10/08/2019

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© The Children’s Mercy Hospital, 2017

Alvin Singh, MD

Assistant professor

Pediatric Pulmonology and sleep medicine

Children’s Mercy – Kansas City

University of Missouri – Kansas city

E-Cigarettes, Vaping

& their Implications

Implications

Scientific Implications

• Historical

– History of tobacco & Intro to E-cigs

• Public Health

– Teenage Trends

• Substance Abuse/Addiction

– Juul; Ingredients/Chemical Make-up &

Exposure; Cessation; FDA Response

Social Implications

• Marketing & Language

– Social Media; Smoking Cessation

• Economical & Political

• Advocacy

Objectives

• 1. Review the trends in tobacco consumption and the emergence of e-cigarettes

– Examine trends in teenage use of tobacco since the emergence of e-cigs

– Look at the emergence of Juul and its role in the tobacco industry with relation to teenage use

– FDA Response

• 2. Discuss the chemical composition of e-cigarettes

– Review e-cigarettes role in smoking cessation, passive exposure

• 3. Review adverse events related to e-cigarette consumption

– Examine how certain formulations, or flavors may be playing a role.

• 4. Discuss Future Directions, Resources, Advocacy

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As of right now…

• 10/1/19

– 1080 possible cases of lung illness

– 48 states and 1 US Territory – 80% < 35 years of age

• 16% under 18 and 21% are 18-20 years of age

– 18 deaths, 15 states

– No evidence of infectious disease

– No specific substance or e-cig product identified

• Reported use of liquids containing cannabinoid products (THC)

Tobacco Statistics

• As of 2019 – WHO

– More than 8 million people die annually due to

tobacco related diseases

• More than 7 million – direct tobacco use

• 1.2 million – 2nd hand smoke

https://www.who.int/en/news-room/fact-sheets/detail/tobacco

Tobacco Use - Teens

• Current E-cigarette use in teens

– 27.5%

• 90% adult smokers

– Started smoking before 18 yrs

• 2/3 become everyday smokers at or before 18 yrs

https://www.tobaccofreekids.org/assets/factsheets/0002.pdf

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Emergence of E-cigarette

• Begins with smoking cessation

• Decrease coronary artery disease risk by 50% after one year

• Decrease risk of lung cancer by 50% after 10 years

• Attempting to quit is difficult

• Relapse within 8 days with no assistance

• 3-5% prolonged abstinence of 6-12 months

Emergence of E-cigarette• Dramatically increased in popularity in 2004

• Addiction driven by multitude of behavioral smoking cues

• Some NRT’s do not address

• People using it as a form of smoking cessation

• Lack of evidence

• Initial literature examining efficacy and safety

• Sparse

• Lacked randomized study designs compared to other NRTs

• More data required (2)

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https://www.vaporplants.com/what-is-a-vape-pen

Juul• 2 components

– Bottom – Battery, temperature regulation system

– Top – E-liquid cartridge- also the mouthpiece

– Rechargeable – USB – laptop!!

– Best tasting- 4 flavors

– https://www.juul.com/shop/pods

• Difference

– No settings

– Not user modifiable

– Temp. regulation – prevent overheating and combustion

• Less likely to burn or explode

JUUL = discrete

• 55% of the e-cigarette market in 2 years (from 5% in 2016)

• FDA decided to crack down on against illegal sales to minors – asking for JUUL documents

• Looks like a flash drive

– Discrete way to sneak devices into school or in public

https://www.thedenverchannel.com/news/local-news/teens-disguising-drugs-at-schools-through-vaping-creative-containers

http://www.chicagotribune.com/news/nationworld/ct-juul-ecigarette-vape-20180424-story.html

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NPR

• https://www.npr.org/sections/health-shots/2018/06/07/615724991/he-started-vaping-as-a-teen-and-now-says-juul-is-impossible-to-let-go

• Talked about vaping in high school

• “…even after an hour and a half or two, I‘m chomping at the bit to find my JUUL”

• JUUL Labs – “alternative to adult smokers, not anyone else, not minors”

• Flavors such as cotton candy, Frutti Tutti, cookies and cream, caramel, cherry, crème brulee

• Safer than cigarettes, and you can use them to quit

• But can also use them to get addicted

Teens and vaping

• 27% high schoolers• Recently vaped

• 2017: 11%• < 5% adults use electronic cigarettes

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https://www.fda.gov/tobacco-products/youth-and-

tobacco/youth-tobacco-use-results-national-youth-

tobacco-survey

https://www.cdc.gov/mmwr/volumes/67/wr/mm6745a5.htm?

s_cid=mm6745a5_w#F1_down

Tobacco Use - KS

9/23/19

• 2017 YRBS

– 34.8% high school

students tried e-cigs

– 10.6% currently use

http://www.kdheks.gov/vaping/index.htmhttps://truthinitiative.org/research-resources/smoking-

region/tobacco-use-kansas-2019

Tobacco Use - MO

https://truthinitiative.org/research-resources/smoking-region/tobacco-use-missouri-2019

Gross Under-Estimation

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FDA Timeline

• June, 2009

– Family Smoking Prevention and Tobacco Control Act (TCA)

• Regulatory authority over tobacco products & smokeless tobacco

• Grandfathered in products already for sale

• Created barriers to for new products to break through the market

• Protect existing brands from competition – fulfill pre-market standards

• Flavorings banned

https://vaping360.com/rules-laws/fda-deeming-regulations-timeline/

http://www.casaa.org/historical-timeline-of-electronic-cigarettes/

FDA Timeline

• July, 2009 FDA:

– Meet definition of drug-delivery devices

– Discourages using e-cigs

• Marketed to young people

• Lack of health warnings

• Contain carcinogens (diethylene glycol)

FDA Timeline

• December 2010

– US Court of Appeals

• FDA can only regulate e-cigs as a tobacco product, unless

therapeutic claims are made

• April 2011

– FDA will regulate e-cigs under tobacco products

– Unless advertised as smoking cessation tool

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FDA Timeline

• October 2013

– EU rejects wholesale ban on e-cigs

• should contain no more than 30mg/ml of nicotine

• should carry health warnings

• should not be sold to anyone under 18 years old

• subject to the same advertising restrictions as tobacco products

FDA Timeline

• April 2014

– FDA releases proposed regulation attempting

to exert regulatory authority of e-cigarettes as

tobacco products

• May 2016 – FDA Issues Regulations

November 2016

• New FDA Director

– Remake the Nicotine landscape

• Reduce nicotine in cigarettes to below addictive

levels

• E-cigs are important – safer nicotine products to

replace cigarettes

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FDA Update

• https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm625884.htm

• “Today, I’m directing the FDA’s Center for Tobacco Products (CTP) to revisit this compliance policy as it applies to deemed ENDS products that are flavored, including all flavors other than tobacco, mint and menthol. The changes I seek would protect kids by having all flavored ENDS products (other than tobacco, mint and menthol flavors or non-flavored products) sold in age-restricted, in-person locations and, if sold online, under heightened practices for age verification.”

Washington post, 2017

– Several senior officials of previous tobacco firms have ties to administration

– Chad Readler – Acting assistant attorney general for civil division – Represented RJ Reynolds Law Firm previously

• Contributed $1 Million to inauguration

– FDA Head Scott Gottlieb

• Served on board of EC firm Kure until May 2016

• March 15, 2018

• FDA states that they plan to reduce the amount of nicotine levels in

cigarettes to help reduce addiction

– Decrease smoking rates

– Limit tobacco related deaths

– Did not specify when or how much

– NO mention of electronic cigarettes

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New Light...

– Postpone with 2018 PMTA submission

deadline for four years, until Aug. 8, 2022

– While applications were reviewed, products

could remain on the market indefinitely

• previously only allowed to be sold for one year,

even if the FDA had not determined their eligibility

Wired Magazine 2017

• What’s inside Vape Juice?

– Water – vapor

– Vegetable Glycerin – sugar alcohol

• Texture enhancer, boosts thickness

• Also found in moisturizers

– Propylene Glycol

• Tasteless, odorless, colorless

– Flavoring

– Nicotine

E-Juice

• https://www.vaporfi.com/vape-juice/juice-deals/

• Any flavor you want

– Combination

• Other ingredients…

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Propylene Glycol

• Synthetic liquid that absorbs water

• Base for de-icing solutions

• Anti-freeze

– Contact with food

– Absorb extra water; maintain moisture in medications, cosmetics and food

– “generally recognized as safe”

• In the body:

– Metabolizes to proprionaldehyde

• EPA: Used in the manufacture of plastics, rubber chemicals; Used as disinfectant, preservatives

Abusing E-cigarettes• Do not deliver CO or other carcinogens

• Users may “tamper” to deliver larger doses of nicotine

• “Dripping”

• Increases exposure to other chemicals

• Can also mix different liquid solutions

• Also mix alcohol, THC oil

• Also increase voltage

• Increase nicotine yield of vapor

• Others may use it as a way to reduce nicotine consumption

• Should also use other means of support to help quit - Behavior treatment with counseling (4)

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Vaping and THC

• https://www.centeronaddiction.org/e-cigarettes/recreational-vaping/beyond-nicotine-vaping-marijuana

• Research is limited

• Study in Connecticut

– 18% high school students who vaped had used e-cigs

• Hash oil or THC-infused wax

• Less smell than joint, pipe

• Higher concentrations of THC

– Mild altering and addictive effects.

Passive exposure• Summarize and review all studies examining potential adverse effects of passive exposure to EC

• Compare to background and cigarette smoke exposures

• Articles from 1996 to 2015

• Effects from passive exposure in animals and humans, Vapor analysis directly or in ambient air

• 16/312 studies relevant

• EC vapor compared to background levels - Increased nicotine, formaldehyde, propylene glycol

• EC vapor compared to cigarette smoke - Lower levels of every compound except nickel, silver

• Small sample sizes, impact of animal studies

• Further research needed (5)

Effect of nicotine on developing

human• Adolescents

• ~250,000 used EC

• Nearly half intending to use cigarettes

• Higher cognitive function development continues into 20s

• Period of neural remodeling, synaptic pruning

• Cholinergic matures

• Cognitive maturation, executive function

• Smoking associated with effects on working memory, attention

• More likely to become dependent on nicotine and traditional smoking (6)

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NEJM

• 886 participants – randomly assigned

– NRT of their choice, or combo – up to 3 months provided

– E-cig starter pack

• Weekly behavioral support for at least 4 weeks

• Primary Outcome:

– Sustained abstinence for one year

– E-cig group: 18% 1 year abstinence rate; NRT group: 9.9%

• E-cig group - Mouth or throat irritation, but did use their assigned product more

Peter Hajek et al. A randomized trial of e-cigarettes versus nicotine replacement therapy. N Engl J

Med 2019; 380:629-637

Takeaway

• E-cigarettes were more effective for [traditional] smoking

cessation than nicotine-replacement therapy,

• when both products were accompanied by behavioral

support.

• Also became addicted to E-cigs

– “The rate of continuing e-cigarette use was high”

Introduction to smoking?

• Increasingly popular among youth

• In never-smokers

– Associated with cigarette smoking

– Studies from California, Hawaii, Mid-Atlantic

– US, Canada, UK samples

• Meta-analysis – greater than 3-fold increase risk of cigarette smoking

– E-cig-users compared to never-smokers

Chaffee et al. Electronic Cigarette Use and the Progression From Experimentation to Established Smoking. Pediatrics

Volume 141, Number 4, March, 2016

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Higher nicotine use

• Evaluate if e-cigs with higher nicotine concentrations is associated with increased increases in combustible smoking

• Prospective cohort study – 10 high schools in LA

• Surveys given to students in 10th and 11th grades

– Reported e-cigs in the last 30 days and nicotine level

– None; low (1-5mg/mL); med (6-17mg/mL); high (<18)

• 6 month follow up

– Frequency in the last 30 days – 0, 1-2, >3

– Daily intensity

• Cigarettes smoked/day, vaping episodes/day, puffs/vaping episode

JAMA Pediatr. 2017;171(12):1192-1199. doi:10.1001/jamapediatrics.2017.3209

JAMA, 2017

• 181 students – 96 boys; 85 girls

• Each increase in nicotine concentration vaped

– Associated with a 2.26 (95%, CI 1.28-3.98) increase in the odds of frequent vs no smoking

– 1.65 (05% CI, 1.09-2.51) increase in the odds of frequent vs. no vaping

• Higher nicotine concentration - Greater number of cigarettes smoked/day

• More vaping episodes/day compared to no nicotine

• Similar for increased puffs/vaping

• Using e-cigs with higher nicotine concentrations by youths may increase frequency and intensity of smoking and vaping

JAMA Pediatr. 2017;171(12):1192-1199. doi:10.1001/jamapediatrics.2017.3209

What about “Experimenters”• Using E-cigs and progressing to smoking

– Smoked cigarettes, but not yet > 100

– 12-17 years of age via survey with 1 year follow up from the Population Assessment of Tobacco and Health Survey

• When using E-cigarettes vs not:

– 2x more likely to:

• Established smoker - > 100 cigarettes

• Current smoker – smoked in the last 30 days

• Both established current smoker

• Among experimenters:

– E-cigarette was positively and independently associated with progression to current est. smoking, suggesting that e-cigarettes do not divert from, and may encourage cigarette smoking

Chaffee et al. Electronic Cigarette Use and the Progression From Experimentation to Established

Smoking. Pediatrics Volume 141, Number 4, March, 2016

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Juul Chemistry

E-cigs & Vape Pens

• Freebase Nicotine

• Basic pH

• Throat Irritation

• Limited tolerability

• Good stability

Juul

• Nicotine salt

– With Benzoic Acid

• Acidic/Neutral pH

• Smoother hit to throat

• Increased tolerability

• Improved stability

Vapeuk.co.uk

Why??

• https://www.vox.com/2019/1/25/18194953/vape-juul-e-cigarette-marketing

• “…new analysis of Juul’s marketing campaign suggests it targeted youth from its inception.”

• Stanford Research Into the Impact of Tobacco Advertising

– Looked at thousands of social media posts

– “…patently youth oriented.”

– “Borrowed directly from the tobacco industry playbook”

• New public Health Crisis

– April, 2018 – FDA – demanding submit documents

• Marketing, research, sales to youth, Restrict sales of flavored vape devices online & in stores

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Marketing

https://www.vox.com/2019/1/25/18194953/vape-juul-e-cigarette-

marketing

Marketing Now

https://www.juul.com/community

Advertising at Schools

• NYT – 7/25/2019

– Paid numerous schools

• $10,000 – $134,000

• “deployed a sophisticated program to enter schools

and convey its messaging directly to teenage

children,”…

https://www.nytimes.com/2019/07/25/health/juul-teens-vaping.html

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$1.3 million: average bonus Juul employees …

• https://www.vox.com/2018/12/20/18150202/juul-altria-deal

• December, 2018 – 35% Juul was purchased by Altria

– Parent company of Philip Morris

– Valued at $38 billion

– More valuable than Airbnb, SpaceX

• $2 billion in bonuses - $1.3 million/person

• During a time when trying to “improve lives of billions of adult smokers”

Immune response to the Lungs

• From 2011 to 2015

• - E-cigarette use increased by 900% in high school students

• Sputum samples from

• - 15 E-cigarette users, 14 cigarette users and 15 non-smokers

• Sputum samples analyzed

– E-cigs

• Neutrophil granulocyte, Neutrophil extracellular trap

– E-cigs & Cigs increases in

• MMP9, thioredoxin, aldehyde detoxification, oxidative-stress - Mucus production – MUC5AC – bronchitis, asthma, wheeze, bronchiectasis

Kesimer, Mehmet et al. E-Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased

Neutrophilic Activation and Altered Mucin Secretion. Am J Resp Crit Care Med October, 2017.

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Conclusion

• “Comparing harm of e-cigarettes with cigarettes is like comparing

apples to oranges…”

• “Our data shows that e-cigarettes have a signature of harm in the

lung that is both similar and unique, which challenges the

concept that switching from cigarettes to e-cigarettes is a

healthier alternative”

But it’s safer…• “You’re inhaling water vapor…”

• Previous reports of eosinophilic pneumonia, lipid pneumonia

• Previously healthy (except for mild asthma) 18 yo female presented to the ED with cough, SOB, pleuritic chest pain

• Began e-cigarettes 2-3 weeks prior – last used a few days before onset of symptoms

• Saturation on room air were 84%, with decreased breath sounds in the bases b/l

• Labs: Elevated WBC with left shift and CRP 17.4

• CXR – b/l opacities; Chest CT: dependent atelectasis, septal thickening, moderate fluid in the lungs

Sommerfeld, Casey et al. Hypersensitivity Pneumonitis and Acute Respiratory Distress Syndrome From E-

Cigarette Use. Pediatrics Vol 141, No 6, June, 2018

• PICU on broad spectrum antibiotics – worsened

• Breathing tube placed needing a lot of oxygen

• B/L chest tubes for worsening fluid in the lungs

• Scope for fluid negative for infections, significant WBC and inflammatory markers

– 26% Neutrophils; 13% Lymphocytes; 14% Monocytes; 22% eosinophils; 25% mononucleated cells

• Started on 40mg IV steroids twice daily

• Improved and breathing tube removed 5 days later

• Discharged on steroid course

• Based on symptoms, imaging, inciting agent, lab results and response to steroids –diagnosed with hypersensitivity pneumonitis

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Eosinophilic pneumonia

• 18 yo female

• Presented with cough, shortness of breath, chest pain

• Started vaping 2 months prior

• Low oxygen saturations on exam

• Blood count showed elevated white blood cells, 0.5% eosinophils

• CXR – possible pneumonia – started on antibiotics

• Had worsening saturations, respiratory distress

• Chest CT – patchy airspace disease and nodules

Arter et al. Acute eosinophilic pneumonia following electronic cigarette use. Respiratory Medicine Case Reports

27 (2019) 100825

AEP• Worsening respiratory failure – transferred to ICU

• Bronchoscopy performed

– 26% eosinophils

– No microbes noted

• Diagnosis of acute eosinophilic pneumonia

• High dose systemic steroids administered

– Marked improvement in 2 days

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Case report

• Life-threatening Vesicular Bronchial Injury Requiring Veno-Venous Extracorporeal Membrane Oxygenation rescue in an Electronic Nicotine Delivery System User

• Came into ED with chest pain and dyspnea

• Admitted for work up

• Increased respiratory support despite normal CXR

• CT showed nodular infiltrates in the lower lobes, mediastinal adenopathy

• Admitted to e-cigarette use – equal to 2 packs/day cigarettes

• Mechanically ventilated with breathing tube

Carter, Thomas et al. Clin Pract Cases Emerg Med.2017;1(3):212-217

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Thomas et al case report

• Bronchoscopy:

- “extensive airway trauma and thermal injury”

- Eventually underwent VV ECMO – lung bypass

- Eventually improved over time

Case report

• Previous research :

- Capable of heating liquid solutions to temperature 350C

- Undergo conversion/breakdown

- Formaldehyde, acetaldehyde, acetone, acrolein, propanal, butanal, glyoxal, methylglyoxal

- Acrolein, formaldehyde, acetaldehyde – pulmonary irritants

- Probable carcinogen, necrosis of living tissues

- Propanal – pulmonary edema

- Butanal – toxic pneumonitis

- More volatile and reactive when heated

Tao, HE et al. AnnalsATS 14:3, March 2017

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DOI: 10.1056/NEJMc1911995

https://www.cnn.com/2019/06/19/health/e-cigarette-vape-explode-teen-study/index.html

Khairudin MN, et al. BMJ Case Rep 2016. doi:10.1136/bcr-2016-214964

Paley et al. Cornea 2016;35:1015-1018

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Fires…

• https://fox61.com/2019/02/13/vape-pen-explodes-on-delta-flight/

https://www.usfa.fema.gov/downloads/pdf/publications/electronic_cigarettes.pdf

Aldehydes & Respiratory

Defenses• Acetaldehyde, Acrolein, Crotonaldehyde

– Respiratory inflammation

– Impair innate and adaptive immune cell responses

– Reduce mucociliary transport – Salathe et al

• “slow ciliary beat frequency, dehydrate airway fluid, make mucus more sticky”

– Dysregulate antioxidant responses

– Increase infection susceptibility

– Lead to emphysema and COPD

– Flavors??

Moghe et al. “Molecular mechanisms of acrolein toxicity: relevance to human disease.” Toxicological Sciences 143.2 (2015): 242-255

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Flavor Implications

• Increased area of research interest

• Cinnamon

– Suppress Nicotine Metabolism – CYP2A6

• Rhanasto et al. Drug Metab Dispos. 2016 Apr;44(4):534-43

– Inhibits immune cell functions

• Macrohages, Neutrophils, Natural Killer Cells

Other Implications

• Nicotine poisoning

– Ingestion

• Seizures

– FDA investigating

• Packaging

– Made to look like cough syrup

– https://www.fda.gov/news-events/fda-brief/fda-brief-fda-warns-companies-stop-making-selling-or-distributing-e-liquids-marketed-resemble

Future directions/research• Evidence to help regulators write reasonable regulations

• Smoking cessation and initiation

• Safety and toxicity

• Use by non-smokers

• Dual use with cigarettes

• Use in public spaces

• Flavor and nicotine content

• Messaging regarding continuum of risk

• “Chasing a moving target” (12)

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https://www.tobaccofreekids.org/assets/factsheets/0146.pdf

Taxing…

https://truthinitiative.org/research-resources/smoking-region/tobacco-use-kansas-2019

https://truthinitiative.org/research-resources/smoking-region/tobacco-use-missouri-2019

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https://www.tobaccofreekids.org/assets/factsheets/0169.pdf

Tobacco 21

Banning E-cigs

9/25/18

• Michigan

• New York

• Massachusetts

• Rhode Island

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Tobacco Lobbying

https://www.opensecrets.org/lobby/indusclient.php?id=A02&year=2019

https://www.opensecrets.org/lobby/indusclient.php?id=H01

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“Comparing harm of e-cigarettes with cigarettes is like comparing apples to oranges…”

“Our data shows that e-cigarettes have a signature of harm in the lung that is both similar and unique, which challenges the concept that switching from

cigarettes to e-cigarettes is a healthier alternative”

Resources

• American Thoracic Society

– https://www.thoracic.org/advocacy/tobacco-kids.php

• CDC

– https://www.cdc.gov/tobacco/basic_information/e-cigarettes/index.htm

• AAP

– https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/Richmond-

Center/Pages/Electronic-Nicotine-Delivery-Systems.aspx

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Resources

• ALA

– https://www.lung.org/stop-smoking/smoking-facts/e-cigarettes-and-lung-health.html

• History with FDA

– http://www.casaa.org/historical-timeline-of-electronic-cigarettes/

Resources

• http://www.kansascity.com/living/health-fitness/article213386814.html

• https://www.kctv5.com/news/e-cigarette-usage-increases-in-missouri-kansas-schools/article_e71ba236-ddb8-

11e8-9493-0b56cf7fd4fa.html

• https://www.435mag.com/in-kansas-city-parents-are-grappling-with-an-epidemic-of-teenage-vaping-heres-how-to-

help-your-child/

• https://www.kmbc.com/article/kansas-city-hospitals-see-patients-with-vaping-related-lung-problems/28930833

• https://us.vocuspr.com/ViewNewsOnDemand.aspx?Email=rlsarafin%40cmh.edu&Date=9%2f17%2f2019+7%3a31

%3a24+AM&ArticleID=1434304_23358_463317921

• https://www.childrensmercy.org/parent-ish/2019/09/vaping/

references

1. Castaldelli-Maia et al. Tobacco smoking: From “glamour” to stigma”. A comprehensive review. Psychiatry and Clinical Neurosciences 2016;70:24-33

2. Franck, Caroline et al. Electronic Cigarettes in North America. History, Use, and Implications for Smoking Cessation. Circulation 2014;129:1945-1952

3. Burstyn, Igor. Peering through the mist: systematic review of what chemistry of contaminants in electronic cigarettes tells us about health risks. BMC Public Health 2014, 14:18

4. Weaver, Michael et al. Clinical case conference electronic cigarettes: a review of safety and clinical issues. J Addict Med. 2014;8(4):234-240

5. Hess, Isabel et al. A systematic review of the health risks from passive exposure to electronic cigarette vapour. Public Health Res Pract. 2016;26(2):e2621617

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references

6. England, Lucinda MD et al. Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate. Am J Prev Med. 2015;49(2):286-293

7. Suter, Melissa et al. Is There Evidence for Potential Harm of Electronic Cigarette Use in Pregnancy? Birth Defects Res A Clin Mol Teratol. 2015;103(3):186-195

8. Lippi, Giuseppe MD et al. E-Cigarettes and Cardiovascular Risk: Beyond Science and Mysticism. Semin Thromb Hemost 2014;40:60-65

9. Kalkhoran MD, Sara et al. E-Cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis. Lancet Respir Med. 2016;4(2):116-128

10. McRobbie, H et al. Electronic cigarettes for smoking cessation and reduction (Review). Cochrane Database of Systematic Reviews. 2014;12: Art. No CD010216

references

11.Lacasse MD Yves et al. E-cigarette use in patients receiving home oxygen therapy. Can Respir J. 2015;22(2):83-85

12.Bhatnagar, Aruni et al. Electronic Cigarettes. A Policy Statement From the American Heart Association. Circulation. 2014;130:1418-1436

13.Breland, Alison et al. Science and Electronic Cigarettes: Current Data, Future Needs. J Addict Med. 2014;8(4):223-233

14.Etter, Jean-Francois. E-cigarettes: Methodological and Ideological Issues and Research Priorities. BMC Medicine. 2015;13:32

References

• 15. Chafee, Benjamin et al. Electronic Cigarette Use and Progression From

Experimentation to Established Smoking. Pediatrics, March, 2018.

• 16. Goldenson, Nicholas et al. Associations of Electronic Cigarette Nicotine

Concentration With Subsequent Cigarette Smoking and Vaping Levels in

Adolescents

• 17. Reidel, Boris et al. E-Cigarette Uses Causes Innate Immune Response

in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin

Secretion.