In a few short months, electronic cigarettes (e-cigarettes) and vaping have gone from a promising harm reduction tool for smoking cessation1 to the suspected cause of a massive outbreak of cases of severe lung injury2 focused on, but not isolated to the United States. What is happening? Could the medical community have seen this coming. Read More
E-cigarettes are battery-powered electronic devices that are used to aerosolize substances for inhalation including flavouring agents, nicotine, tetrahydrocannabinol (THC), cannabidiol (CBD), and potentially other illicit drugs. They were initially marketed as a safer alternative to cigarette smoke since they contain no tar or products of combustion. They were introduced to the US market in 2006 and nicotine-containing e-cigarettes became legally available for sale in Canada in May 2018.3 However, even before they were “legally available” in Canada, their use became popular among youth. In Ontario in 2017, 18.9% of grade 12 students used e-cigarettes during the past year4 and rates of use have been rising.5
An overwhelming number of e-liquid flavours ranging across fruity, candy, menthol, and tobacco flavours, can be easily purchased at various retailers and online in Canada. In addition to this, e-liquids can be customized by the user to create new flavours, change the nicotine content or add other substances such as THC, etc.6 The act of vaping exposes the user to a complex mix of substances, including a carrier fluid, such as propylene glycol or vegetable glycerin, multiple flavouring chemicals, as well as varying concentrations of nicotine, THC or CBD.6,7 Almost unbelievably, the majority of flavouring agents used in e-liquids, although labelled as “generally recognized as safe” under the United States Federal Food, Drug, and Cosmetic Act, have been tested for safety only for ingestion and not inhalation.6 In addition to this, the process of heating the e-liquid changes the chemical composition producing a number of aerosol emissions including formaldehyde, volatile organic compounds, particulates and even metal emissions from the devices.7
What is EVALI?
When first recognised in August 2019, the cluster of lung complications that were tied to vaping was called “vaping associated pulmonary injury” (VAPI). This name has now morphed to “e-cigarette, or vaping, product use-associated lung injury” (EVALI) as the outbreak has expanded. The United States Centres for Disease Control and Protection (CDC) has provided case definitions for this diagnosis that have also been used by Health Canada and the Public Health Agency of Canada. The criteria to diagnose a confirmed case of EVALI is 1) airspace opacities on chest x-ray or CT scan; 2) no evidence of infection; and 3) no other alternative plausible cause in a patient using e-cigarettes or dabbing in the 90 days before symptom onset. The probable EVALI case definition is the same, with the exception that there may be some evidence of infection, or testing to rule out infection was not completed.2
As of November 20, 2019, over 2000 cases of EVALI have been reported to the CDC2 with 11 confirmed or probable cases in Canada.8 What is most alarming is that many of the severe cases have required mechanical ventilation and advanced life support measures, with one reported case requiring a double lung transplant, and 47 deaths to date.2,9 The outbreak is affecting a disproportionate number of otherwise young, healthy people with 77% of cases reported in patients under 35 years old, including 15% in youth under 18 years old.2 Yet, the cause is not clear.
Certain trends have emerged: 83% of cases reported use of THC-containing products, 61% reported nicotine-containing products, but 4% reported using neither. Findings of lipoid pneumonia and vitamin E acetate – an adulterant added to THC have been identified in some case samples, but not all. In addition to this, many of the cases seem to be related to products containing THC that have been purchased off the streets, on-line, or from acquaintances leading the recommendation from CDC to not use THC products from these sources.2
What about flavouring agents?
Speculation about the toxicity of flavouring agents used in e-liquids continues to be unresolved. A form of bronchiolitis obliterans or constrictive bronchiolitis also known as “popcorn lung ”is a well described lung condition associated with inhalation of flavouring-agents This flavouring-associated lung disease was first described by Kreiss et al. in a cluster of workers exposed to diacetyl that was used as the butter flavouring at a Missouri microwave popcorn plant.10 Similar clusters of irreversible obstructive lung disease have been reported in other groups of workers in diacetyl and flavouring manufacturing, cookie manufacturing and a coffee processing plant.11 Diacetyl has been identified in more than 60% of e-cigarette liquid samples analyzed in one study6, including in samples where diacetyl was not labelled as an ingredient.12 Another study described the spontaneous chemical conversion of acetoin (another flavouring agent used in e-cigarettes) to diacetyl in e-liquids.13 This process seemed to be accelerated when nicotine was added and resulted in increased concentrations of diacetyl over time13, suggesting that e-liquids that have been stored for longer periods of time may have higher diacetyl concentrations. The Canadian Vaping Association has issued a statement recognizing this issue and their recommendations that e-liquids have a 2 year shelf-life with a labelled expiry date.14 Despite this recommendation, it is not clear how this would be enforced in this largely unregulated industry.
Knowing that that diacetyl could be a risk factor for pulmonary injury, it is interesting to note that the pattern of bronchiolitis lung injury that would be most expected to be associated with diacetyl has only been described in one recent case report so far.15 However, diacetyl should not be the only flavouring agent or substance of concern. In addition to diacetyl, chemical analysis of e-liquids have identified a long list of chemicals for which we have little, if any information about the injury pattern that can result from heating and inhaling them into the lungs.16 The reported patterns of lung injury associated with e-cigarettes and vaping have been diverse including organizing pneumonia, diffuse alveolar damage, hypersensitivity pneumonitis and lipoid pneumonia to name a few15, suggesting that there may be more than a single injury pathway involved. Additionally, despite extensive ongoing analyses of e-liquid samples associated with EVALI cases by the FDA and CDC, there has not been a single substance that has been associated with all of the cases and it seems likely that there are multiple contributing factors.17
If anything can been learned from experience with occupational and environmental exposures to inhaled toxins in exposed cohorts, it should be recognized that there can be a range of presentations and inter-individual variability in responses, and it often requires time to identify the association with certain exposures.11 It is clear that it will take further investigations to understand the cause of this current outbreak of EVALI as well as to identify the long-term risks associated with e-cigarette use and vaping. For example, it took decades to understand and appreciate the risks associated with smoking tobacco cigarettes. The question is – how long will it take to understand and act on the risks of e-cigarettes and vaping this second time around?
- Hajek P et al. A randomized trial of e-cigarettes versus nicotine- replacement therapy. N Engl J Med 2019
- https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/healthcare-providers/index.html. Accessed November 24, 2019.
- https://www.canada.ca/en/health-canada/services/smoking-tobacco/vaping/product-safety-regulation.html. Accessed November 23, 2019.
- Boak, A., Hamilton, H. A., Adlaf, E. M., & Mann, R. E. (2017). Drug use among Ontario students, 1977-2017: Detailed findings from the Ontario Student Drug Use and Health Survey (OSDUHS) (CAMH Research Document Series No. 46). Toronto, ON: Centre for Addiction and Mental Health.
- Hammond David, Reid Jessica L, Rynard Vicki L, Fong Geoffrey T, Cummings K Michael, McNeillAnn et al. Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys BMJ 2019; 365 :l2219
- Klager S, Vallarino J, MacNaughton P, et al. Flavoring chemicals and aldehydes in e-cigarette emissions. Environ Sci Technol 2017;51:10806-13.
- Christiani DC. Vaping-induced lung injury. N Engl J Med 2019 Sept. 6 [Epub ahead of print]. doi: 10.1056/NEJMe1912032.
- https://www.canada.ca/en/public-health/services/diseases/vaping-pulmonary-illness.html Accessed November 24, 2019.
- https://www.cbc.ca/news/canada/windsor/vaping-lung-transplant-1.5359105. Accessed November 24, 2019.
- Kreiss K, Gomaa A, Kullman G, et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 2002;347:330-8.
- Kreiss,K. Curr Opin Allergy Clin Immunol. 2013 13(2):167–172.
- Joseph G. Allen, Skye S. Flanigan, Mallory LeBlanc, Jose Vallarino, Piers MacNaughton, James H. Stewart, and David C. Christiani. 2016. Environmental Health Perspectives 124:6
- Vas CA, Porter A, McAdam K. Acetoin is a precursor to diacetyl in e-cigarette liquids. Food Chem Toxicol 2019;133:110727.
- https://www.newswire.ca/news-releases/let-s-be-clear-thc-vapes-or-other-non-regulated-non-water-soluble-devices-are-not-classified-as-e-cigarettes–892987513.html Accessed November 24, 2019.
- Simon T. Landman, Inderdeep Dhaliwal, Constance A. Mackenzie, Tereza Martinu, Andrew Steele, Karen J.Bosma. CMAJ Nov 2019, cmaj.191402
- Esther E. Omaiye, Kevin J. McWhirter, Wentai Luo, James F. Pankow, and Prue Talbot. Chemical Research in Toxicology 2019 32 (6), 1058-1069
https://www.fda.gov/news-events/public-health-focus/lung-illnesses-associated-use-vaping-products Accessed November 22, 2019