EC

98

users identified themselves as never having used CC or as former users of CC(9). The more

99

recent 2014-2015 US Census Bureau Current Population Survey-Tobacco Use Supplement

100

surveying more than 160,000 adults reported that 2.4% of the general U.S. population were

101

current EC users, while 8.5% of the population reported having tried EC at least once. In

102

addition to age, race, and education level, this survey also found male sex to be a significant

103

predictor of current use(8).

104

Regardless of the survey examined, it is clear that EC use is on the rise, and the consistent

105

report of highest use among young adults begs the question whether this trend is seen among

106

adolescents. Jamal et al provide evidence for this through analysis of data from the 2011–2016

107

National Youth Tobacco Surveys (NYTS), cross-sectional questionnaires administered to U.S.

108

middle and high school students. In 2015, 16.0% of all high school students and 5.3% of all

109

middle school students reported using EC on more than one day in the 30 days prior to the

110

survey, the definition of “current use” for this analysis. Increasing EC use was observed

111

between 2011 and 2015 for both high school students (1.5% to 16.0%) and middle school

112

students (0.6% to 5.3%). Moreover, EC have replaced CC since 2014 as the most commonly

113

used tobacco product in middle school and high school youth(11).

114

Several studies have alluded to reasons for this growth in usage. In a global survey of more

115

than 19,000 participants, former and current CC smokers reported using EC as a means to

116

reduce smoking-related adverse health effects and to reduce second-hand smoke exposure for

117

family members(1). While smoking cessation and overall health improvement are cited as

118

common reasons for use in middle-aged to older adults, flavorings(12), enjoyment(13), peer use

119

and curiosity(14) are more frequently cited by youth and young adults. In fact, three-fourths of

AC C

EP

TE D

M AN U

SC

RI PT

95

ACCEPTED MANUSCRIPT

flavored-product users in a survey of young adults and youths in Texas claimed they would

121

discontinue EC use if their preferred flavor was no longer available(15). Adding to the presumed

122

relative harmlessness of EC and purported benefits for smoking cessation, increasing exposure

123

to robust advertising campaigns, including discounted price promotions, have also been

124

associated with increased use of EC(16-19).

125

In youth and young adults, there is growing concern that the inception of EC use provides a

126

“gateway” for use of additional tobacco products, though some find this theory to be

127

unwarranted(20). In the 2016 NYTS, 9.6% of high school students and 3.1% of middle school

128

students reported current use of two or more tobacco products(11), but whether EC use came

129

first and/or perpetuated use of additional tobacco products is unclear. A recent meta-analysis

130

pooled data from 9 studies examining the effect of EC use on subsequent cigarette smoking in

131

17,389 participants aged 14-30 years(21). The pooled odds ratio for subsequent CC use after

132

ever having used EC was 3.62 (95% CI, 2.42-5.41) while the pooled odds ratio for CC use in the

133

past 30 days in those with EC use in the past 30 days was 4.28 (95% CI, 2.52-7.27)(21),

134

indicating a higher likelihood of smoking CC among adolescent and young adult EC users. In

135

addition, while the EC device is designed to be used with nicotine-containing or nicotine-free

136

liquids, they have been adapted by young adults for use with other substances, including

137

cannabis(14). Thus, while the data in support of the “gateway” theory is overall still limited, the

138

increasing prevalence of EC use among youth and adults either alone or in combination with

139

other products is concerning enough that understanding the beneficial and/or harmful effects of

140

EC is of paramount importance. A key first step to achieving this goal is through in-depth

141

knowledge of the components of ENDS.

142

E-cigarettes and their constituents

143

The specific design of ENDS varies with each subsequent generation but continues to consist of

144

three primary components: a power-source (typically a rechargeable lithium battery), the heating

AC C

EP

TE D

M AN U

SC

RI PT

120

ACCEPTED MANUSCRIPT

element (an atomizer coil), and a reservoir containing the e-liquid (EL) (Figure 1). Newer

146

generation models allow for customization of power, resistance, and/or temperature based on

147

user preferences. The EL itself also consists of three primary components: the solvent (either

148

vegetable glycerin and/or propylene glycol), various flavorings, and nicotine in various doses.

149

Heat from the atomizer coil after activation of the power source aerosolizes the EL, which is

150

then inhaled, or “vaped,” from the attached mouthpiece.

151

While EL solvents and flavors are generally regarded as safe for oral consumption, the effects

152

of their aerosilization and subsequent inhalation are not clearly understood and may prove

153

damaging to airway mucosa and function(22). Moreover, manufacturing labels are not always

154

comprehensive in regards to EL constituents(23) and therefore may not alert the consumer to the

155

potential for harmful effects. Depending on the combination of solvents and flavors used, a large

156

variation in chemicals can be detected in the resultant aerosol(24, 25) (Figure 1). These chemicals

157

include carbonyl compounds, such as formaldehyde, acetaldehyde, acetone, acrolein; volatile

158

organic compounds, such as benzene and toluene; tobacco-specific nitrosamines; particulate

159

matter; and metals, such as nickel, copper, zinc, tin and lead(24-35). Even when controlling for EL

160

solvent, flavor, and nicotine content, variabilities in the chemical composition of aerosols have

161

been detected within brands(27) as well as within samples of the same product(33) and with the

162

voltage of power used for generation of aerosol(28, 30, 31). Such variability in EC aerosol

163

composition highlights some of the challenges in evaluating health effects of EC. Additionally,

164

while the concentrations of these chemicals are often reported to be below those found in CC

165

and below occupational safety standards(29, 35), this is not a consistent finding across all

166

studies(27, 30, 34), raising concern for the potential of untoward toxicities and health effects.

167

Unfortunately, the plethora of EC brands and designs and unique flavorings available(36) along

168

with the ability to customize the power, resistance, and/or temperature of newer generation EC

169

results in immense difficulty in not only developing a comprehensive list of chemical constituents

AC C

EP

TE D

M AN U

SC

RI PT

145

ACCEPTED MANUSCRIPT

in EC aerosols but also developing well-designed, population-based studies of the long-term

171

health effects of ENDS usage.

172

Biological Effects

173

As a first step to assessing the safety of EC use, several studies have examined the biological

174

effects of EC constituents through in vitro and animal models. However, given the hurdle

175

presented by EC design variability and possible EL permutations, the generalizability of these

176

studies is limited. In addition, it is well accepted that murine studies present less than ideal

177

models for extrapolation to humans. Nonetheless, we present here some of the most recent

178

data available on the effects of EC on cytotoxicity, inflammation, barrier dysfunction, and

179

microbial defense.

180

Cytotoxicity

181

A number of studies have evaluated the cytotoxic potential of EC liquids and aerosols either in

182

isolation or compared to CC. In a recent study, Behar and colleagues assessed the sensitivity of

183

human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells to 35 EL

184

and their aerosols(37). Twenty of the 35 (57%) EL and 27/35 (77%) aerosols were found to be

185

cytotoxic while 20% of EL and their aerosols were non-cytotoxic. Embryonic stem cells were

186

more sensitive to the cytotoxic effects of these products compared to differentiated cells, raising

187

concern for potential effects of maternal EC use on fetal and neonatal health. Fruit-flavored,

188

tobacco-flavored, and nicotine-free and flavor-free EL were also cytotoxic to human pharyngeal

189

tissue cultures with the fruit-flavored e-liquids significantly increasing DNA fragmentation(38).

190

Similarly, decreased viability, increased oxidative stress, diminished cell proliferation, and

191

increased DNA damage are all biological effects demonstrated in other healthy and malignant

192

cell cultures treated with EC aerosols(39-42).

AC C

EP

TE D

M AN U

SC

RI PT

170

ACCEPTED MANUSCRIPT

In contrast, when directly comparing EC liquids and aerosols to CC smoke using identical

194

assays, Mirsa and colleagues found no cytotoxic, mutagenic, or genotoxic effects of EC liquids

195

or aerosols(43), a finding also reported by others(44, 45). Of note, the degree of cytotoxicity of EC,

196

when reported, has generally been less so when compared to CC(39, 40, 46-49), supporting those

197

who argue in favor of the harm-reduction use of EC in chronic smokers. Inconsistent results

198

regarding the cytotoxic effects reported amongst studies are likely due to variables such as cell

199

culture models used, the brand of EC studied, the composition of EC themselves, the

200

voltage/wattage applied for aerosol generation, testing of the EL itself versus the aerosol, and

201

the method of aerosol collection. Nonetheless, the available data still provides valuable

202

information for the potential harmful effects of EC, albeit less so than those of CC, highlighting

203

the need for additional research.

204

Inflammation

205

Similar to cytotoxic effects, inconsistent data exists on EC induction of pro-inflammatory

206

responses. In vitro exposure of airway epithelial cells, pulmonary fibroblasts, and innate

207

immune cells (i.e. neutrophils, macrophages) to components of EL and EC vapors (i.e. acrolein

208

and metals) demonstrated release of inflammatory cytokines, including interleukin (IL)-1β, IL-6,

209

IL-8, IL-10, CXCL1, CXCL2 and CXCL10(49-58). In an in vivo model, mice were exposed for 6

210

hours per day for 3 days to either control air, EC aerosol, or CC smoke. Transcriptional

211

expression of IL-1β was significantly elevated in those exposed to EC aerosol compared to

212

control air, but overall inflammatory cytokine expression was lower than that in mice exposed to

213

CC smoke(59). Similarly, exposure of mice to EC aerosol for 5 hours per day for 3 days,

214

demonstrated increased IL-6 and IL-13 cytokine levels in bronchoalveolar lavage fluid(60). In a

215

model of allergic inflammation, a dilute EL solution was intratracheally administered twice

216

weekly for 10 weeks in ovalbumin-sensitized mice. This resulted in increased airway

AC C

EP

TE D

M AN U

SC

RI PT

193

ACCEPTED MANUSCRIPT

eosinophilia, production of T helper-2 cytokines (IL-4, IL-5, IL-13), and ovalbumin-specific IgE

218

production(61).

219

However, inflammatory responses driven by EC exposure are not a consistent finding among in

220

vitro or in vivo murine models. Lacrombe and colleagues demonstrated no increased

221

inflammation in mice exposed for 8 weeks to EC aerosols derived from EL with differing nicotine

222

content and solvents(62). In vitro assays performed by Misra and colleagues also failed to show a

223

pro-inflammatory effect after exposure of human lung epithelial cells to 4 different EL, varying in

224

flavor and nicotine concentrations, and their respective vapors(43). In another study, macrophage

225

secretion of inflammatory cytokines, TNFα, IL-1β, and IL-6, actually decreased when cultured

226

on media infused with nicotine and certain flavors compared to media infused with control air(63).

227

Though not a consistent finding, the potential pro-inflammatory properties of ECs does heighten

228

the concern for promoting development or worsening of chronic inflammatory airway diseases.

229

Effects on barrier dysfunction, airway mucus & clearance

230

In addition to cytotoxic and pro-inflammatory effects, EC use may also impair innate barrier

231

defenses, though the data in favor of this is nascent. Lung endothelial cell permeability, as

232

measured by cell-substrate impedance sensing, increased after exposure to EC aerosols

233

independent of nicotine concentration. These barrier defects enhanced oxidative stress and

234

inflammation triggered by EC exposure(56). Cell substrate impedance sensing has also identified

235

impaired lung epithelial barrier defenses secondary to exposure with various flavors, including

236

diacetyl, coumarin, acetoin, maltol, and cinnamaldehyde, that are commonly added to EL(51).

237

Similarly, exposure of mouse tracheal epithelial cells to 2,5-dimethylpyrazine (present in vanilla

238

and chocolate flavorings) resulted in transient losses in transepithelial resistance and ion

239

conductance(64).

AC C

EP

TE D

M AN U

SC

RI PT

217

ACCEPTED MANUSCRIPT

The airway mucus layer also provides an important component of innate defense. Increased

241

mucus production and altered mucus clearance are hallmarks of airway inflammation in chronic

242

conditions including COPD and asthma. In vitro studies of normal human bronchial epithelial

243

cells (NHBE) cells have been used to examine EC effects on airway mucus. NHBEs repeatedly

244

exposed to EC vapor over 8 weeks had a reduction in mucus-producing cells(65). Additionally,

245

EC vapor appears to have potential to impair mucociliary clearance through impairment of ciliary

246

beat frequency in NHBE cells(66). Murine studies have provided more insight on in vivo EC

247

effects on airway mucus. Mice exposed to daily EC aerosol for 4 months had alterations in the

248

mucus layer present in healthy airways, notably with increased production of the mucin

249

glycoprotein 5AC (MUC5AC)(66). Increased MUC5AC levels have important implications in the

250

pathophysiology of asthma and COPD(67), contributing to increased airway obstruction and

251

nonspecific airway hyperreactivity(68). These murine studies were lately confirmed in humans,

252

with a recent publication noting elevated levels of MUC5AC in induced sputum from both EC

253

and CC smokers compared to nonsmokers(69). Collectively, these data, though limited, do

254

provide evidence for impairment of important innate barrier defenses following EC exposure.

255

Impaired microbial defense

256

The previously-discussed biological effects of EC likely contribute to impaired defenses against

257

microbes; other mechanisms of defective microbial defenses may also be involved including

258

impairment of Toll-like receptor (TLR) function and phagocytosis by innate immune cells. In vitro

259

exposure of a human macrophage cell line to EL showed reduced surface expression of pattern

260

recognition receptors, such as TLRs and scavenger receptors with a subsequent decrease in

261

macrophage phagocytosis(63). Alveolar macrophage cultures from EC-exposed mice exhibited

262

significant decreases in internalized S. pneumoniae with concurrent significant increases in

263

extracellular S. pneumoniae, indicating that EC exposure impaired bacterial phagocytosis(70).

264

Similarly, survival of methicillin-resistant S. aureus (MRSA) when cultured with murine alveolar

AC C

EP

TE D

M AN U

SC

RI PT

240

ACCEPTED MANUSCRIPT

macrophages exposed to E-vapor was over 350% greater compared to being cultured with

266

control macrophages exposed to air alone(71), although it was unclear from these studies if the

267

defect existed with phagocytic capacity versus intracellular bacterial killing. Additionally, MRSA

268

colonies exposed to E-vapor demonstrated enhanced virulence when inoculated into mice(71).

269

The adverse effects related to EC exposure also appear to impact susceptibility to viral

270

infection. Among EC-exposed mice, experimental infection with influenza A resulted in higher

271

viral titers and viral-related mortality(70). Providing further evidence of immunosuppressive

272

effects of EC, RNA analysis of nasal scrape biopsies of EC users revealed suppression of

273

significantly more genes involved in innate immunity compared to CC smokers(72). Taken

274

together, these data highlight the impairment of anti-bacterial and anti-viral defenses that may

275

occur with EC use and emphasizes the need for additional research to determine if the findings

276

in these in vitro and in vivo murine models translates to humans.

277

Efficacy of e-cigarettes in smoking cessation

278

Trends from US population surveys over the last 10 years note an association between an

279

increase in EC use and a concomitant increase in overall smoking cessation rates(8), suggesting

280

the potential role of EC as smoking cessation tools. While the bulk of human studies focusing on

281

the efficacy of EC as smoking cessation tools use observational designs, a few randomized

282

controlled trials have been conducted. In the largest trial conducted to date by Bullen and

283

colleagues, 657 smokers interested in quitting were randomized to receive either 16 mg nicotine

284

EC, 21 mg nicotine patches, or placebo EC and were followed for 6 months. Though tobacco

285

cessation for the entire study population was less than predicted resulting in insufficient power

286

to draw conclusions, abstinence was highest in those who received nicotine EC (7.3% vs 5.3%

287

for nicotine patches vs 4.1% with placebo EC)(73). In a more recent, smaller randomized-

288

controlled trial of 99 young adult smokers not willing to quit in New York City, a significantly

289

greater reduction in CC occurred in those randomized to receive a nicotine EC versus those

AC C

EP

TE D

M AN U

SC

RI PT

265

ACCEPTED MANUSCRIPT

receiving a nicotine-free EC over a three week time period(74), a finding similar to that

291

demonstrated in 48 other smokers randomized to either receive or not receive an EC during a 2

292

month trial (34% vs 0% achieved tobacco cessation, respectively)(75). Alternatively, Caponnetto

293

et al demonstrated no difference in smoking reduction or quit rates among 183 smokers

294

randomized into three arms to receive EC containing either 2.4%, 1.2%, or 0% nicotine and

295

followed for 52 weeks(76). The conclusions of meta-analyses examining the effectiveness of ECs

296

in smoking cessation may tip the scale ever so slightly in favor of their use with the caveat that

297

available data is of low certainty and is severely limited in terms of long-term efficacy(77-79) as

298

demonstrated by the heterogeneity of findings of the aforementioned randomized clinical trials.

299

It should be noted, however, that though complete cessation of CC use has clear health

300

benefits, the benefits of reduced smoking in the setting of dual use with EC are uncertain as are

301

the clinical effects of long-term EC use.

302

Effects of e-cigarette use on clinical biomarkers and symptoms

303

A paucity of data exists on the short-term and long-term health effects of EC use in humans

304

since their inception a decade ago. It is important to recognize that not all individuals will

305

demonstrate similar measurable outcomes following initiation of EC use. Thus, it is imperative to

306

study these health effects in population subsets, such as those naïve to CC, chronic smokers

307

who either switch to vaping or become dual users, and vulnerable individuals including youth

308

and those with underlying airway inflammatory disease. To this effect, we have subdivided the

309

following discussion on the clinical effects of EC use with respect to these subgroups.

310

Nonsmokers

311

Available information on health effects in those naïve to CC is limited, as most human studies

312

have focused on comparing EC to CC. Ferrari and colleagues assessed the effect of smoking a

313

CC and nicotine-free EC for 5 minutes each in both non-smokers and smokers who were naïve

AC C

EP

TE D

M AN U

SC

RI PT

290

ACCEPTED MANUSCRIPT

to EC by measuring pulmonary function tests (PFTs) and fractional excretion of nitric oxide

315

(FeNO) and carbon monoxide (FeCO). This short exposure to a nicotine-free EC revealed no

316

significant changes in outcomes measured in this small sample size of non-smokers (n=10)

317

while slight decreases in lung function were noted in smokers (n=10)(80). Passive exposure to

318

cigarette smoke and EC aerosol in two separate sessions in 15 non-smokers failed to produce

319

any changes in PFTs, but did generate similar increases in serum cotinine levels, a biomarker

320

and metabolite of nicotine(81), indicating comparable nicotine absorption when exposed second-

321

hand to either EC vapor or cigarette smoke, a finding also reported by others(82).

322

Chronic Conventional Cigarette Smokers

323

Various measures of health-related outcomes, including biomarker assessments and changes

324

in symptoms and lung function, have been assessed in chronic CC smokers who switch to using

325

EC either partially or completely. A one-year randomized trial found that smokers who

326

completely switched from CC to EC had improvements in FeNO and FeCO, which also

327

correlated with improvements in self-reported symptoms(83). No such beneficial effects were

328

seen in those who only partially substituted CC with EC. Similar improvements in biomarkers

329

were also reported in 105 study participants who either partially or completely replaced CC with

330

EC for only 5 days(84). In contrast, decreased FeNO and increased peripheral airway resistance

331

resulted from only 5 minutes of vaping in 30 smokers(85). Though the authors note that the small

332

changes may not be clinically relevant, longer durations of exposure may yield more deleterious

333

effects. However, abstaining from cigarette smoking over the course of one year through

334

substitution with EC improved forced expiratory flow at 25–75% of forced vital capacity (FEF25–

335

75%)

336

Vulnerable Populations

AC C

EP

TE D

M AN U

SC

RI PT

314

with a reduction in dyspnea and cough noted in quitters and reducers of CC(86).

ACCEPTED MANUSCRIPT

In those with underling inflammatory airway disease such as asthma and COPD, tobacco

338

smoke has long been known to be an exacerbating factor, with studies now beginning to

339

examine whether EC will play a similar role in these patients. A recent study of smokers with

340

mild intermittent asthma found increased airway resistance and reduced FeNO levels after a

341

single vaping session and required twice as long to return to baseline measures compared to

342

“healthy” smokers (87). In contrast, a retrospective study evaluating complete or partial transition

343

of CC by EC reported improvements in lung function, airway hyper-responsiveness, as well as

344

patient-reported asthma control at 12 months in 18 smokers with mild-to-moderate asthma(88).

345

These improved outcomes persisted in both sole EC users as well as dual users after

346

prospective follow-up for an additional 12 months(89). The short-term or long-term health effects

347

of EC use among asthmatics naïve to CC remain currently unknown.

348

Studies regarding EC use among patients with COPD yield inconsistent results. Two

349

observational cohorts in adults at risk for or with COPD suggested worse pulmonary-related

350

outcomes in those with EC use (either alone or in combination with CC)(90). In contrast, a

351

retrospective chart review noted significantly reduced COPD symptoms and exacerbations in

352

EC and dual users compared to CC users alone(91). This limited and varying data in patients

353

most susceptible to the potential harmful effects of ECs, or alternatively the most likely to benefit

354

from them, stresses the need for well-designed clinical trials assessing long-term health effects

355

in these subgroups.

356

In addition to those with underlying airway disease, youth represent another high risk patient

357

population to suffer from long-term adverse health effects from EC use. Recent studies have

358

reported increased risk of chronic respiratory symptoms among youth who use EC. High school

359

juniors and seniors from Southern California who use EC had twice the risk of reporting

360

respiratory symptoms (chronic cough, phlegm, and/or bronchitis) compared to their non-vaping

361

peers, even when adjusting for dual use with CC or exposure to second-hand smoke.

AC C

EP

TE D

M AN U

SC

RI PT

337

ACCEPTED MANUSCRIPT

Additionally, risk of chronic bronchitic symptoms increased with frequency of vaping(92). What is

363

unclear, though, is if these symptoms are secondary to chronic airway inflammation, and/or to

364

increased susceptibility to infection. Other cross sectional studies of adolescents support that

365

EC use is associated with increased prevalence of asthma symptoms and chronic bronchitis(93,

366

94)

367

harmonized objective and patient reported outcome measures, to determine the risks of EC

368

products on preventable infection and chronic respiratory disease in highly susceptible

369

populations.

370

Conclusions and Future Directions

371

Both the incidence and prevalence of ENDS use is increasing rapidly in the U.S. and throughout

372

the world, being partially fueled by the general notion that EC are harmless, particularly in

373

comparison to CC. Research efforts studying these assumptions are only beginning to emerge

374

in recent years. Notably, while this review focused on the potential respiratory toxicities of EC,

375

the addictive properties and neurocognitive effects of nicotine itself(95), used by the

376

overwhelming majority of EC users, as well as the effects of second-hand smoke exposure due

377

to ECs should certainly be considered. Likewise, physical injuries from EC explosions(96) and

378

from accidental exposures to nicotine-containing e-liquids, particularly in children(97), are

379

increasingly being reported, and should enter the discussion when counseling on EC use.

380

In regards to pulmonary effects, airway inflammation, respiratory infections, increased mucus

381

secretion, epithelial barrier defects, and oxidative stress are all features well-described in the

382

pathogenesis of asthma and COPD, as well as in acute exacerbations of these illnesses(67, 98-

383

104)

384

models suggests the possibility that recurrent exposure to EC has the potential to induce similar

385

airway inflammatory disease processes. This has yet to be elucidated in human models,

386

however, but is a vital area of needed research.

RI PT

362

AC C

EP

TE D

M AN U

SC

. It will be imperative to design larger scale longitudinal studies in those naïve to CC, with

. Triggering of these same biological effects by EC use as seen in some in vitro and in vivo

ACCEPTED MANUSCRIPT

While EC are frequently touted as less harmful than CC, clinical data regarding the safety of EC

388

use is still scant. Classifying an individual’s smoking status is imperative when considering

389

specific recommendations for EC use as the same recommendation may not apply to chronic

390

smokers and those naïve to CC, such as adolescents, or to those with underlying airway

391

disease. We have summarized the clinical data presented in this review with respect to chronic

392

smokers and individuals naïve to CC in Figures 2 and 3, respectively. Emerging data on clinical

393

respiratory effects currently tips the scale slightly in favor of use of EC in chronic smokers

394

(compared to CC use) (Figure 2). However, the potential benefits of replacing CC with EC has

395

only been demonstrated in the short-term as data for long-term respiratory effects and smoking

396

cessation efficacy with EC use is lacking, highlighting the danger in prematurely advocating

397

prolonged use of EC in smokers. In contrast, the increased risk of adopting CC among

398

adolescent EC users and the available short-term evidence of EC-triggered clinical respiratory

399

effects in those naïve to CC tip the scale against EC for these individuals (Figure 3). Further

400

research efforts should be devoted to studying the long-term respiratory effects in these specific

401

population subgroups, particularly in youth with underlying respiratory conditions such as

402

asthma who may be more prone to EC use compared to their non-asthmatic peers(105). This

403

information will allow for individualized recommendations of EC use and guidance for

404

appropriate federal regulatory measures.

405

Additionally, most studies to date are observational or retrospective, which inherently are

406

fraught with biases, and, as mentioned before, only assess the short-term effects of EC in small

407

sample sizes. Moreover, some research efforts are funded by EC manufactures or anti-smoking

408

foundations, necessitating caution in interpretation of data. Little consistency in methodologies

409

and outcome measurements between studies limits the accumulation of reproducible data from

410

which to draw meaningful conclusions. The inconsistency in available data could possibly

411

suggest that various features of EC may work in concert to either promote or prevent harmful

AC C

EP

TE D

M AN U

SC

RI PT

387

ACCEPTED MANUSCRIPT

effects (i.e. particular flavors, nicotine content, base solvent, power used, frequency of

413

exposure, etc). As previously discussed, the vast array of device designs and EL combinations

414

available to consumers presents an insurmountable hurdle for the research community in

415

obtaining reproducible results that can be compiled and compared.

416

For these reasons, both the regulation and standardization of ENDS is imperative for the

417

protection of vulnerable populations against future tobacco use, for the protection against the

418

development of chronic preventable disease should harm be incurred by use of these products,

419

and for the development of well-designed and unbiased generalizable longitudinal trials. While a

420

number of regulatory efforts have already taken place(106), additional research efforts are

421

urgently needed to further guide legislative processes of this booming industry as highlighted by

422

the recent recommendations of the ENDS Committee under the National Academies of

423

Sciences, Engineering, and Medicine(107). Though the last decade of research has made

424

important contributions to our current understanding of EC, the uncertainty that remains

425

regarding the safety and efficacy of EC (Table 1) needs to be addressed to arm the medical and

426

lay community with the knowledge necessary to promote long-term health and well-being.

429 430 431 432 433 434

SC

M AN U

TE D

EP

428

AC C

427

RI PT

412

ACCEPTED MANUSCRIPT

References:

436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479

1. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Characteristics, perceived side effects and benefits of electronic cigarette use: a worldwide survey of more than 19,000 consumers. International journal of environmental research and public health. 2014;11(4):4356-73. 2. Pericot-Valverde I, Gaalema DE, Priest JS, Higgins ST. E-cigarette awareness, perceived harmfulness, and ever use among U.S. adults. Preventive medicine. 2017. 3. Services. UDoHaH. E-cigarette Use Among Youth and Young Adults. In: Services UDoHaH, editor. Atlanta, GA2016. 4. Polosa R, Russell C, Nitzkin J, Farsalinos KE. A critique of the US Surgeon General's conclusions regarding e-cigarette use among youth and young adults in the United States of America. Harm reduction journal. 2017;14(1):61. 5. Nickels AS, Warner DO, Jenkins SM, Tilburt J, Hays JT. Beliefs, Practices, and Self-efficacy of US Physicians Regarding Smoking Cessation and Electronic Cigarettes: A National Survey. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2017;19(2):197207. 6. Ofei-Dodoo S, Kellerman R, Nilsen K, Nutting R, Lewis D. Family Physicians' Perceptions of Electronic Cigarettes in Tobacco Use Counseling. Journal of the American Board of Family Medicine : JABFM. 2017;30(4):448-59. 7. Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, et al. 21st-century hazards of smoking and benefits of cessation in the United States. The New England journal of medicine. 2013;368(4):341-50. 8. Zhu SH, Zhuang YL, Wong S, Cummins SE, Tedeschi GJ. E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys. Bmj. 2017;358:j3262. 9. McMillen RC, Gottlieb MA, Shaefer RM, Winickoff JP, Klein JD. Trends in Electronic Cigarette Use Among U.S. Adults: Use is Increasing in Both Smokers and Nonsmokers. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2015;17(10):1195-202. 10. Schoenborn CA, Gindi RM. Electronic Cigarette Use Among Adults: United States, 2014. NCHS data brief. 2015(217):1-8. 11. Jamal A, Gentzke A, Hu SS, Cullen KA, Apelberg BJ, Homa DM, et al. Tobacco Use Among Middle and High School Students - United States, 2011-2016. MMWR Morb Mortal Wkly Rep. 2017;66(23):597603. 12. Patel D, Davis KC, Cox S, Bradfield B, King BA, Shafer P, et al. Reasons for current E-cigarette use among U.S. adults. Preventive medicine. 2016;93:14-20. 13. Saddleson ML, Kozlowski LT, Giovino GA, Goniewicz ML, Mahoney MC, Homish GG, et al. Enjoyment and other reasons for electronic cigarette use: Results from college students in New York. Addictive behaviors. 2016;54:33-9. 14. Kenne DR, Fischbein RL, Tan AS, Banks M. The Use of Substances Other Than Nicotine in Electronic Cigarettes Among College Students. Substance abuse : research and treatment. 2017;11:1178221817733736. 15. Harrell MB, Loukas A, Jackson CD, Marti CN, Perry CL. Flavored Tobacco Product Use among Youth and Young Adults: What if Flavors Didn't Exist? Tobacco regulatory science. 2017;3(2):168-73. 16. Dai H, Hao J. Direct Marketing Promotion and Electronic Cigarette Use Among US Adults, National Adult Tobacco Survey, 2013-2014. Preventing chronic disease. 2017;14:E84. 17. Wills TA, Knight R, Williams RJ, Pagano I, Sargent JD. Risk factors for exclusive e-cigarette use and dual e-cigarette use and tobacco use in adolescents. Pediatrics. 2015;135(1):e43-51.

AC C

EP

TE D

M AN U

SC

RI PT

435

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

18. Singh T, Agaku IT, Arrazola RA, Marynak KL, Neff LJ, Rolle IT, et al. Exposure to Advertisements and Electronic Cigarette Use Among US Middle and High School Students. Pediatrics. 2016;137(5). 19. Villanti AC, Rath JM, Williams VF, Pearson JL, Richardson A, Abrams DB, et al. Impact of Exposure to Electronic Cigarette Advertising on Susceptibility and Trial of Electronic Cigarettes and Cigarettes in US Young Adults: A Randomized Controlled Trial. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2016;18(5):1331-9. 20. Etter JF. Gateway effects and electronic cigarettes. Addiction (Abingdon, England). 2017. 21. Soneji S, Barrington-Trimis JL, Wills TA, Leventhal AM, Unger JB, Gibson LA, et al. Association Between Initial Use of e-Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults: A Systematic Review and Meta-analysis. JAMA pediatrics. 2017;171(8):788-97. 22. Clapp PW, Jaspers I. Electronic Cigarettes: Their Constituents and Potential Links to Asthma. Current allergy and asthma reports. 2017;17(11):79. 23. Cheng T. Chemical evaluation of electronic cigarettes. Tobacco control. 2014;23 Suppl 2:ii11-7. 24. Rawlinson C, Martin S, Frosina J, Wright C. Chemical characterisation of aerosols emitted by electronic cigarettes using thermal desorption-gas chromatography-time of flight mass spectrometry. Journal of chromatography A. 2017;1497:144-54. 25. Herrington JS, Myers C. Electronic cigarette solutions and resultant aerosol profiles. Journal of chromatography A. 2015;1418:192-9. 26. Lee MS, LeBouf RF, Son YS, Koutrakis P, Christiani DC. Nicotine, aerosol particles, carbonyls and volatile organic compounds in tobacco- and menthol-flavored e-cigarettes. Environmental health : a global access science source. 2017;16(1):42. 27. Williams M, Bozhilov K, Ghai S, Talbot P. Elements including metals in the atomizer and aerosol of disposable electronic cigarettes and electronic hookahs. PloS one. 2017;12(4):e0175430. 28. Ogunwale MA, Li M, Ramakrishnam Raju MV, Chen Y, Nantz MH, Conklin DJ, et al. Aldehyde Detection in Electronic Cigarette Aerosols. ACS omega. 2017;2(3):1207-14. 29. Flora JW, Wilkinson CT, Wilkinson JW, Lipowicz PJ, Skapars JA, Anderson A, et al. Method for the Determination of Carbonyl Compounds in E-Cigarette Aerosols. Journal of chromatographic science. 2017;55(2):142-8. 30. El-Hellani A, Salman R, El-Hage R, Talih S, Malek N, Baalbaki R, et al. Nicotine and Carbonyl Emissions From Popular Electronic Cigarette Products: Correlation to Liquid Composition and Design Characteristics. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2016. 31. Gillman IG, Kistler KA, Stewart EW, Paolantonio AR. Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e-cigarette aerosols. Regulatory toxicology and pharmacology : RTP. 2016;75:58-65. 32. Farsalinos KE, Gillman G, Poulas K, Voudris V. Tobacco-Specific Nitrosamines in Electronic Cigarettes: Comparison between Liquid and Aerosol Levels. International journal of environmental research and public health. 2015;12(8):9046-53. 33. Uchiyama S, Senoo Y, Hayashida H, Inaba Y, Nakagome H, Kunugita N. Determination of Chemical Compounds Generated from Second-generation E-cigarettes Using a Sorbent Cartridge Followed by a Two-step Elution Method. Analytical sciences : the international journal of the Japan Society for Analytical Chemistry. 2016;32(5):549-55. 34. Khlystov A, Samburova V. Flavoring Compounds Dominate Toxic Aldehyde Production during ECigarette Vaping. Environmental science & technology. 2016;50(23):13080-5. 35. Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tobacco control. 2014;23(2):133-9. 36. Zhu SH, Sun JY, Bonnevie E, Cummins SE, Gamst A, Yin L, et al. Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation. Tobacco control. 2014;23 Suppl 3:iii3-9.

AC C

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

37. Behar RZ, Wang Y, Talbot P. Comparing the cytotoxicity of electronic cigarette fluids, aerosols and solvents. Tobacco control. 2017. 38. Welz C, Canis M, Schwenk-Zieger S, Becker S, Stucke V, Ihler F, et al. Cytotoxic and Genotoxic Effects of Electronic Cigarette Liquids on Human Mucosal Tissue Cultures of the Oropharynx. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 2016;35(4):343-54. 39. Anderson C, Majeste A, Hanus J, Wang S. E-Cigarette Aerosol Exposure Induces Reactive Oxygen Species, DNA Damage, and Cell Death in Vascular Endothelial Cells. Toxicological sciences : an official journal of the Society of Toxicology. 2016;154(2):332-40. 40. Putzhammer R, Doppler C, Jakschitz T, Heinz K, Forste J, Danzl K, et al. Vapours of US and EU Market Leader Electronic Cigarette Brands and Liquids Are Cytotoxic for Human Vascular Endothelial Cells. PloS one. 2016;11(6):e0157337. 41. Holliday R, Kist R, Bauld L. E-cigarette vapour is not inert and exposure can lead to cell damage. Evidence-based dentistry. 2016;17(1):2-3. 42. Yu V, Rahimy M, Korrapati A, Xuan Y, Zou AE, Krishnan AR, et al. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral oncology. 2016;52:58-65. 43. Misra M, Leverette RD, Cooper BT, Bennett MB, Brown SE. Comparative in vitro toxicity profile of electronic and tobacco cigarettes, smokeless tobacco and nicotine replacement therapy products: eliquids, extracts and collected aerosols. International journal of environmental research and public health. 2014;11(11):11325-47. 44. Teasdale JE, Newby AC, Timpson NJ, Munafo MR, White SJ. Cigarette smoke but not electronic cigarette aerosol activates a stress response in human coronary artery endothelial cells in culture. Drug and alcohol dependence. 2016;163:256-60. 45. Neilson L, Mankus C, Thorne D, Jackson G, DeBay J, Meredith C. Development of an in vitro cytotoxicity model for aerosol exposure using 3D reconstructed human airway tissue; application for assessment of e-cigarette aerosol. Toxicology in vitro : an international journal published in association with BIBRA. 2015;29(7):1952-62. 46. Leslie LJ, Vasanthi Bathrinarayanan P, Jackson P, Mabiala Ma Muanda JA, Pallett R, Stillman CJP, et al. A comparative study of electronic cigarette vapor extracts on airway-related cell lines in vitro. Inhal Toxicol. 2017;29(3):126-36. 47. Antherieu S, Garat A, Beauval N, Soyez M, Allorge D, Garcon G, et al. Comparison of cellular and transcriptomic effects between electronic cigarette vapor and cigarette smoke in human bronchial epithelial cells. Toxicology in vitro : an international journal published in association with BIBRA. 2017. 48. Azzopardi D, Patel K, Jaunky T, Santopietro S, Camacho OM, McAughey J, et al. Electronic cigarette aerosol induces significantly less cytotoxicity than tobacco smoke. Toxicology mechanisms and methods. 2016;26(6):477-91. 49. Cervellati F, Muresan XM, Sticozzi C, Gambari R, Montagner G, Forman HJ, et al. Comparative effects between electronic and cigarette smoke in human keratinocytes and epithelial lung cells. Toxicology in vitro : an international journal published in association with BIBRA. 2014;28(5):999-1005. 50. Clapp PW, Pawlak EA, Lackey JT, Keating JE, Reeber SL, Glish GL, et al. Flavored e-cigarette liquids and cinnamaldehyde impair respiratory innate immune cell function. American journal of physiology Lung cellular and molecular physiology. 2017;313(2):L278-l92. 51. Gerloff J, Sundar IK, Freter R, Sekera ER, Friedman AE, Robinson R, et al. Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas ChromatographyMass Spectrometry in e-Liquids and e-Vapors on Human Lung Epithelial Cells and Fibroblasts. Applied in vitro toxicology. 2017;3(1):28-40.

AC C

528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

52. Leigh NJ, Lawton RI, Hershberger PA, Goniewicz ML. Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS). Tobacco control. 2016;25(Suppl 2):ii81-ii7. 53. Lerner CA, Rutagarama P, Ahmad T, Sundar IK, Elder A, Rahman I. Electronic cigarette aerosols and copper nanoparticles induce mitochondrial stress and promote DNA fragmentation in lung fibroblasts. Biochemical and biophysical research communications. 2016;477(4):620-5. 54. Higham A, Rattray NJ, Dewhurst JA, Trivedi DK, Fowler SJ, Goodacre R, et al. Electronic cigarette exposure triggers neutrophil inflammatory responses. Respir Res. 2016;17(1):56. 55. Rubenstein DA, Hom S, Ghebrehiwet B, Yin W. Tobacco and e-cigarette products initiate Kupffer cell inflammatory responses. Molecular immunology. 2015;67(2 Pt B):652-60. 56. Schweitzer KS, Chen SX, Law S, Van Demark M, Poirier C, Justice MJ, et al. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures. American journal of physiology Lung cellular and molecular physiology. 2015;309(2):L175-87. 57. Wu Q, Jiang D, Minor M, Chu HW. Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells. PloS one. 2014;9(9):e108342. 58. Sun Y, Ito S, Nishio N, Tanaka Y, Chen N, Isobe K. Acrolein induced both pulmonary inflammation and the death of lung epithelial cells. Toxicology letters. 2014;229(2):384-92. 59. Husari A, Shihadeh A, Talih S, Hashem Y, El Sabban M, Zaatari G. Acute Exposure to Electronic and Combustible Cigarette Aerosols: Effects in an Animal Model and in Human Alveolar Cells. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2016;18(5):6139. 60. Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, et al. 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. 2015;10(2):e0116732. 61. Lim HB, Kim SH. Inhallation of e-Cigarette Cartridge Solution Aggravates Allergen-induced Airway Inflammation and Hyper-responsiveness in Mice. Toxicological research. 2014;30(1):13-8. 62. Larcombe AN, Janka MA, Mullins BJ, Berry LJ, Bredin A, Franklin PJ. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. American journal of physiology Lung cellular and molecular physiology. 2017;313(1):L67-l79. 63. Ween MP, Whittall JJ, Hamon R, Reynolds PN, Hodge SJ. Phagocytosis and Inflammation: Exploring the effects of the components of E-cigarette vapor on macrophages. Physiological reports. 2017;5(16). 64. Sherwood CL, Boitano S. Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine. Respir Res. 2016;17(1):57. 65. Aufderheide M, Emura M. Phenotypical changes in a differentiating immortalized bronchial epithelial cell line after exposure to mainstream cigarette smoke and e-cigarette vapor. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie. 2017;69(6):393-401. 66. Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, et al. Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax. 2016;71(12):1119-29. 67. Zhou-Suckow Z, Duerr J, Hagner M, Agrawal R, Mall MA. Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases. Cell and tissue research. 2017;367(3):537-50. 68. Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun. 2015;6:6281.

AC C

574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

69. Reidel B, Radicioni G, Clapp P, Ford AA, Abdelwahab S, Rebuli ME, et al. E-Cigarette Use Causes a Unique Innate Immune Response in the Lung Involving Increased Neutrophilic Activation and Altered Mucin Secretion. Am J Respir Crit Care Med. 2017. 70. Sussan TE, Gajghate S, Thimmulappa RK, Ma J, Kim JH, Sudini K, et al. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PloS one. 2015;10(2):e0116861. 71. Hwang JH, Lyes M, Sladewski K, Enany S, McEachern E, Mathew DP, et al. Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria. Journal of molecular medicine (Berlin, Germany). 2016;94(6):667-79. 72. Martin EM, Clapp PW, Rebuli ME, Pawlak EA, Glista-Baker E, Benowitz NL, et al. E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke. American journal of physiology Lung cellular and molecular physiology. 2016;311(1):L135-44. 73. Bullen C, Howe C, Laugesen M, McRobbie H, Parag V, Williman J, et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet (London, England). 2013;382(9905):1629-37. 74. Tseng TY, Ostroff JS, Campo A, Gerard M, Kirchner T, Rotrosen J, et al. A Randomized Trial Comparing the Effect of Nicotine Versus Placebo Electronic Cigarettes on Smoking Reduction Among Young Adult Smokers. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2016;18(10):1937-43. 75. Adriaens K, Van Gucht D, Declerck P, Baeyens F. Effectiveness of the electronic cigarette: An eight-week Flemish study with six-month follow-up on smoking reduction, craving and experienced benefits and complaints. International journal of environmental research and public health. 2014;11(11):11220-48. 76. Caponnetto P, Campagna D, Cibella F, Morjaria JB, Caruso M, Russo C, et al. EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study. PloS one. 2013;8(6):e66317. 77. El Dib R, Suzumura EA, Akl EA, Gomaa H, Agarwal A, Chang Y, et al. Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: a systematic review and meta-analysis. BMJ open. 2017;7(2):e012680. 78. Vanderkam P, Boussageon R, Underner M, Langbourg N, Brabant Y, Binder P, et al. [Efficacy and security of electronic cigarette for tobacco harm reduction: Systematic review and meta-analysis]. Presse medicale (Paris, France : 1983). 2016;45(11):971-85. 79. Malas M, van der Tempel J, Schwartz R, Minichiello A, Lightfoot C, Noormohamed A, et al. Electronic Cigarettes for Smoking Cessation: A Systematic Review. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2016;18(10):1926-36. 80. Ferrari M, Zanasi A, Nardi E, Morselli Labate AM, Ceriana P, Balestrino A, et al. Short-term effects of a nicotine-free e-cigarette compared to a traditional cigarette in smokers and non-smokers. BMC Pulm Med. 2015;15:120. 81. Flouris AD, Chorti MS, Poulianiti KP, Jamurtas AZ, Kostikas K, Tzatzarakis MN, et al. Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function. Inhal Toxicol. 2013;25(2):91-101. 82. Ballbe M, Martinez-Sanchez JM, Sureda X, Fu M, Perez-Ortuno R, Pascual JA, et al. Cigarettes vs. e-cigarettes: Passive exposure at home measured by means of airborne marker and biomarkers. Environmental research. 2014;135:76-80. 83. Campagna D, Cibella F, Caponnetto P, Amaradio MD, Caruso M, Morjaria JB, et al. Changes in breathomics from a 1-year randomized smoking cessation trial of electronic cigarettes. European journal of clinical investigation. 2016;46(8):698-706.

AC C

621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

84. O'Connell G, Graff DW, D'Ruiz CD. Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers. Toxicology mechanisms and methods. 2016;26(6):443-54. 85. Vardavas CI, Anagnostopoulos N, Kougias M, Evangelopoulou V, Connolly GN, Behrakis PK. Short-term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest. 2012;141(6):1400-6. 86. Cibella F, Campagna D, Caponnetto P, Amaradio MD, Caruso M, Russo C, et al. Lung function and respiratory symptoms in a randomized smoking cessation trial of electronic cigarettes. Clinical science (London, England : 1979). 2016;130(21):1929-37. 87. Lappas AS, Tzortzi AS, Konstantinidi EM, Teloniatis SI, Tzavara CK, Gennimata SA, et al. Shortterm respiratory effects of e-cigarettes in healthy individuals and smokers with asthma. Respirology. 2017. 88. Polosa R, Morjaria J, Caponnetto P, Caruso M, Strano S, Battaglia E, et al. Effect of smoking abstinence and reduction in asthmatic smokers switching to electronic cigarettes: evidence for harm reversal. International journal of environmental research and public health. 2014;11(5):4965-77. 89. Polosa R, Morjaria JB, Caponnetto P, Caruso M, Campagna D, Amaradio MD, et al. Persisting long term benefits of smoking abstinence and reduction in asthmatic smokers who have switched to electronic cigarettes. Discovery medicine. 2016;21(114):99-108. 90. Bowler RP, Hansel NN, Jacobson S, Graham Barr R, Make BJ, Han MK, et al. Electronic Cigarette Use in US Adults at Risk for or with COPD: Analysis from Two Observational Cohorts. Journal of general internal medicine. 2017. 91. Polosa R, Morjaria JB, Caponnetto P, Prosperini U, Russo C, Pennisi A, et al. Evidence for harm reduction in COPD smokers who switch to electronic cigarettes. Respir Res. 2016;17(1):166. 92. McConnell R, Barrington-Trimis JL, Wang K, Urman R, Hong H, Unger J, et al. Electronic Cigarette Use and Respiratory Symptoms in Adolescents. Am J Respir Crit Care Med. 2017;195(8):1043-9. 93. Cho JH, Paik SY. Association between Electronic Cigarette Use and Asthma among High School Students in South Korea. PloS one. 2016;11(3):e0151022. 94. Wang MP, Ho SY, Leung LT, Lam TH. Electronic Cigarette Use and Respiratory Symptoms in Chinese Adolescents in Hong Kong. JAMA pediatrics. 2016;170(1):89-91. 95. Siqueira LM. Nicotine and Tobacco as Substances of Abuse in Children and Adolescents. Pediatrics. 2017;139(1). 96. Patterson SB, Beckett AR, Lintner A, Leahey C, Greer A, Brevard SB, et al. A Novel Classification System for Injuries After Electronic Cigarette Explosions. Journal of burn care & research : official publication of the American Burn Association. 2017;38(1):e95-e100. 97. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clinical toxicology (Philadelphia, Pa). 2017;55(10):1072-252. 98. Webley WC, Hahn DL. Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respir Res. 2017;18(1):98. 99. Kleniewska P, Pawliczak R. The participation of oxidative stress in the pathogenesis of bronchial asthma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2017;94:100-8. 100. Gon Y, Hashimoto S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergology international : official journal of the Japanese Society of Allergology. 2017. 101. Desai M, Oppenheimer J. Elucidating asthma phenotypes and endotypes: progress towards personalized medicine. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2016;116(5):394-401.

AC C

668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713

ACCEPTED MANUSCRIPT

RI PT

102. Leung JM, Tiew PY, Mac Aogain M, Budden KF, Yong VF, Thomas SS, et al. The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD. Respirology. 2017;22(4):634-50. 103. Berg K, Wright JL. The Pathology of Chronic Obstructive Pulmonary Disease: Progress in the 20th and 21st Centuries. Archives of pathology & laboratory medicine. 2016;140(12):1423-8. 104. Gao W, Li L, Wang Y, Zhang S, Adcock IM, Barnes PJ, et al. Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology. 2015;20(5):722-9. 105. Larsen K, Faulkner GEJ, Boak A, Hamilton HA, Mann RE, Irving HM, et al. Looking beyond cigarettes: Are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes? Respiratory medicine. 2016;120:10-5. 106. Dobbs PD, Hammig B, Sudduth A. 2015 Legislative update of e-cigarette youth access and exposure laws. Preventive medicine. 2016;88:90-4. 107. National Academies of Sciences E, Medicine. Public Health Consequences of E-Cigarettes. Stratton K, Kwan LY, Eaton DL, editors. Washington, DC: The National Academies Press; 2018. 680 p.

SC

714 715 716 717 718 719 720 721 722 723 724 725 726 727 728

M AN U

729 730 731

735 736 737 738 739 740 741

EP

734

AC C

733

TE D

732

ACCEPTED MANUSCRIPT

Table 1: What is still unknown regarding electronic cigarette use and its effect on respiratory health?

the most harmful and least harmful biological and clinical effects?

RI PT

What particular combinations of e-liquid constituents (solvent, nicotine, and flavors) result in

What factors may predict the subsequent use of conventional cigarettes in adolescents who use electronic cigarettes, thus providing areas for regulatory focus?

SC

Do the biological effects of e-liquids and aerosols demonstrated in vitro and in murine models translate into humans?

M AN U

What are the long-term clinical respiratory effects of e-cigarette use in chronic smokers and in those naïve to conventional cigarettes, such as youth and young adults? Does e-cigarette use predispose individuals to the development of chronic airway respiratory disease and exacerbate symptoms in those with existing disease?

What are the short- and long-term health effects of e-cigarette use in adolescents and adults

TE D

with asthma who are naïve to conventional cigarette use?

Does use of e-cigarettes result in long-term smoking cessation, and therefore function similar

743 744 745 746 747 748

AC C

742

EP

to nicotine replacement products already regulated by the FDA?

ACCEPTED MANUSCRIPT

Figure Legends

750

Figure 1. Electronic cigarette design and constituents. E-cigarettes consist of three basic

751

components: a battery source, heating element (atomizer coil), and cartridge. Heat from the

752

atomizer coil after activation of the power source aerosolizes e-liquid, which is then inhaled, or

753

“vaped,” from the attached mouthpiece. The exact constituents detected in the vapor depends

754

on various factors, including the flavor and solvent used, the nicotine content, temperature

755

generated, and material of heating element. Each generation of electronic cigarettes varies in

756

size and design with newer generations least resembling a conventional cigarette. PG:

757

polyethylene glycol; VG: vegetable glycerin; TSNAs: tobacco-specific nitrosamines; VOCs:

758

volatile organic compounds.

759

Figure 2. Short-term clinical effects of substituting electronic cigarettes for conventional

760

cigarettes in chronic smokers. While the available data for replacement of conventional

761

cigarettes with e-cigarettes in chronic smokers suggests slightly more respiratory benefits and

762

smoking cessation efficacy in the short term, the long-term effects of e-cigarette usage on

763

clinical outcomes and persistent smoking cessation in this population are lacking, hindering

764

strong recommendations for their longstanding use. FeNO: fractional excretion of nitrogen

765

oxide; PFT: pulmonary function test; FeCO: fractional excretion of carbon monoxide; CC:

766

conventional cigarettes; COPD: chronic obstruction pulmonary disease; ∆: changes.

767

Figure 3. Short-term clinical effects of electronic cigarette use those naïve to

768

conventional cigarette. The available clinical data regarding the short-term respiratory effects

769

of e-cigarette use in those naïve to conventional cigarettes and the increased risk of initiating

770

cigarette smoking in youth EC users argue against their adoption in these individuals.

771

Moreover, long-term effects have yet to be elucidated in this population, including those with

772

underlying airway inflammation such as asthma. FeNO: fractional excretion of nitrogen oxide;

773

PFT: pulmonary function test; ∆: changes.

AC C

EP

TE D

M AN U

SC

RI PT

749

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT