19 September 2019

A touch of the vapours

Policy Respiratory

“People are dying with vaping,” US President Donald Trump said while announcing a ban on flavoured e-cigarettes last month. “A lot of people think vaping is wonderful, it’s great. It’s really not wonderful.”

At that point six people had died (that number has now at least doubled) and around 400 cases had been identified of acute vaping-linked lung disease across the US.

It was “a new problem”, President Trump said – a telling comment from the leader of a country where six gun deaths would be a slow news day, and where half a million people die each year from tobacco-related causes. Good old-fashioned risks are always more tolerable than whatever the kids are doing.

But on this issue, as on few others, President Trump has allies among eminent health experts who think the teen vaping “epidemic” is a new health disaster in the making, while others warn that curbing vapers’ enjoyment will send them back to smoking.

The President’s move – which has drawn protests from business, conservative groups and senior Republicans – follows flavoured e-cigarette bans in San Francisco and Michigan state, and New York soon followed suit with a 90-day ban.

It flies in the face of advice from veteran tobacco control expert Professor Michael Siegel, of Boston University’s School of Public Health, who had reacted to Michigan’s ban: “I cannot overemphasise how insane this policy is … it makes absolutely no sense to ban these fake cigarettes, but to allow the real ones to remain on the shelves … [It] is going to have devastating public health consequences. This is an example to the nation of exactly what not to do to respond to the epidemic of youth vaping.”

The Centers for Disease Control says vapers should consider stopping – especially THC products – until it figures what is behind the outbreak of vaping-related lung injury.

And Australia’s Chief Medical Officer and state and territory counterparts have released a joint statement warning of the link between e-cigarettes and lung illness, and saying there is “insufficient evidence to promote the use of e-cigarettes for smoking cessation”.

Early tests showing lipid-laden macrophages in the lungs of some of the affected patients led to a tentative diagnosis of exogenous lipoid pneumonia, inflammation from inhaling fats.

But subsequent histopathology, described by Mayo Clinic doctors in the New England Journal of Medicine in early October, has found no evidence of that. The injuries more resembled those from chemical burns.

Biopsies from 17 patients “showed patterns of acute lung injury, including acute fibrinous pneumonitis, diffuse alveolar damage, or organizing pneumonia, usually bronchiolocentric and accompanied by bronchiolitis”, the doctors wrote. The histologic changes “suggest that vaping-associated lung injury represents a form of airway-centered chemical pneumonitis from one or more inhaled toxic substances rather than exogenous lipoid pneumonia as such, but the agents responsible remain unknown”.

Most patients have a history of vaping not just nicotine but also THC liquid, still a black market product in many states.

An early suspect was vitamin E acetate, though this oily substance was found in only 10 samples of liquid tested.

Only a few sporadic, non-fatal cases of acute lung illness have been reported in vapers in the roughly 10 years since e-cigarettes became widely used, suggesting something new is going on.

But that nuance is being lost in the media storm, which may threaten the efforts of those who want e-cigarettes made easily available to help more smokers quit.

Colin Mendelsohn, chairman of the Australian Tobacco Harm Reduction Association and a conjoint associate professor in the School of Public Health and Community Medicine at the University of NSW, became interested in smoking cessation during his 30 years as a GP. He now helps patients quit smoking, and recently wrote about how to prescribe nicotine e-cigarettes for The Medical Republic.

While the states and territories have some different rules, selling nicotine liquid is banned across Australia. It’s legal to import it with a GP’s prescription, but the paperwork is burdensome and anecdotal reports suggest many vapers are buying nicotine online or in stores without a prescription.

To date, the Therapeutic Goods Administration has not approved a single e-cigarette product as a smoking cessation aid.

Professor Mendelsohn says e-cigarettes have helped smokers quit when nothing else could, and should be available here in a consumer-friendly way. For one thing, that would remove the need to import nicotine liquid in highly toxic concentrated form, in non-childproof bottles, like the one that killed a toddler in Victoria last year.

“If the mother had been able to go to the local shop and buy a little childproof bottle of low-concentration nicotine, that wouldn’t have happened,” he tells TMR.

Professor Mendelsohn is “very, very confident” there’s nothing nasty down the track for vapers of nicotine. He says snus, a moist powder smokeless tobacco product, has given Sweden the lowest smoking rates in the world “with no known serious harmful effects” after several decades.

In the other corner is longtime anti-tobacco campaigner Simon Chapman, an emeritus professor in Sydney University’s School of Public Health, who is far more wary of e-cigarettes, believing their benefits to be oversold and their potential harms still unknown.

Unlike Professor Mendelsohn, who says e-cigarettes should be treated as a consumer good to better compete with the more harmful alternative, Professor Chapman says since therapeutic claims are made for e-cigarettes they should continue to be regulated as such by the TGA. He backs the Trump flavour ban.

“If they’re serious about doing everything they can to make these products unattractive to young people then removing flavours is really important,” he tells TMR. “It’s a balance between minimising the attractiveness of the products to kids and having a product which will be acceptable to people who want to quit by vaping.”

There are three big questions for the science: whether vaping helps smokers quit; whether it opens the door to cigarette smoking for young non-smokers; and whether it is in itself harmful.

But the science to date is somewhat mixed and open to interpretation. Take the recent randomised controlled trial of more than 1100 subjects, published in The Lancet Respiratory Medicine, which found e-cigarettes plus nicotine patches produced more than twice the rate of smoking cessation as patches alone; but the numbers were low, just 7% to 2%.

“These products are hyped as game-changers and disrupters and revolutionary, but they are just marginally better than nicotine-replacement therapy,” Professor Chapman says. “So it’s really hugely, hugely overhyped.”

Professor Mendelsohn takes the opposite view of the same results, saying cessation numbers are low with any method and it’s the odds ratio that matters. A British study published earlier this found an 18% cessation rate for e-cigarettes versus 9.9% with traditional NRT.

The existence of a “gateway” effect is a notoriously difficult thing to prove since causation must be established, and you can’t randomise a bunch of teenagers to a course of vaping.

study in Pediatrics last year concluded that “using e-cigarettes was positively and independently associated with progression to current established smoking”. Another in JAMA Network Open in February found that “tobacco-naive youths who initiate e-cigarettes may be at greater risk of subsequently initiating cigarette smoking”.

But both were observational and as the second study notes, “we cannot establish causal relations or rule out the possibility of residual confounding by underlying risk-taking propensities”.

“Many studies show that kids who try vaping are more likely to try smoking later,” Professor Mendelsohn says. “It’s likely that young people who try vaping have an increased risk for risk-taking and are more likely to take up smoking anyway, and this may account for the relationship between vaping and future smoking, rather than the vaping itself. This is called common liability.”

He says the continued declines in adolescent smoking in the UK and US – where e-cigarettes are easier to obtain – are inconsistent with vaping significantly increasing smoking rates. He cites two studies that found banning the sale of e-cigarettes to minors in two US states was associated with a significant rise in youth smoking compared with states without bans.

Professor Mendelsohn says while it is regularly stated that most vapers are “dual users” – i.e. also smoking – that proportion is coming down around the world as e-cigarettes become more effective.

So, if vaping does replace smoking but creates a new habit, is that a problem (leaving aside the fact that the vaping devices occasionally literally blow up in your face)?

“They should be less dangerous because you’re not inhaling smoke which is full of carbon monoxide, particulate matter, carcinogens, et cetera,” Professor Chapman says. “But we actually don’t know what the long-term effects are of inhaling, on average 200 times a day, ultrafine particles and these flavouring chemicals in particular.

“There are something like 8000 flavours and none of them have been approved by the regulatory agencies as being safe for inhalation – they have been deemed safe for ingestion as food flavourants.”

He cites a new systematic review in Preventive Medicine looking at the cardiovascular effects of e-cigarettes in human, animal and in vitro studies, 74% of which suggested potential harms, mainly atherosclerosis and thrombosis via oxidative stress, endothelial dysfunction, platelet activation and sympathetic nerve activation.

“There’s some quite alarming stuff that could be down the track,” Professor Chapman says. “I think most people probably agree there is reduced cancer risk, but if you combine cardiovascular risk and respiratory diseases like COPD, you’re still looking at enormous potential for widespread chronic disease.

“It’s just frankly too early to tell. The diseases we get from smoking manifest 10, 20, 30 years after you start. So yes, it sounds like a cop-out to say we don’t know. But anyone who says we do know is really blowing hot air.”

Professor Mendelsohn concedes there is little certainty about flavours, but says vaping has been around long enough to know if there were acute risks.

“We do know that if you keep smoking your chances of death are up to two in three,” he says. “So you’ve got to weigh up any risks from that against the risks of smoking and [studies show] flavours play an important role in switching adults from smoking to vaping.”

E-cigarettes are commonly said to be 95% safer than cigarettes. This figure originated with a multicriteria decision analysis study led by neuropsychopharmacologist David Nutt, and has been reaffirmed by Public Health England and the UK’s Royal College of Physicians.

But do you know what you’re getting when you buy a vape liquid?

Mislabelling is quite common, according to Associate Professor Alexander Larcombe from the School of Public Health at Curtin University and head of Respiratory Environmental Health at the Telethon Kids Institute.

Dr Larcombe co-authored a small study in the Medical Journal of Australia this year showing that of 10 “nicotine-free” liquids tested, six contained nicotine – some in trace amounts, suggesting contamination from uncleaned equipment, but others at 2-3mg/mL, enough to be considered low-concentration nicotine liquid.

He says while this could amount to accidental mislabelling, other similar studies have found concentrations of up to 20mg/mL, which looks deliberate.

“We also had some other potentially nasty chemicals in there, one called 2-chlorophenol, which can be used in pesticides and cleaning products, and some other chemicals that are byproducts of biological processes, which indicated the process of making these things wasn’t necessarily particularly clean,” he tells TMR.

Besides contaminants, there’s the flavours, most of which are approved as foodstuffs but not for heating, aerosolising and inhaling.

“They contain a list as long as your arm of all sorts of chemicals,” Professor Larcombe says. “We’ve tested some of the fruity flavour ones, which are quite popular, and [one] came up with 75 different chemicals in there, of which 20 had no clear reason to be in there. They weren’t flavourings.”

Finally, there’s the excipients or inactive substances that bulk out the liquid, generally propylene glycol, which is used in nightclub smoke machines, and glycerine.

“One thing that has been reported in the literature and what we’ve seen in one of our studies is that the glycerine can cause health impacts in and of itself,” Professor Larcombe says. “It’s a greasy, oily sort of substance … and it seems that over periods of time glycerine can build up in people’s lungs and possibly cause inflammation, and that’s what’s potentially causing some of these lipoid pneumonia-type illnesses that are coming out [in the US].

“There are however, cases in which there is no evidence of features associated with lipoid pneumonia, so what is really the cause of these illnesses is still unknown. Recent reports indicate illnesses might be due to vapers inhaling other toxic substances produced by e-cigarettes.”

The fact that there have been so few cases before now means there must be some individual differences that lead to adverse events.

“There’s some published case reports of people having lipoid pneumonia from e-cigarette glycerine dating back quite a few years,” he says. “That might be one of those things that is down to the specific user – how long they’ve been using it for, how frequently, what sort of e-liquid they use as well, because some have a lower proportion of glycerine.

“There’s all sorts of complicating factors as to why it’s hitting some people and not others.”

The harm-reduction side of the argument probably suffers unfairly from the participation of Big Tobacco in the $US11 billion global e-cigarette business.

Philip Morris International’s “Unsmoke Your World” campaign displays “an unprecedented degree of corporate hypocrisy”, in the words of a recent Lancet editorial, as it continues furiously marketing cigarettes in low-income countries while promoting its heat-not-burn technology.

Altria, which spun off Philip Morris 10 years ago but is in talks to re-merge into what would be a $US200 billion company, recently spent almost $US13 billion buying 35% of Juul, the market leader in vaping devices.

This month the Food and Drug Administration sent a warning letter to Juul for calling its products “99% safer” than cigarettes and “totally safe” in a presentation to children at a school.

“Big Tobacco is saying that they want their smoking customers to switch over to the harm-reduction products,” Professor Chapman says. “But as they’re saying that their foot is flat to the floor in promoting cigarettes.

“They’re bullshit artists, and they want people to vape and smoke. They’re hoping for new markets. Because in Australia at the moment only 1.9% of 15-to-17-year-olds smoke. That’s absolute death to the industry if that cohort goes through without taking it up.”

A year-long inquiry by federal parliament’s Standing Committee on Health, Aged Care and Sport came down in favour of keeping e-cigarettes regulated as a therapeutic good – in effect, banned – as argued for by the Thoracic Society of Australia and New Zealand and others.

A dissenting report by MPs Trent Zimmerman and Tim Wilson, however, argued that e-cigarettes should be available as a consumer good, “subject to regulations which will limit their appeal to non-smokers and young people”.

That led Health Minister Greg Hunt, despite his continued opposition to vaping, to agree to an independent inquiry by the National Centre for Epidemiology & Population Health at the Australian National University, whose first report is due at the end of this month.

MP Andrew Laming also filed a dissenting report from the committee inquiry. It read, in its entirety: “Life is short and shorter for smokers. Just legalise vaping.”

But for pure succintness, even that can’t beat the European Respiratory Society’s official position on vaping, as announced at its recent congress in Madrid by former ERS president Jorgen Vestbo: “Don’t.”

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