e-cigaretteper smettere o iniziare a fumare?

E-cigarette per smettere o iniziare a fumare?

Francesco Blasi

Dipartimento Fisiopatologia Medico-Chirurgica e Trapianti

Università degli Studi di Milano

Direttore Dipartimento Medicina Interna, UOC Pneumologia e Centro Adulti Fibrosi Cistica, Fondazione IRCCS Cà Granda

Ospedale Maggiore Policlinico di Milano

– I have accepted grants, speaking and conference invitations from Angelini, AstraZeneca, Almirall, Bayer, Chiesi, Dompé, GSK, Guidotti-Malesci, Menarini, Novartis, Pfizer, Sanofi, Teva and Zambon

– I have had recent or ongoing consultancy with AstraZeneca, Chiesi, GSK, Menarini, Mundipharma, Novartis, and Zambon

Disclosures

New nicotine delivery system• Users achieve same level of nicotine in blood as smokers

• More than 500 brands• First, second and third generation

• Disposable/refilled

• Look like cigarettes or pipes/containers with fluid

Charlotta Pisinger, RCPH

Explosive increase of sale

• Recent years:

– tobacco industry is buying up

– aggressive marketing

– explosive increase of sale

– largely unregulated global market

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Sale of e-cig


How it works

• Liquid container + a battery-operated heating element– Puffing activates the heating element and the liquid is vaporized


New terms

”I’m not a smoker”

o Vaper

It’s not smoke

o Vapor

I don’t smoke

o Vape

o Puffing


Content of an e-cigarette

• Vapor producing agents (>90%)

– Propylene glycol

– Glycerin

• Nicotine

• Flavours (>8000)

• Water

• Alcohol

• Chemical additives…


SexGlamourFreedomIndependenceEnjoying lifeSafety


E-cigarettes and health

Update of systematic reviewWHO - last search Oct 2015: 175 studies

identified

32

11

105

31Human experiments

Animal experiments

Fluid/vapor

Adverse events

(4 studies are mentioned both in Animal experiments and Fluid/vapor)Charlotta Pisinger, RCPH

+ Non-systematic search, Aug 2016: 215 studies identified

39

16

123

38Human experiments

Animal experiments

Fluid/vapor

Adverse events

(5 studies are mentioned both in Animal experiments and Fluid/vapor)Charlotta Pisinger, RCPH

General findings

• New research field with many methodological challengeso No ‘standard e-cigarette’

o No ‘standard vaping-machine’

• Most studies compare with cigarettes/smokingo An e-cig is a completely different product

• Misleading/missing information on product ingredients

• No long-term effect studies


34% of studies has conflict of interest

9211

1622

11

68

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40

60

80

100

120

Humanexperi.

Animalexperi.

Fluid/vapor Adverseevents

No conflicts ofinterest

Tobacco industry

Other conflict ofinterest

Results from the systematic review.

13


Studies on fluid/vapor

Harmful substances identified• Fine/ultrafine particles

• Carcinogenic tobacco specific nitrosamines

• Carcinogenic carbonyls

• Harmful metals

• Volatile organic compounds

• Polycyclic aromatic hydrocarbons

Mostly lower/much lower concentrations than in cigarettes

Very conflicting results! o Most/few/no brands or

samples

o High concentrations /low or trace levels

In general: studies with severe conflicts of interest have findings indicating no or little harm on health


Studies on fluid/vaporToxicity

• 42 samples/15 brands: none of the products were totally exempt of potentially toxic compounds and a minority of liquids, especially those with flavorings, showed particularly high ranges of chemicals Varlet V 2015

• Toxicants and potentially carcinogenic substances found in urine Schober 2014; Hecht 2015


Studies on fluid/vaporFlavors

• Essential part of e-liquids

• Approved as safe for oral intake

• Diacetyl: in 75% of the e-cig samples Allen 2015

o a food sweetener approved as completely safe

o workers exposed to inhalation: airway obstruction caused by bronchiolitis obliterans, (‘pop-corn lung’) Starek-Swiechowicz 2014

=Charlotta Pisinger, RCPH

Experiments: cells exposed to fluid/vapor/vapor extract

• Dysregulation of gene expression; genotoxicity; vapor can change gene expression in a similar way to tobacco smokePark 2014; Palpant 2015; Lerner 2016

• Increased DNA strand breaks and cell death -independently of nicotine content Ji 2016

• Dose-dependent loss of lung endothelial barrier function Schweitzer 2015


Experiments: cells exposed to fluid/vapor/vapor extract

• Cytotoxic effects Scheffler 2015; Varlet 2015; Tierney 2015; Farsalinos 2013

Bahl 2012; Willershausen 2014; Sherwood 2016; Hwang 2016

Ji 2016; Putzhammer 2016; Kosmider 2016

• Increased oxidative stress and inflammationDinicola S 2013, Shivalingappa et al. April 201, Cervellati F 2014, Schweitzer KS 2015, Rubenstein D 2015 , Higham 2014, Lerner 2015, Schweitzer KS 2015, Scheffler S 2015; Higham 2016

• Promotes Human rhinovirus and Staphylococcus aureusinfection Dinicola 2013; Hwang 2016

• Platelet aggregation and adhesion is enhanced Chen 2015; Hom2016


High toxicity

o Some flavors

o High voltage devices

o Overheating

o “Dripping” and “Dry puff” conditions

o Second half of a vaping period; re-use

o Type of vaporiser


Animal experimental studies

• Neonatal mice – short term exposure McGrath-Morrow 2015

– Diminished alveolar cell proliferation

– Impairment in postnatal lung growth

• Mice – short term exposure Lim 2014; Sussan 2015; Lerner 2015; Hwang 2016

– Asthmatic reaction and inflammation of airways

– Decreased pulmonary anti-bacterial defense

– Higher mortality when exposed to virus infection

• Mice - longer term exposure: development of asthma and emphysemaGeraghty 2014


Human experimental studiesPulmonary system • significant inhibition of cough reflex sensitivity Dicpinigaitis 2015

• particle dose in lungs as with smoking Marini 2014

• reductions in exhaled nitric oxide (eNO) Marini 2014; Vardavas 2012 and fractional exhaled nitric oxide (FeNO) Vakali 2014 /FeNO increased Schober 2014

• Significant airway obstruction

o increased flow resistance Chorti 2012

o significant decrease in flow Ferrari 2014

o immediate significant airway obstruction Gennimata 2014

o increased airway resistance Marini 2014; Palamidas 2014; Vardavas 2012

o decrease in specific airway conductance Palamidas 2014

Healthy (smoking) volunteersMethodological problems: small studies, insufficient + short term exposure

Patients with asthma and COPD


Lung function – experimental sessions

• Baseline

• Immediately after exposure

• One hour after exposure

Smoking Vaping (e-cig)Flouris 2013

o Smoking: significantdecrease in lung function

o Vaping: Non-significantdecrease

*

Effects that remind of those seen with smoking But less pronounced


Human experimental studies

Cardiovascular system• No negative effect on stiffness of aorta Farsalinos 2013

/negative effect on stiffness similar to smoking Vlachopoulos 2016

• Blood pressure and heart rate increased Vansickel 2012; Czogala 2012; Vakali 2014; Tsikira 2014; Battista 2013; Yan 2015; Papaseit 2014; Farsalinos 2014

/not increased Eisenberg 2010; Vansickel 2010; van Staden 2013

• Unfavorable effects on flow-mediated dilatation Carnevale 2016

• No influence complete blood count or cardiac function Flouris 2012

Healthy (smoking) volunteersMethodological problems: small studies, insufficient + short term exposure


Adverse events

• Symptoms from all organ systems

– Most frequent: respiratory symptoms and symptoms from the mouth

• No serious adverse events in prospective studies or in RCT Bullen 2013

• Decrease in respiratory symptoms (and objective improvements in asthma outcomes) Polosa 2014

• Improvements in general health

Selection bias

Surveys and longitudinal studies

Conflicting results


Adverse eventsCase reportso Contact dermatitis

o Acute eosinophilic pneumonitis

o Subacute bronchial toxicity

o Exogenous lipid pneumonia

o Reversible cerebral vasoconstriction syndrome

o Atrial fibrillation

o Arterial vasospasm

o Lichen planus

o Lingua villosa nigra

o Colonic necrotizing enterocolitits in a new born child

o Inflammatory reaction mimicking metastatic cancer

o Relapse of colitis ulcerosa symptoms

o Remission in a colitis ulcerosa patient

o Beneficial effects on idiopathic chronic neutrophilia

Time association and reversibility


Two cross-sectional epidemiologicalstudies

• > 45,000 Chinese students Wang 2015

• E-cig use: significantly associated with self-reported respiratory symptoms in analyses adjusted for sex, age, perceived family affluence, secondhand smoke exposure, and school clustering effect (OR= 1.28 (1.06-1.56))

• >35,000 high school students in South Korea Cho 2016

• E-cig users: significant association with student's self-reported doctor diagnosis of asthma (OR=2.74 (1.30-5.78))

o More likely to have had days absent from school due to severe asthma symptoms


E-cigarettes and the respiratory system

Fluid/vapor/exposure of cells:o Cytotoxic effects, dose-dependent loss of lung endothelial barrier functiono Diacetyl (ingredient), safe for ingestion but known to give pop corn lungsAnimal studies:o Diminished alveolar cell proliferation and impairment in postnatal lung growtho Asthmatic reaction and inflammation of airwayso Development of asthma and emphysemao Decreased pulmonary anti-bacterial defense and higher mortality when exposed to virus infectionHuman experimental studies: o Increased airway resistance and airway obstructiono Effects that remind of those seen with smoking Case reports: Acute eosinophilic pneumonitis, subacute bronchial toxicity, exogenous lipid pneumonia

Epidemiology: Cross sectional studies show increase in resp./asthma symptomsAdverse events: Contradicting results. Increased/ improved resp. symptomso Smokers who completely abstained from smoking showed improvements in exhaled breath

measurements and symptoms scores, even if they were still using e-cig

The lungs are the primary target organ


General conclusions on health effects• Many methodological problems, many studies with severe conflicts

of interest, inconsistencies and contradictions in results, relatively few high-quality studies, rapidly changing designs of the product and lack of long-term follow-up: no firm conclusions can be drawn on the safety of e-cig

• There is an increasing body of evidence indicating harm

• It is not meaningful to speak of risk of vaping of e-cig as risk of one product. Risk depends on: the brand and batch, the flavor, the heating of the e-cig, the vaporizer, how dirty or worn the e-cig is, the way of vaping, and factors still unknown…


My patient is a reluctant smoker, unwilling/unable to quit.

Isn’t it better for him to switch to e-

cigarettes?

The rationale for ‘’harm reduction”


Real-life: 8 out of 10 vapers also smoke

Danish nationally representative sample. Survey: ”Rygevaneundersøgelse 2013. Udført af Gallup

for Sundhedsstyrelsen, Kræftens Bekæmpelse, Hjerteforeningen og Danmarks Lungeforening”

• >80% UK, nationally representative sample English Smoking Toolkit Aug 2015

• 74 % Poland. Youth. Goniewicz 2015

• 76% USA. Youth. CDC, MMWR, 62(35), Sept 6, 2013

• 77% Georgia. Youth. King 2014.

• 77% Kansas US (2012-2013). Adults Christensen 2014

• >80% Korea. Youth. Lee 2014

• 78% Canada, nationally representative sample Reid 2015


The reality

+


Dual use (e-cig vaping + smoking)

Buy e-cigto quit

Try to quit RelapseE-cig +

smoking

..but if they reduce the number of cigarettessusbstantially –thendual use might be

good for theirhealth?

1. Reduction of number of cigarettes has significant effect on health

2. Vapers significantly reduce number of cigarettes


Health benefits of reduced smoking intensity?

• Halving (or more) of daily intake of number of cigarettes :

o No reduction in all-cause mortality, incidence of cardiovascular disease or smoking related cancer/cancer mortality Song 2008; Hart

2013; Tverdal 2006; Godtfredsen 2002; Godtfredsen 2003

o Reductions in lung cancer risk Godtfredsen 2005; Song 2008


Reduction in number of conventionalcigarettes?

• Substantial reductions are not reported in dual users– no change in consumption after one year Etter 2014; Huh 2015

– 9 of 10 did not cut back substantially Brose 2015

– reduction of only approx. 5 cig/day Manzoli 2015


Health effects of dual use

Extremely little evidence on health effects of combined vaping and smokingo 6 studies Polosa 2014; McRobbie 2015; Adriaens 2014; Manzoli 2015; Wang 2015;

Vannier 2015

o Most short term, max. 1 year follow-up

o Positive effect reported in very few dual users ( 2 studies, total n=25)

o Rest: No change or negative health effects


“Switch to a safer product”


The facts of the matter are straightforward. (A)There is little evidence that e-cigarettes are an aid to

smoking cessation, and much evidence that tobaccomanufacturers are advertising e-cigarettes as a bridge to starting nicotine and as a vehicle for long termcontinuation;

(B) no-one, expert or otherwise, can credibly assert that e-cigarettes are safer than tobacco in the long term, given thatthey contain a whole new tranche of unregulated and unstudied compounds being inhaled into the lung

Can the current authors or anyone else propose a biologically credible model whereby long-term inhalation of such compounds is anything but highly risky?

ERS NEWSLETTER 23 02 2018

• Furthermore, besides being unhealthy to the individual user, smoking, vaping and any form of inhaling and exhalingsubstances, affects not only that user but everyone sharingthat user’s space.

• So, allowing vaping in public places is a breach of the right to health of all; there is no credible public health case for treating vaping as any different from tobacco smoking.

• It is important to take a stand now and not wait for another30 years to start fighting “healthier” alternatives to smoking. Smoking cessation should be strongly recommended, with evidence-based interventions and supported by accreditedprofessionals and peer help; and in this context, the evidence that e-cigarettes are at all helpful is exceedinglyweak . Nicotine is addictive, and any recreational nicotine use should be opposed root and branch. Instead, we shouldpromote a healthy lifestyle.

ERS NEWSLETTER 23 02 2018

ERJ IN PRESS

Thank youfor your

attentionCharlotta Pisinger, RCPH

e-cigaretteper smettere o iniziare a fumare?

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