E-cigarettes have been marketed as a form of harm reduction from traditional cigarette smoking, but neither the safety nor the efficacy of these devices has been established, and little is known about the short and long term pulmonary and systemic health effects. This review focuses on the known and unknown toxins contained in e-cigarette aerosols, lung diseases induced by vaping, and the predicted long-term consequences of e-cigarette use. Particular attention is given to the e-cigarette or vaping product use-associated lung injury epidemic that began in 2019 and is ongoing. E-cigarettes are devices composed of a power source, heating element, and liquid reservoir that heat and aerosolize e-liquids to make vapor that is inhaled into the lungs in a process known as vaping. E-liquids are most often composed of 1) Addictive substances such as nicotine and/or tetrahydrocannabinol , 2) Flavorings, and 3) Solvents . There are many types of vaping devices, but the most frequently used include pod vapes, box mods, and vape pens . The pod devices were widely popularized by the company Juul, which developed its sleek device to look like a flash-drive that quickly became the most profitable e-cigarette by the end of 2017. The e-liquids in Juul pods contain high concentrations of the more rapidly absorbed nicotinic salts complexed with benzoic acid, compared to free based nicotine, thus increasing the addictive potential and toxicity. Given that nicotine exposure influences long-term molecular, biochemical, and functional changes in the adolescent brain, it is not surprising that teens who vape are at increased risk of subsequent use of traditional cigarettes, marijuana, opioids, and other illicit drugs with addictive potential.
THC also induces alterations in reward networks in the adolescent brain, which increases risk for future drug use,plant bench indoor and regular cannabis users of any age have poorer neurocognitive functioning and functional brain alterations relative to nonusers. Although vaping devices are not an approved nicotine replacement therapy, the Federal Drug Administration has allowed e-cigarette manufacturers to design e-liquids using components that have been ”generally recognized as safe” . Compounds that have GRAS status are only assessed as safe to ingest via the gastrointestinal tract, or put on the skin. Thus, the vast majority of compounds with this designation have not been tested for safety via the inhalation route. There are thousands of different flavoring ingredients used, and thermal decomposition of propylene glycol, glycerol, and flavoring agents result in the production of toxic aldehydes at levels that exceed occupational safety standards. Chemical flavorings such as diacetyl and 2,3-pentanedione, present in many e-liquids, have been found to induce transcriptomic changes that disrupt cilia function in human airway epithelium, impairing mucociliary clearance. Cumulative exposure to diacetyl is well known to be associated with the development of the irreversible airway fibrosing disorder bronchiolitis obliterans , with the term “popcorn lung” used when referring to BO described in microwave popcorn factory workers. Other toxins found in e-cigarette vapor with inhalant and systemic toxicities including terpenes, acrylonitrile, formaldehyde, crotonaldehyde, propylene oxide, acrylamide, and heavy metals. None of these products are currently regulated, but there is even greater cause for concern regarding the inhalant toxicity for the components in “black market” or counterfeit e-liquids and devices as well modified devices. Finally, microbial toxins may contaminate vaping devices even prior to use.
One study tested the leading U.S. pod vape and found that 81% of devices contained B-D-glucan, a fungal cell wall marker, and 23% contained endotoxin, found in the outer wall of gram-negative bacteria. Both of these microbial contaminants are associated with asthma and hypersensitivity pneumonitis.E-cigarettes have been marketed as a form of harm reduction from traditional cigarette smoking, but neither the safety nor the efficacy of these devices has been established, and little is known about the short and long term pulmonary and systemic health effects. There have been increasing reports in the literature of negative pulmonary effects with the recent epidemic of e-cigarette or vaping product use-associated lung injury being the most immediately concerning. Reports of the development of chronic respiratory symptoms, increased asthma morbidity, and the development of diffuse lung disease in both adolescents and adults highlight significant pulmonary toxicity and compel further research. E-cigarette users are more likely to report chronic respiratory symptoms and conditions in both adolescents and adults. In a large study from Hong Kong of 45,000 adolescents who vaped in the previous month reported chronic cough or phlegm production with increased odds. In a smaller study of 2,000 high school students in Southern California, past and current vaping was associated with a nearly two-fold increase in the risk of chronic bronchitis symptoms. In a longitudinal analysis of adults in the Population Assessment of Tobacco and Health Waves 1, 2, and 3 with data collected from 2013-2016, a significant association between former and current use at Wave 1 and incident respiratory disease at Waves 2 or 3 was demonstrated, controlling for combustible tobacco smoking and other demographic, and clinical variables. In this study, dual use of cigarettes and ecigarettes had increased odds of developing respiratory disease of 3.30 compared with a never smoker/vaper. Among asthmatic patients, primary e-cigarette use and secondhand exposure confers increased morbidity.
Interestingly, vaping is more popular among asthmatic teenagers as compared to their non-asthmatic peers. The reason for this observation is unclear, but may be related to the commonly held belief that vaping is safer than smoking cigarettes. Among adult never cigarette smokers, current e-cigarette use was associated with 39% higher odds of self-reported asthma compared to never e-cigarette users. In South Korea, vaping in high school students was associated with increased odds of being diagnosed with asthma and more missed days of school secondary to asthma. The Florida Youth Tobacco Survey showed that past-30-day e-cigarette use was associated with having an asthma attack in the past 12 months among high school participants with asthma. This survey later revealed that 33% of 11- to 17-year-olds with asthma had secondhand ecigarette exposure, and this exposure was associated with increased risk of asthma exacerbation. There are also case reports of two adolescent asthmatic e-cigarette users who presented with life-threatening status asthmaticus requiring VV-ECMO[36]. This may indicate increased risk for more severe exacerbations among asthmatic teens who are vaping. In addition, EVALI cases from both the Illinois and Wisconsin cohort and Rochester cohort reported higher- than expected rate of EVALI in asthmatics. Vaping has been linked to various rare pulmonary conditions and pathologic abnormalities. There have been multiple case reports of different types of severe and life-threatening diffuse lung disease in patients using vaping products including hypersensitivity pneumonitis, eosinophilic pneumonitis, diffuse alveolar hemorrhage, lipoid pneumonia and bronchiolitis. These case reports demonstrate that there is undeniable harm associated with vaping even before decades of use. Among patients with EVALI, pathology results included findings consistent with acute lung injury including acute fibrinous pneumonitis,greenhouse rolling racks diffuse alveolar damage, and organizing pneumonia. Taken together these pathological findings indicate that severe lung injury in multiple different patterns can occur in the setting of vaping. Although the mechanism of injury in these patients is currently unknown, it is presumed that there are both product and host related factors contributing to lung injury. Given that multiple components of vaping products can cause pulmonary toxicity, it is unlikely that there is only one chemical component leading to these diverse patterns of toxic lung injury. Beyond the scope of this review are systemic toxicities as well as trauma due to explosions, thermal injuries and acute intoxications including ingestion of e-liquids.The national outbreak of e-cigarette, or vaping, product use-associated lung injury has been the first vaping related disease to affect thousands of people . At its core, it is a chemical inhalation injury, most likely caused by heating, aerosolization and inhalation of Vitamin E within THC liquids and vape pens. Examination of airways and lungs of those affected has yielded a pattern of epithelial and alveolar damage. Neutrophils and foamy macrophages are often documented, with lipid laden phagosomes when directly tested through appropriate lipid stains; however, lipid laden macrophages are most likely evidence of vaping in general, not specific to EVALI.
Although it has been clear for years that users of e-cigarettes and vaping devices were inhaling known toxins such as diacetyl and formaldehyde, this disease entity was the first to demonstrate that inhalation of clouds of chemicals that have never been tested for safety via inhalation methods can lead to significant impacts on public health. EVALI was first recognized in August 2019, with the number of recognized cases rising precipitously until December 2019. The connection with THC was made within several weeks – approximately 82% of those affected had vaped THC – while the identification of Vitamin E acetate as a prime suspect took months, and has not been confirmed as the etiologic agent at this time. Fourteen percent of those affected vaped nicotine containing e-liquids only, but upon review these subjects were older, female and had less leukocytosis, suggesting that they may have been suffering from a different vaping induced lung disease. Overall, EVALI is a disease of the young, with a median age of 24 years. It also predominantly affects males , which may be directly related to epidemiologic patterns of THC vaping. The majority of patients present with respiratory , gastrointestinal and systemic symptoms, and are found to have elevations in erythrocyte sedimentation rate , Creactive protein , white blood cell counts, and liver function tests. Beyond these factors, bilateral lung infiltrates are the key diagnostic finding on radiographic imaging. The mortality rate is quite low, at 2.4% , with the highest mortality rate in older e-cigarette users with comorbidities. The median age of deceased EVALI patients was 49.5 years, with a range from 15 up to 75 years. Of the cases identified up to December, approximately 47% required ICU admission and 22% required intubation. Because only moderate to severe cases were tracked, the reported numbers are likely to severely underestimate those affected. Since Vitamin E acetate within THC e-liquids has been identified as a likely causal agent, and with the intense media coverage of this disease entity, there is hope that the incidence of this particular vaping disease will decrease. However, as vaping increases across society, with millions of users inhaling hundreds of thousands of chemicals including lipophilic agents similar to VEA, it is clear that vaping associated lung diseases are here to stay. Conventional tobacco has been smoked for over 5000 years and is very well known to cause a myriad of long-term health problems, not the least of which is lung disease. Because modern vaping devices have been on the market for less than 16 years, and only widely used for 5, very little is known about how chronic use will affect human health. Murine data suggest that some vapers will develop emphysema, heart disease, renal failure, and even liver fibrosis, but these diseases will be couched in genetic predisposition, type of e-device used and the chemicals within the inhaled aerosol. Because vaping aerosols contain chemicals that cytotoxic and cause DNA damage, it is unsurprising that murine models have demonstrated increased occurrence of lung toxicities. Thus, it is hypothesized that long-term vaping will lead to increased incidence of cancer. Because acute and subacute vaping can increase airway resistance and airway reactivity, it is believed that chronic use of e-cigarettes will lead to more severe disease in asthmatics. Vaping alters the function of myeloid cells, including granulocytes, such that it is likely that vaping will alter the function of eosinophils as well, leading to vaping induced changes in allergic diseases. Asthma has many phenotypes, including eosinophilic and neutrophilic subtypes, and with the knowledge that vaping has broad effects on immune cells, e-cigarette use may impact multiple asthma phenotypes. Studies in humans thus far are limited to acute and short-term effects, but consistently demonstrate that vaping impacts both pulmonary and cardiovascular function. Gene expression from airway samples evidence changes that parallel those in cigarette smoking, which is worrisome in that it predicts that vapers will develop the same lung diseases that smokers do – namely emphysema, chronic obstructive pulmonary disease , and respiratory bronchiolitis interstitial lung disease. In addition, altered human neutrophil function suggests that vapers will be at higher risk for bacterial infections as well as autoimmune disease. While longitudinal studies on the health effects of chronic e-cigarette use are needed, the data thus far suggest that vaping will have substantial adverse impacts across organ systems, leading to significant morbidity and mortality over time.