Podcast: Unique lung injury related to vaping in a Canadian adolescent
Transcript
Andreas Laupacis: Hi, I'm Andreas Laupacis, editor in chief for the Canadian Medical Association Journal. Today we published in the CMAJ, what we believe is the first case of bronchiolitis obliterans, associated with e-cigarette use, reported by Dr. Karen Bosma, and colleagues. And today I'm delighted to be joined by Dr. Matthew Stanbrook, deputy editor at the CMAJ and a respirologist at Toronto Western Hospital. Matthew has written an accompanying editorial. So Matthew, welcome.
Matthew Stanbrook: Thank you for taking the time to talk to me about this important issue.
Andreas Laupacis: So this is an issue, I think, that's near and dear to your heart?
Matthew Stanbrook: I am a respirologist and I've been looking at the issue of e-cigarette vaping for a long time, ever since they've come to Canada. And it's become a part of my clinical and research focus as well. So definitely a topic of great interest to me.
Andreas Laupacis: So why don't we start by talking about the young man who was described in the Canadian Medical Association Journal. There have been well over 1,000 of these vaping related lung injuries already described, Matthew, what was unique about this case?
Matthew Stanbrook: So one thing unique about the case we're reporting in CMAJ, is that it is different in some important ways from the epidemic currently going on in North America. So back in the late summer, we began to hear reports about this outbreak of cases of people coming into hospital being very sick, in respiratory failure, having CT scans that had airspace disease on them, most of them ending up in the ICU. Most of them recovering but sadly, about 40 of them having died from this now. These are almost all in the United States, but we've had two confirmed and five possible cases of this in Canada. A small number compared to the over 2,000 in the United States but still a few. And so this was something very, very different from from what we had ever seen before. And these were happening in clusters and they were growing, the way an outbreak grows, and the outbreak has not yet ended, it continues to grow. So the public health officials in the United States who have caught on to this and been investigating this, have put a term to this, they've called it EVALI — E-cigarette Vaping Associated Lung Illness — and there was a case definition for it. And that is what the media has mainly been reporting in the last few months about.
Andreas Laupacis: And what is a case definition?
Matthew Stanbrook: The case definition requires that someone have an acute respiratory illness associated with the use of e-cigarette products within the previous 90 days, and featuring new infiltrates on imaging that are of an airspace or ground glass pattern. And the other criterion is that an infectious cause should be ruled out to be a definite case, or an infectious cause may be found but is not thought to be responsible for the illness, and that would be a probable case. So that explains the difference between the two cases that are definite and the five that are probable in Canada, for example. So that's the epidemic definition for this cluster of illnesses, which again, is nothing like we've ever seen before in relation to e-cigarette use which to give some perspective, have been around for a decade or so. But even before this outbreak, there were sporadic reports of respiratory illnesses, single cases or a couple of cases, of a variety of pathological and clinical patterns, reporting in association with e-cigarette use. And the case report we're publishing does an excellent thorough review of the literature, and documents these cases. And so, there is the epidemic definition which is EVALI, but beyond that there are other vaping associated patterns of lung illness that are not EVALI. The case we are reporting in CMAJ is one of those. It is not EVALI because it doesn't fit the EVALI case definition, the radiographic picture was not one of diffuse airspace disease. It was not a an ARDS picture, an inflammatory pneumonia picture, it was in stark contrast, a picture of bronchiolitis. This is an inflammation of the small airways of the lungs. And that's salient for some very important reasons. We have long suspected that e-cigarette use could be capable of causing bronchiolitis, in particular a subtype of bronchiolitis called bronchiolitis obliterans, which is an inflammatory obstruction of the small airways that becomes a chronic disease and can be fatal. It's associated with a number of known causes that can include connective tissue diseases and a lung transplant. But it's also known to be associated with some toxic inhaled exposures, and of relevance, it was described to be associated with breathing in butter flavouring used for microwave popcorn, among workers in a plant that made this in the United States a couple of decades ago, and that came to be known as popcorn workers lung. The chemical that is responsible for popcorn lung is called diacetyl, which is a buttery flavouring compound. It turns out the diacetyl is found, or generated, in a majority of the liquids that are used in e-cigarette liquids sold on the market nowadays. So knowing that for several years now, we had long suspected that we might see a case that resembled bronchiolitis obliterans, and the current case being reported and CMAJ fits that clinical definition very well, in many ways. So that is what is unique and different about it and why we felt it's so important to publish this for our readers.
Andreas Laupacis: So, it strikes me as a bit odd, if many of the flavours have this diacetyl and people have been vaping for many years now, that this would be the first case. What am I missing here?
Matthew Stanbrook: It's what we're all missing. We don't yet know why there are differences in what we're seeing in different countries with e-cigarette use. Why, for example, the EVALI epidemic is almost entirely in the United States and not in Europe, and only a little bit in Canada. Obviously, with the EVALI epidemic, something very different is going on in the United States in whatever products are being sold. There are some clues to that, that have come out as the CDC in the United States has been investigating it. In particular, there has been increasing focus on something called vitamin E acetate, which is an oily substance that is being used to dilute preparations of cannabis oil to be able to sell more of it because it looks the same as cannabis oil. And this is just, in the last few days, been reported to be found in bronchoalveolar lavage specimens from a number of these cases. So that is clearly part of the story now, it seems. But again, what is noteworthy about cases like this, and the couple of dozen that came before the epidemic is the heterogeneity of different pathologies that have been associated with use. Which suggests that the ability of e-cigarettes to cause harms to the lungs is not likely to be limited to any one product or any one contaminant. There appears to be a heterogeneity of different things that can happen. And so, as time goes on, we are seeing more and more of these. And that isn't unusual, because we have to remember the lessons we've learned from tobacco. If tobacco were introduced on the market today or even a decade ago, and all we had was the evidence of health effects over that time, we would conclude that tobacco was perfectly safe. It takes at least a decade, and usually many decades, before you see all the dire health consequences that we now all know all too well happened with tobacco. We are just a decade in with e-cigarettes, so perhaps it's not surprising that now is the time where we're starting to see this.
Andreas Laupacis: But the difference between the tobacco example is that these are very acute, really severely ill people with their lung disease, right? But we're not talking about needing 10 to 20 years to see the COPD and the cancers. We're talking about, like acute respiratory illnesses that get people in the ICU and some of them die, right?
Matthew Stanbrook: Yes. So they are quite different in that respect. And we still don't fully understand what the causal substances are that are driving that. We know a great deal about the toxic substances that are emitted from e-cigarettes. Some of those things are things that are in tobacco cigarettes although usually, albeit not always, at lower concentrations that in tobacco, but some of them are chemicals that we have never studied before when inhaled into the lungs. And among those are a lot of these flavouring compounds that are being used in the e-liquids. These things have been put in there using the consumer legislation that was designed to designate substances that are safe to swallow. There is no regulations on what is safe to breathe in. And so people have used what it is safe to swallow and said: "Well, we can put this in liquids that are meant to be heated up very rapidly." Which of course, changes their chemical properties, and then inhaled. With many of these chemicals, we have no idea prior to now, what effects could result to the lungs. So, I suspect that these acute illnesses that we're seeing represent some of those unknown effects. And it's going to take time and study to figure out exactly which components are linked to which patterns of illness.
Andreas Laupacis: And are there laboratory models - my God, I'm not an expert in this - but it does strike me as a big leap to say, you know: "You can swallow this butter tasting thing that we put on popcorn. And by the way, because it's safe to swallow, it's safe to inhale in your lungs." Are there, I don't know, laboratory models or something that people can assess the safety of these things?
Matthew Stanbrook: There is. So we now have a fair bit of preclinical research that's been done. There's been a lot of research in animals. And yes, indeed, in animal models, which are usually mice or rats, you can reproduce a whole variety of pathologies. You can reproduce popcorn lung in a rodent model, you can reproduce COPD and asthma in a rodent model with vaping. Now, it's taken some time to figure out how to deliver vaping in a way that's analogous to what humans do, but we've come a long way with that and the research is very active in that area. We have some very preliminary human data, and again, too soon to draw direct links to diseases like COPD and lung cancer, but we have within the last few months shown evidence that vaping in humans induces changes in protective enzymes in the lungs' metalloproteases, in a pattern that is the same pattern we see in people who go on to develop COPD and lung cancer. That does not mean that we have shown that e-cigarettes cause COPD and lung cancer. We have shown that they can cause a similar change in biology that we see as a precursor though, and that is concerning. So yes, the preclinical research is well developed, more needs to be done, but we have clear evidence of toxicity from that.
Andreas Laupacis: So, I'd just like to go back to the EVALI cases. When was the first patient described?
Matthew Stanbrook: The EVALI epidemic has just been this year. The first case though, looking back, was in June of this year, but the e-cigarette associated illnesses go back several years. There were some in 2012, I think, may be the earliest one. These were one offs though. They were - you would hear one case and there would not be another like it, and there would be another different case. And there are a wide variety of pathologies; lipoid pneumonia, hypersensitivity pneumonitis, eosinophilic pneumonia. All very different from what we're seeing in the EVALI epidemic, all very different from the case that CMAJ is reporting today.
Andreas Laupacis: And people have been using e-cigarettes for quite, and vaping, for quite some time. We've had these sporadic cases and then literally 2,000 plus since June. It seems to me, I think you're saying I'm right, that I mean, I guess maybe one thing would be people are reporting them more? But these strike me as such dramatic cases, that it'd be hard to imagine that they would have gone under the radar. That there probably is something new being inhaled with cigarettes more recently to explain this acute epidemic, and we don't know what it is?
Matthew Stanbrook: I would agree with that. Certainly the present epidemic is a different type of thing. There must be something going on recently in the US market of these products. And we have some clues as to, at least what part of it might be, with the vitamin E acetate in cannabis oil that we have not seen before. And so some people are saying: "Okay, well, now that we found that..." They were seeing that even before we found it, and we still haven't answered all the questions, but anyway: "Now that we found that, everything else is safe, right?" But that would be very much the wrong message to take away from this. So the EVALI epidemic will go away when we get whatever the particular cause of that is off the market.
Andreas Laupacis: And we're a ways from knowing what that is, right?
Matthew Stanbrook: We're working on figuring that out. But the pattern of these sporadic illnesses associated with vaping is unlikely to go away. And the lesson to be learned from EVALI is that there was nothing to prevent this from happening. There were no regulations to govern the quality of manufacture, the standard of how these devices are produced, the toxins and carcinogens that could be in the liquid, the ways in which this could be sold online or marketed to youth. And so there is nothing to prevent the next disease that might come out of vaping. There's nothing to say that any brand or product of e-cigarettes or e-liquid is going to be safe from these because the lack of regulations that allow whatever is driving the EVALI epidemic to happen, still applies to every vaping product. And until governments get together and put the right regulations in place to protect the public from this happening, people who use e-cigarettes are not safe from bad things potentially happening to their health as a result of using these products.
Andreas Laupacis: If we don't know what the causes of these sporadic cases, like the one that CMAJ just reported or the EVALI are yet, how do we make regulations other than banning them?
Matthew Stanbrook: We have been calling at CMAJ for some very reasonable evidence-informed responses to this, right from the start. We published our first editorial on e-cigarettes in 2013 and at that time, they were very new and we knew very little about them, certainly in Canada. And at that time, we called for regulating them as medical devices, because most reasonable people, I think, would agree that the only legitimate use of these products is to help people quit smoking. And as that, at least in 2013, there was perhaps the potential for that to work out if they were made safely and if they were regulated properly. You would never sell a medical device or an asthma inhaler that didn't meet quality control standards, and standards for ensuring that batch to batch composition was the same, and making sure that didn't release toxic byproducts, and had an a body of research to look into safety and efficacy of that. But it seems that when it came to e-cigarettes or governments decided to not apply the same standards that we apply to what, you know, by any other evidence, should be regarded as medical devices. And, frankly, the governments had a lot of helping not looking at it that way, because they faced heavy lobbying from industry, and the cigarette industry is heavily dominated by the tobacco industry with all the leading brands on the market being either owned outright, or substantially owned, by tobacco companies. And so there was very powerful incentives working against government to regulate these rationally. So as a result, they didn't regulate them rationally. And so we're faced with a situation where you can have epidemics like EVALI.
Andreas Laupacis: How do we know what regulations the government should introduce? Now, I noticed that some governments in Canada, for example, I think Saskatchewan has just announced that they're going, I think all parties in Saskatchewan agree, that they were going to introduce legislation around their advertising, how close they could be sold to schools, etc. So there's regulations around advertising, which I think they've been probably fairly more aggressive in the United States than us, you can tell me if I'm wrong about that. But in terms of the actual products, what do you think government should do around what should be allowed to be sold now?
Matthew Stanbrook: So what governments have done both in Canada and the United States in regard to regulating e-cigarettes is laughably weak. Saskatchewan coming on board, finally, with its first e-cigarette laws ever, as of a day or so ago, makes it the ninth province to do so. Alberta still hasn't done anything on that. And even those regulations are just about things that say about where you can use them and how old someone can be to buy them, and what kind of advertising they can be. And there is federal legislation providing a broader framework for that. But that's only been in place since May of 2018. In the United States there is, until very very recently, been no legislative impetus at all. Now we have States banning flavoured e-cigarette products, a few of them, and we have the FDA finally promising new Act after it had to be sued by several health organizations for failing to act when it had the power to do so and said it would. And yet Health Canada with its relatively weak legislation that really just says Here's how old you can be and here's how you can advertise it, promotes its regulation as being very strong regulations. When really again, the basics that we need, which are ensuring quality control of manufacture, ensuring safe manufacture, ensuring toxins are not in the products. When you read what Health Canada actually says to the industry about that, it's laughable how weak it is. They are suggested to employ quality control measures. They are suggested to make their batteries in a way to adhere to standards so that they don't explode in people's hands, which they have done. They are suggested to avoid diacetyl in their liquids because, as Health Canada says in their statement, we know it's been associated with lung disease. But in none of those cases has government made that illegal, which they have the power to do. The 2018 legislation gave Health Canada the power to go further when it chooses. And on its own, say: "We are going to take this product off the market. We are going to say that no liquid can contain this substance. We are going to require that the products be manufactured in this way." That is the kind of regulation we need and the legislation is in place now to do that. We need Health Canada to act and impose the same kind of quality manufacturing standards that we do to medical devices.
Andreas Laupacis: And so to be specific, you would say that diacetyl should not be allowed in vaping products on the basis of this case, and what we know about its association with lung disease?
Matthew Stanbrook: I said in 2013 that diacetyl should not be allowed based on what we know. And I mean, it really illustrates our failures to learn the lesson of history. We used to say, as respirologists, you know, if tobacco were discovered today, fortunately, given what we know about it, it would never be able to go to market and cause this terrible epidemic of disease. E-cigarettes have been the test of that assertion. And frankly the world, and Canada included, has failed that test miserably. We knew so much a decade ago, about what the potential of the toxins in e-cigarettes were to cause disease. And yet we failed to act on that knowledge in the way we should have acted, in a precautionary manner based on very analogous evidence to what we knew from tobacco and other substances. We failed to keep that out of the airways of Canadians. So we don't learn from history, and it really engenders quite a bit of pessimism going forward as to what we're going to be able to do to contain the potential health consequences of e-cigarette use.
Andreas Laupacis: So maybe just to switch the conversation a bit Matthew, how do we know that in Canada, the cases of e-cig or an associated lung injury are being reported? It seems to me that given the EVALI cases south of the border, we need to make sure that our public health agencies are on top of this and collecting the data, and making it available for clinicians and patients in the public.
Matthew Stanbrook: I think you raise a good point, which is that we've only been paying attention recently to the potential of e-cigarettes to do bad things to the lungs in this way. And it was really the summer's epidemic that's crystallized that. I've seen in my own clinics, residents have started routinely asking patients about vaping and about e-cigarette use, where they weren't a year ago in the same way. And so this has really been a wake up call, and maybe we needed that. It's sad that so many people had to suffer before we woke up to that. But it may well be that if we look back, we may find cases that look like the definition, that were unexplained acute respiratory illnesses, which I mean, of course, we've always seen severe respiratory illnesses, and we don't always find a cause and, you know, we attribute those to various possible things, but we never find the answer. It's possible that some of those were actually due to vaping and we never asked the question. I have picked up cases in my practice of - not EVALI - but things in the lungs that may be associated with vaping that were not picked up by the clinicians who saw them before me because they didn't ask about it. So we're starting to wake up to these things. But in terms of mandating reporting, governments in Canada have been acting based on what's going on in the US with the EVALI epidemics. So at the provincial level, which is where the level of regulation is, several provinces have made reporting of vaping associated lung illnesses mandatory. So that means that if you see a case of vaping associated lung illness, you have to let the public health agency know just like you would if you saw a case of measles. And at the federal level, the Public Health Agency of Canada is doing epidemiological monitoring to look for patterns in disease, to see if we can learn more about what's happening in Canada with respect to this.
Andreas Laupacis: So Matthew, anything that we haven't talked about that you think we should talk about, stimulated in particular by this one patient?
Matthew Stanbrook: I think that what this case illustrates is that there's more to e-cigarettes than just the EVALI epidemic, and that we have to think beyond, you know, one particular bad product or ingredient and look broadly at the circumstances that allowed this to happen, and what unknown risks in the future we face if we don't change those regulations. I also think it's an opportunity. So the practical reality is that nicotine containing e-cigarettes, at least, were illegal in Canada until 2018 and yet, were widely available here. Why is that? Well, because they were widely legal in the United States and if that's the case, then they're going to come across the border. Now the United States appears to be taking action. If we act, as Canadian governments act, in concert with the United States, we have a real opportunity actually to remove some of these products from our market if we act in parallel. So if we were all aligned to do so, we could remove flavoured e-cigarettes from the market as many have called for, myself included, and get the diacetyl and these other compounds out of there. So we have an opportunity to move on it and we must not lose that. And that's going to take public attention and advocacy. And frankly, it's going to take a lot more advocacy from the medical profession and health professions.
Andreas Laupacis: Okay, Matthew, thanks very much. Dr. Matthew Stanbrook is deputy editor of the CMAJ and a respirologist at Toronto Western Hospital. To read the case of e-cigarette associated lung disease, and the editorial Matthew wrote, please visit cmaj.ca. Also, don't forget to subscribe to CMAJ Podcasts on Soundcloud or a podcast app and let us know how we're doing by leaving a rating. I'm Dr. Andreas Laupacis, editor in chief for CMAJ. Thank you for listening.