Abstract
“E-Cigarette (e-cig) Vaping-Associated Acute Lung Injury” (EVALI) has been linked to vitamin-E-acetate (VEA) and Δ-9-tetrahydrocannabinol (THC), due to their presence in patients’ e-cigs and biological samples. Lacking standardized methodologies for patients’ data collection and comprehensive physicochemical/toxicological studies using real-world-vapor exposures, very little data are available, thus the underlying pathophysiological mechanism of EVALI is still unknown. This review aims to provide a comprehensive and critical appraisal of existing literature on clinical/epidemiological features and physicochemical-toxicological characterization of vaping emissions associated with EVALI. The literature review of 161 medical case reports revealed that the predominant demographic pattern was healthy white male, adolescent, or young adult, vaping illicit/informal THC-containing e-cigs. The main histopathologic pattern consisted of diffuse alveolar damage with bilateral ground-glass-opacities at chest radiograph/CT, and increased number of macrophages or neutrophils and foamy-macrophages in the bronchoalveolar lavage. The chemical analysis of THC/VEA e-cig vapors showed a chemical difference between THC/VEA and the single THC or VEA. The chemical characterization of vapors from counterfeit THC-based e-cigs or in-house-prepared e-liquids using either cannabidiol (CBD), VEA, or medium-chain triglycerides (MCT), identified many toxicants such as carbonyls, volatile organic compounds, terpenes, silicon compounds, hydrocarbons, heavy metals, pesticides and various industrial/manufacturing/automotive-related chemicals. There is very scarce published toxicological data on emissions from THC/VEA e-liquids. However, CBD, MCT, and VEA emissions exert varying degrees of cytotoxicity, inflammation, and lung damage, depending on puffing topography and cell line. Major knowledge gaps were identified, including the need for more systematic-standardized epidemiological surveys; comprehensive physicochemical characterization of real-world e-cig emissions, and mechanistic studies linking emission properties to specific toxicological outcomes.
Keywords: EVALI, Vitamin E Acetate (VEA), Δ-9-tetrahydrocannabinol (THC), e-cigarettes, vaping, counterfeit cartridges, pneumonia, acute lung injury, acute respiratory distress syndrome (ARDS)
1. Introduction
The “E-cigarette (e-cig), or Vaping product use, associated Acute Lung Injury” (EVALI) outbreak started in the United States in July 2019, leading to 2807 hospitalizations, including 68 deaths, until February 18, 2020, when the Centers for Disease Control and Prevention (CDC) ended case reporting as SARS-Cov2 arose in the USA. The EVALI outbreak raised public health concerns about the health risks associated with vaping, especially among the young population (CDC 2020a).
The use of e-cigs in the USA has constantly and rapidly grown, since they became commercially available in the marketplace in 2007, among the general population, mainly young adults and middle and high school students.(Wang and Wu 2020; Wang L et al. 2020). Despite the slow decline registered in 2020 in terms of e-cigs’ sales and users, the number of current young consumers is still relatively high (3.6 million) (Wang TW et al. 2020), and the e-cig market continues to expand exponentially especially in North America, reaching a market value of 12.41 billion US dollars in 2019, and projected to reach 104.51 billion US dollars by 2028 (Research 2021). Some of the reasons that favored such exponential growth included the misconception that e-cigs are a healthier and safer alternative to conventional cigarettes (Gilbert 1965; CDC 2016). In addition, the extensive availability of more than 466 e-cig brands and 7700 flavors (2014 data) (Zhu et al. 2014; CDC 2016) and the recent introduction of Δ-9-tetrahydrocannabinol (D9THC) and cannabinoid (CBD) oils in the vape market further contributed to their increased marketability. Moreover, the lack of regulations and controls in manufacturing and commercialization allowed the tremendous expansion of the e-cig market (Gottlieb 2019).
There is a growing literature on the potential short- and long-term health effects associated with e-cigs and vaping, including mechanical injury, nicotine poisoning (Hua M. and Talbot 2016; Jonas AM and Raj 2020), and effects on the respiratory, cardiovascular system, and gastrointestinal systems (Darnell and Sofi; Hureaux et al. 2014; Thota and Latham 2014; Atkins and Drescher 2015; Modi et al. 2015; Moore et al. 2015; Ring Madsen et al. 2016). However, the recent EVALI outbreak posed even more serious questions about the health risks and safety of vaping.
To date, many medical case reports have been published, which highlighted the main features of the EVALI patients: a healthy white male, adolescent or young adult, predominantly vaping THC and vitamin E acetate (VEA) containing e-cigs, obtained from illicit sources (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Blount et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020; Tanz et al. 2021). In addition, in a small percentage of cases, nicotine has also been linked to EVALI (Blount et al. 2020). The clinical signs and symptoms of EVALI are unspecific, similar to an acute viral infectious disease or other respiratory diseases characterized by diffuse alveolar damage and hypoxemia, therefore, the diagnosis is a process of elimination. As clearly stated from CDC, the main diagnostic criteria are: 1) history of e-cigs vaping in the 90 days before the onset of the symptoms; 2) signs of pulmonary infiltrates, such as opacities, on chest radiograph, or ground-glass opacities on chest-computed tomography (CT); 3) respiratory symptoms in absence of pulmonary infection or any alternative diagnosis for lung injury (CDC 2019).
Although the CDC investigations indicated that counterfeit THC/VEA containing e-cigs were strongly linked to the EVALI outbreak based on the presence of THC and VEA in patients’ bronchoalveolar-lavage (BAL) (Blount et al. 2020), the presence of many more toxicants, including pesticides, oils, diluents, plasticizers in the illicit THC vaping products (Muthumalage, Friedman, et al. 2020; Ciolino, Falconer, et al. 2021; Lu SJ et al. 2021), and the decreased but not erased number of EVALI cases even after banning the VEA as well as illicit vaping products (Helfgott et al. 2022; Lim et al. 2022; Schaffer et al. 2022; Singh A 2022), increased the needs for a comprehensive physicochemical and toxicological properties of THC/VEA e-cig vapors.
While to date many efforts have been made to characterize physicochemically and toxicologically the nicotine-based e-cig vapors (Williams et al. 2013; Zhao et al. 2016; Zhao, Nelson, et al. 2018; Zhao, Zhang, et al. 2018; Hwang et al. 2020; Lee M-S and Christiani 2020), the literature regarding vapors emitted from THC/VEA-based e-liquids is very scarce, making it difficult for health risk assessors to perform risk assessment evaluations. To date, the majority of published studies focus on the physicochemical characterization (Meehan-Atrash et al. 2019; Duffy B et al. 2020; Jiang et al. 2020; Lanzarotta et al. 2020; Mikheev et al. 2020; Muthumalage, Friedman, et al. 2020; Wagner et al. 2020; Ciolino, Falconer, et al. 2021; Ciolino, Ranieri, et al. 2021; Duffy BC et al. 2021; Gonzalez-Jimenez et al. 2021; Guo et al. 2021; Kovach et al. 2021; Lu SJ et al. 2021; Lynch et al. 2021; Brosius et al. 2022; Marrocco et al. 2022; McGuigan et al. 2022; Mikheev and Ivanov 2022) or biological in vivo/in vitro assessment (Muthumalage and Rahman 2019; Bhat et al. 2020; Jiang et al. 2020; Matsumoto et al. 2020; Muthumalage, Lucas, et al. 2020a; Marrocco et al. 2022; Matsumoto et al. 2022) of e-liquids or vapors generated from a single e-liquid compound (i.e., THC or VEA or other additives). Despite the paucity of data, many lung irritants and toxicant chemicals have been identified in the vaping emissions, which can play crucial roles in the development of EVALI, such as carbonyls, alkyl alcohols, esters, carboxylic acids, short-chain alkanes, silicon compounds, hydrocarbons, volatile organic compounds (VOC), terpenes, reactive oxygen species (ROS) and heavy metals, which have been found to exert varying degrees of cytotoxicity, alveolar epithelial damage and lung inflammation both in vivo and in vitro.
The complex chemistry of these chemicals depends on many variables, such as e-liquid composition, the device type (coil materials, heating power, operational voltage, temperature, etc.), and users puffing topography. The lack of regulations on manufacturing and commercialization allows for wide customizability of the devices that consequently drives the generation of a variety of chemical mixtures in the e-cig vapors, in which the toxic components can potentially exert a synergistic effect in the development of EVALI.
Moreover, the lack of standardized methodologies to generate e-cig emissions under “real-world” vaping conditions prevents the generation of reliable and generalizable physicochemical and toxicological characterization data, which are necessary to link specific properties of e-cig vapors to the etiopathogenesis of EVALI.
The current risk uncertainties related to EVALI are also hindered by the limited and inconsistent clinical data. Many pieces of information are often missing, improperly collected, or misreported, on the human behavior, clinical history, specimen collection, or analysis. The limited physicochemical and toxicological data based on “real world” vaping conditions also make it difficult to derive proper hazard characterization data and understand potential mechanistic pathways related to EVALI.
This review aims to provide a comprehensive and critical appraisal of the existing literature on the clinical and epidemiological aspects of EVALI, as well as the physicochemical and toxicological characterization of vaping emissions associated with the EVALI syndrome in order to identify current knowledge gaps and future research needs.
2. Methods.
Online searches were performed using, Science.gov (www.science.gov), PubMed, EMBASE, and Web of Science search engines with the search phrases: “electronic cigarette or vaping and associated lung Injury”, “EVALI”, “electronic cigarette and acute lung injury”, “vaping and acute lung injury”, “electronic cigarette and pneumonia”, “vaping and pneumonia”, “EVALI and vitamin E acetate”, “EVALI and tetrahydrocannabinol”, “electronic cigarette and vitamin E acetate”, “vaping and vitamin E acetate”, “electronic cigarette and tetrahydrocannabinol”, “vaping and tetrahydrocannabinol”, “electronic cigarette and acute respiratory distress syndrome”, “vaping and acute respiratory distress syndrome”. A literature search for regulations and policies related to electronic cigarettes was also performed. This search included the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), Food and Drug Administration’s Center for Tobacco Products (FDA-CTP), and the World Health Organization (WHO). For this review, only the papers that reported clinical case reports, physicochemical characterization of emissions generated from THC and VEA e-cigs, and in vivo/in vitro toxicological studies associated with the EVALI syndrome, as defined by the CDC, were included. All other studies evaluating the general health consequences of e-cigs, as well as toxicological and physicochemical characterization of emissions not directly associated with EVALI syndrome, were excluded. The search was also restricted to peer-reviewed publications in English from the years 2019–2022.
3. Results and Discussion.
A total of 3903 peer-reviewed articles were identified and then screened for duplicates. It is worth noting that editorials, commentary, notes, conference papers, and perspective papers were excluded from the review. Finally, 186 peer-reviewed articles specifically related to EVALI, THC, and VEA were identified and reviewed. Among these articles, 161 were medical reports, including 85 clinical case reports, 59 clinical case series, 17 epidemiological reports, and 25 were research articles addressing the physicochemical (18 studies) and toxicological (7 studies) characterization of the e-cig liquids or vapors. In more detail:
3.1. Demographic pattern, prior medical history, and symptoms manifestation of EVALI patients.
The analysis of the patients from the 161 medical reports showed that the predominant demographic pattern of the EVALI patients is a healthy white male, adolescent, or young adult. In more detail, among the 15,748 cases reported and summarized in supplemental Table S1, 65% of patients were males, and 35% females (Figure 1A). 37% of 15,748 patients had an age between 18 and 24 years, followed by age 25–34 (26%), 13–17 (17%), 35–44 (16%), 45–64 (16%) and over 65 (4%) (Figure 1B). Non-Hispanic White adults (68%) were more likely than Hispanic (18%), Non-Hispanic black (14%), Non-Hispanic Asian (3%), or Native American (1%) to develop EVALI (Figure 1C) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Heinzerling et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020; Hassoun et al. 2021; Kligerman et al. 2021; Sangani et al. 2021; Tanz et al. 2021; Helfgott et al. 2022; Podguski et al. 2022; Schaffer et al. 2022; Singh A 2022).
Figure 1.
Summary of the demographic, medical history and clinical symptoms at presentation in emergency department observed in EVALI patients (n=15,748 unless otherwise specified).
Interestingly, 17% of 15,748 patients were between 13 and 17 years of age, which may be related to the current spread of e-cigs among high school students (27.5%, 4.11 million, in 2019) and middle school students (10.5%, 1.24 million, in 2019) (Cullen et al. 2019). Despite the measures taken at the local, state, or federal level to moderate the epidemic of e-cigs among the younger population, including increasing the minimum age for purchase from 18 to 21 years (Congress 2019) and prohibition of attractive advertisements or packaging (FDA 2018), still, the number of middle or high school students currently vaping is not declining.
The case reports were also screened for pre-existing conditions. Even though the majority of EVALI patients were healthy or without any documented pre-existing condition (80% of 15,748 patients) (Figure 1D), from the records available, some patients reported suffering from “one or more” and “two or more” chronic conditions (Blagev et al. 2019; Gaub et al. 2019; Lewis et al. 2019; Ghinai et al. 2020; Mikosz et al. 2020). Specifically, among the patients that reported pre-existing conditions (n=3,171/15,748, 20%) the most common referred disorders included mental health diseases (n=1,205/3,171, 38%), of whom 30% (n=362/1,205) suffering from mental behavioral disorder, 26% (n=313/1,205) anxiety, 21% (n=253/1,205) depression, 17% (n=205/1,205) substance use disorder, and 6% (n=73/1,205) attention deficit hyperactivity disorder. In addition, among the 3,171 patients, 37% were former/current tobacco smokers, 37% were former/current marijuana smokers, and 31% reported chronic respiratory diseases (asthma, chronic obstructive pulmonary disease, obstructive sleep apnea) (Figure 1D) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020; Pitlick et al. 2021; Reddy et al. 2021; Regmi et al. 2021; Tanz et al. 2021; Schaffer et al. 2022). Other pre-existing syndromes referred to by EVALI patients were cardiovascular diseases (i.e. hypertension, heart failure, and congenital malformation), chronic pain, metabolic diseases (i.e. diabetes mellitus and obesity), gastrointestinal diseases (i.e. chronic liver diseases, gastroesophageal reflux, and inflammatory bowel diseases) (Figure 1D), allergies, immune suppression, chronic kidney diseases, and seizures/epilepsy (Supplemental Table S1) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020). The correlation between conventional cigarette smoke, chronic respiratory disease, such as asthma or chronic obstructive pulmonary disease (COPD), and EVALI is intuitive. Cigarette smoke affects almost every organ in the body, causing many diseases, including coronary heart disease, stroke, COPD, and lung cancer (CDC 2014). The underlying epithelial inflammatory status and lung damage due to the chemicals, irritants, and toxicants released in the cigarette smoke can sensitize the respiratory epithelium and induce a stronger response even against inhalants that are normally well-tolerated. In contrast, mental health and substance addiction have been underestimated in vapers and smokers (Patten 2021), and very few studies have examined the correlation between substance abuse/addiction and vaping (Young-Wolff et al. 2021), while none are available on the correlation with EVALI.
The initial EVALI manifestation, that drove the patients to the emergency department, was unspecific, but included respiratory, gastrointestinal, and constitutional symptoms (fever, weight loss, fatigue, etc.), resembling the general presentation of a relatively acute viral disease (Figure 1E) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Heinzerling et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020; Kligerman et al. 2021; Sangani et al. 2021; Tanz et al. 2021; Podguski et al. 2022; Schaffer et al. 2022; Singh A 2022). In particular, 95% of the 15,748 patients experienced respiratory symptoms, more frequently including dyspnea and cough (>80% of 15,748), accompanied by chest pain, hemoptysis, dyspnea on exertion, and/or wheezing. In addition, 80% of the 15,748 patients reported gastrointestinal symptoms, characterized primarily by emesis and nausea, followed by diarrhea, and abdominal pain. Lastly, 86% of the 15,748 patients manifested constitutional symptoms, including fever, fatigue, chills, weight loss, night sweats, headache, and myalgia (Supplemental Table S1) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Kalininskiy et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Aberegg, Cirulis, et al. 2020; Adkins et al. 2020; Artunduaga et al. 2020; Chidambaram et al. 2020; Doukas et al. 2020; Ellington et al. 2020; Ghinai et al. 2020; Heinzerling et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Layden J. E. et al. 2020; Mikosz et al. 2020; Rao et al. 2020; Reagan-Steiner et al. 2020; Kligerman et al. 2021; Sangani et al. 2021; Tanz et al. 2021; Helfgott et al. 2022; Podguski et al. 2022; Singh A 2022). The duration of symptoms before hospitalization was generally 20 days (range 1–240 days) (Supplemental Table S1) (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Lewis et al. 2019; Adkins et al. 2020; Ghinai et al. 2020; Mikosz et al. 2020; Rao et al. 2020).
3.2. Clinical presentation: signs and symptoms of EVALI.
The 161 identified medical case reports present a complete clinical history of 1160 cases of EVALI. Their main findings are summarized in Tables 1–4 and Supplemental Table S1.
Table 1.
Results from the physical examination and biological specimen testing of EVALI patients.
Abbreviations: ANA antinuclear antibodies, ANCA Antineutrophil cytoplasmic antibody, GBM-Ab Anti–glomerular basement membrane antibodies, APA anti-phospholipid antibodies, RF rheumatoid factor anti–CCPA Cyclic citrullinated peptide antibodies, anti MPO-Ab Myeloperoxidase-antibodies, anti-dsDNA Anti-double stranded DNA, Anti-RNP anti ribonucleoprotein.
Table 4.
Summary of histo-pathology patterns from transbronchial lung biopsy of EVALI patients.
Table 1 provides a summary of the clinical presentation of the EVALI patients, at their first admission to the emergency department or urgent care facility.
The observed acute lung injury was associated with a heterogeneous pattern of clinical signs and symptoms, including temperature ≥38 °C, heart rate >100 beats/min, respiratory rate >20 breaths/min, oxygen saturation <95% on room air or with supplemental oxygen, leukocytosis with neutrophil predominance, increased inflammatory biomarkers [including erythrocyte sedimentation rate (ESR) >30 mm/hr, C-reactive protein (CRP)> 10 mg/l, procalcitonin >0.07 ng/ml, lactate dehydrogenase (LDH) >280 U/L and pro-BNP >125 pg/ml], and absence of bacterial, viral or fungal infection, or autoimmune disease (Table 1 and S1). Lung auscultation was positive for diffuse bibasilar crackles, wheezes, or rhonchi; when performed, the pulmonary function test revealed either an obstructive or a restrictive pattern, while the arterial blood gas analysis was mostly diagnostic for a primary respiratory alkalosis, both documented only in a few patients. Interestingly, the urine toxicological screening was reported only in a small number of case reports, and it resulted often positive for cannabinoid use. (Table 1 and S1)
The heterogeneity of clinical signs and symptoms was reflected in the varying pathologic findings, at chest radiograph and CT, BAL, and lung biopsy (Tables 2–4 and S1). While chest radiographs and CT scan findings are variable in 929 EVALI patients, they showed a predominant pattern characterized by diffuse bilateral ground-glass opacity (71%, n=661), parenchymal consolidation (12%, n=111) bilateral parenchymal/nodular opacities (24%, n=228), bilateral interstitial infiltrates (19%, n=175), interlobular septal thickening (17%, n=158) and pleural/subpleural sparing (43%, n=399). Very few cases have been described showing bilateral pleural effusion (11%, n=106), pneumothorax (2%, n=20), pneumo-mediastinum (4%, n=38), mediastinal/hilar lymphadenopathy (16%, n=147), and pulmonary emboli (0%, n=3). (Table 2).
Table 2.
Summary of the imaging characteristics of EVALI patients: Chest radiographs and CT.
In a cohort of 304 patients (Table 3 and S1), bronchoscopy and collection of broncho-alveolar lavage fluid (BALF) showed the absence of any infectious agent (bacteria, virus, and fungi), fundamental for the exclusion of any other possible cause of disease. The cytological findings revealed a non-specific cellular pattern, characterized by increased total cell count with the predominance of neutrophils (38%, n=120), macrophages (22%, n=68), lymphocytes (3%, n=10), or eosinophils (2%, n=7), which was not revealing in the diagnosis of EVALI. The increased number of red and white blood cells was registered in 7% (n=21) and 7% (n=22) of patients respectively. In contrast, a more common finding in BAL of EVALI patients was the lipid-laden macrophages reported in 50% (n=158) of patients.
Table 3.
Summary of the biochemical analyses of bronchoalveolar lavage (BAL) samples collected from EVALI patients.
The presence of lipid-laden macrophages in the alveolar or interstitial spaces of vaping patients was first noted in a case of acute lung injury in 2012 (McCauley et al. 2012), and subsequently, it was commonly detected in the BAL of EVALI patients, which initially misguided the physicians toward the diagnosis of exogenous lipoid pneumonia, possibly correlated to the presence of VEA in the e-cigs. This finding was later found to be not specific to EVALI, since it was detected also in the BAL of healthy adult smokers, e-cig users, and never-smokers (Shields Peter G et al. 2020), and was not always consistent with histopathological or radiological evidence of exogenous lipoid pneumonia (Butt et al. 2019).
On 85 BALF samples out of 313, chemical analysis was also performed aimed at detecting the presence of a causative agent such as THC, VEA, nicotine, or metabolites. THC, VEA, and nicotine were detected in 70 (82%), 82 (96%), and 46 (54%) samples respectively. (Blount et al. 2019; Taylor et al. 2019; Blount et al. 2020); other chemicals were found in BALF and were probably associated with EVALI symptoms, like cannabinoid (CBD) oils, coconut oil, and terpenes, such as limonene (Blount et al. 2019; Taylor et al. 2019; Blount et al. 2020). (Table 3 and S1)
The cyto- and histo- pathological assessments through the trans-bronchial lung biopsy, summarized in Table 4 and S1, showed a variety of patterns including acute lung injury, diffuse alveolar damage, and organizing pneumonia in 21%, 25%, and 46% (total cases n=249) respectively, accompanied by foamy macrophages in airspace in 76% of the 249 cases. The most common findings were type II pneumocytes hyperplasia, acute fibrinous pneumonitis with organization, fibrinous exudates in airspaces, interstitial chronic inflammation, respiratory bronchiolitis, lymphocytic infiltration, mild interstitial fibrosis, diffuse alveolar hemorrhage, and lipoid pneumonia.
To date, neither the bronchoscopy/BALF nor the lung biopsy is required for the diagnosis of EVALI, mostly because the main purpose of these exams is the exclusion of pulmonary infection or alternative cause of disease. In this regard, the chemical analysis of the BAL can be beneficial to detect chemical toxic compounds involved in the development of EVALI (Brosius et al. 2022). Many variables can negatively affect the result, such as the time window between the last use of e-cigs and bronchoscopy, variation in collection technique, and fluid dilution. Nevertheless, on a small number of samples (n=85) the chemical analysis of BALF was crucial to detect THC, VEA, and nicotine (82%, 96%, and 54% of samples respectively), even when any THC use was denied, as well as other chemicals probably related to EVALI, such as cannabinoid oils, coconut oil, and terpenes, such as limonene (Blount et al. 2019; Taylor et al. 2019; Blount et al. 2020). In addition, making the toxicological testing for cannabinoids routinely would be beneficial in reducing EVALI diagnosis delay, especially for those patients that hide this crucial information.
In summary, such differences in clinical and radiographic EVALI manifestation may be due to a variety of factors, including underlying conditions, individual host response to the inhaled substances, but most importantly, the diversity of toxic compounds inhaled, which are still difficult to determine, given the multitude of e-cig compositions and operating parameters of the cartridges prevalent among the vaping population.
3.3. Vaping devices, e-liquids, and frequency of vaping by EVALI patients.
Among the 11,350 EVALI patients that disclosed information on vaping products and behavior, an average of 34% (n=3879) and 17% (n=54) patients reported exclusive use of THC- and nicotine-based e-cigs, respectively, while 51% (n=5742) patients reported using both THC and nicotine e-cigs (Figure 2A). Moreover, 2% (n=227) of patients reported exclusive CBD oil e-cigs, while 8% (n=851) reported using CBD and THC, 4% (n=397) reported using CBD and nicotine, and 10% (n=1078) reported using all three substances (THC, nicotine, and CBD) in e-cigs. (Blagev et al. 2019; Chatham-Stephens et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Layden Jennifer E. et al. 2019; Lewis et al. 2019; Lozier et al. 2019; Moritz et al. 2019; Navon et al. 2019; Perrine et al. 2019; Taylor et al. 2019; Adkins et al. 2020; Chidambaram et al. 2020; Ellington et al. 2020; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington, et al. 2020; Pray et al. 2020; Rao et al. 2020; Tanz et al. 2021) (Figure 2A). In addition to vaping, patients reported using combustible marijuana, combustible tobacco, or both. (Ghinai et al. 2019; Layden Jennifer E. et al. 2019; Lewis et al. 2019; Adkins et al. 2020) (Supplemental Table S1)
Figure 2.
Relative frequencies of different vaping substances; e-cig device types, brand names and sources; and vaping behavioral patterns of EVALI patients.
Very few papers described in more detail the length of use, type of device, brand, and source of e-cigs or e-liquids. With regard to the type of device used among the interviewed patients, irrespective of THC or nicotine e-liquids used, the majority used disposable type of e-cigs (n=135/187, 72%), followed by reusable devices (n=63/187, 34%), reusable devices for wax or dry herbs (n= 41/187, 22%), vape rig (n=36/187, 20%), and pods for vaping salts (n=24/187, 13%).(Blagev et al. 2019; Ghinai et al. 2019; Perrine et al. 2019) (Figure 2B)
The frequency of THC vaping reported by EVALI patients is summarized in Figure 2C. 62% (n=1677/2727) reported daily vaping use, with 54% (n=1473/2727) of them reporting between 1–5 times/day, 43% (n=1182/2727) more than 5 times/day, and 24% (n=654/2727) more than 25 times/day. 25% (n=691/2727) reported vaping 2–3 times/week, 6% (n=164/2727) a few times per month, and 16% (n=427/2727) monthly or less (Figure 2C) (Blagev et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Lewis et al. 2019; Navon et al. 2019; Taylor et al. 2019; Adkins et al. 2020; Ellington et al. 2020; Pray et al. 2020; Rao et al. 2020). Regarding the duration of being an e-cig user, Baglev et al. reported that of the 23 patients examined, 43% vaped for less than 1-year, 17% vaped for 1–2 years, 26% vaped for 2–3 years, 13% vaped for ≥ 3 years. (Blagev et al. 2019) The duration of use was not correlated to the onset of symptoms. (Supplemental Table S1)
The most common brands of THC-containing devices used were Dank Vape, followed by Rove, Golden Gorilla, Smart Carts / Exotic Carts, Chronic Carts, and Cereal Carts. (Figure 2D). Interestingly, 81% (n=1439/1773) of them were obtained from informal sources, such as family or friend, illicit dealer, online, or out-of-state dispensary, but only 15% (n=271/1773) of THC products were purchased from formal sources, including dispensary, vape or smoke shop, pop-up shop, or grocery, drug, or convenience store. (Blagev et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Lewis et al. 2019; Navon et al. 2019; Adkins et al. 2020; Ellington et al. 2020; Pray et al. 2020; Rao et al. 2020) (Figure 2E)
Because, as mentioned before, 64% of 11,244 EVALI patients also reported the use of nicotine-containing e-liquids, the frequency of use, inhalation device, and source were investigated as well. Similarly to the THC users, 69%, of the 2100 nicotine users vaped daily, among whom 64% reported vaping frequency more than 5 times/day and 55% more than 25 times/day. (Supplemental Table S1). (Blagev et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Lewis et al. 2019; Navon et al. 2019; Taylor et al. 2019; Adkins et al. 2020; Ellington et al. 2020; Rao et al. 2020) The most common brands of nicotine-based devices were Juul, Njoy, and Smok, (Blagev et al. 2019; Gaub et al. 2019; Ghinai et al. 2019; Rao et al. 2020), more frequently (n=845/1280, 66%) purchased through formal sources (such as vape shops and convenience stores) than informal sources (n=341/1280, 27%) (online dealers, friends, out of state dispensary). (Ghinai et al. 2019; Lewis et al. 2019; Adkins et al. 2020; Ellington et al. 2020; Rao et al. 2020) (Supplemental Table S1).
Previous studies have highlighted the simultaneous increase of e-cigs and/or cannabis use and mental disorders such as depressive symptoms and suicidality in the young population, emphasizing the need for screening, prevention, and intervention strategies to help mitigate both substance abuse and mental health outcomes (Chadi et al. 2019). This issue is particularly relevant in those states where THC e-cigs are illegal for non-medical use, such as Utah or Minnesota, where the burden of EVALI reached the highest rate nationally (Lewis et al. 2019; Cole et al. 2021), which could be attributed to the high prevalence of illicit THC-cartridges (Arons et al. 2021).
No major difference was found in the use of disposable and reusable e-cigs (72% vs 56% of 187, respectively); therefore, it was not possible to correlate the type of device utilized to the specific active ingredient (THC or nicotine). Nonetheless, the commercially available reusable CCell 510 thread cartridges were most commonly associated with EVALI patients, because of the higher suitability for a thick and viscous liquid, such as THC (Wagner et al. 2020), high rate of availability and reproducibility in the illicit market, and high customizability by the users and manufacturers. The latter aspect is particularly important because the inappropriate manipulation of cartridges and e-liquid compositions often evades oversight from the regulatory agencies and increases the likelihood of generating and inhaling toxic chemical vapors.
As clearly stated by the Centers for Disease Control and Prevention (CDC), much crucial information is missing due to the lack of a standardized data collection methodology, which generates an obvious inconsistency. The information on patients’ demographics and vaping behavior was collected through anonymous surveys or telephone interviews taken from the patients or their families. The applied methodologies give space to a lot of intrinsic bias, such as selection bias, recall bias, response bias, and social desirability bias. In addition, the patients or their families were not always aware of the chemical substances contained in the cartridges, especially because the majority of vaping products were obtained from an illicit/informal source, leading to unreliable reporting. In addition, reporting potentially mislabeled cartridges leads to exposure’s misclassification errors in epidemiological studies. For all these reasons, it is difficult to draw strong and generalizable conclusions about the factors responsible for the evolution of EVALI.
A more accurate characterization of the vaping history is needed, especially in the younger population, including start date, last use, and method of use (aerosol, dabbing or dripping), length and frequency of vaping, device type (refillable or disposable), product brand name, source of THC- or nicotine-containing products, relative composition of the e-liquid components, number of cartridges consumed per day and volume of e-liquids vaped per day. Current or former use of combustible tobacco or marijuana or other substance abuse should be included as well.
3.4. Physicochemical characterization of emissions from vaping.
The topic of physicochemical characterization of emissions from e-cigs has been widely studied since their release in the global market in 2007 and the complex chemistry of the emissions is well-documented (Margham et al. 2016; Zhao et al. 2016; Pourchez et al. 2018; Zhao, Nelson, et al. 2018; Zhao, Zhang, et al. 2018; El-Hellani et al. 2019; Erythropel et al. 2019; Omaiye et al. 2019; Strongin 2019; Jiang et al. 2020; Nicol et al. 2020). Of special note is the lack of regulations concerning manufacturing and commercialization of e-cig devices. As a result, a plethora of devices is available including widely customizable ones in terms of temperature, operational voltage, puffing duration, and e-liquid composition. This enormous variability makes it difficult to characterize the emissions physicochemically and toxicologically and to generalize or predict their potential health risks.
Furthermore, the available literature on the topic is limited to the physicochemical characterization of emissions from nicotine-based e-liquids, while very little is known for the case of THC, VEA, or their combination-based e-liquids. We found only ten studies focusing on the characterization of real-world liquids or emissions from counterfeit or patient-provided cartridges (Table 5), and nine on the characterization of gas and particles released from in-house prepared e-cigs containing VEA or THC/VEA. (Table 6).
Table 5.
Summary of chemical analysis of counterfeit or patient-provided cartridges used by EVALI patients
| Author | Method | Results | ||||
|---|---|---|---|---|---|---|
| (Muthumalage, Friedman, et al. 2020) |
|
|
||||
| (Wagner et al. 2020) |
|
|
||||
| (Duffy B et al. 2020) |
|
|
||||
| (Duffy BC et al. 2021) |
|
|
||||
| (Guo et al. 2021) |
|
|
||||
| (Ciolino, Ranieri, et al. 2021) |
|
|
||||
| (Ciolino, Falconer, et al. 2021) |
|
|
||||
| (GGonzalez-Jimenez et al. 2021) |
|
|
||||
| (Lu SJ et al. 2021) |
|
|
||||
| (McGuigan et al. 2022) |
|
|
Table 6.
Summary of physicochemical characterization of vapor/aerosol generated from in-house prepared e-cigs containing THC and/or VEA.
| Author | Method | Results |
|---|---|---|
| (Mikheev et al. 2020), |
|
Aerosol size distribution characterization:
Chemical analysis of intermediate of VEA degradation not conclusive. Identified vaping emission product (not confirmed with standards): 1-pristene, durohydroquinone monoacetate (DHQMA), and duroquinone (DQ). No direct evidence for ATMMC, DQM, and ketene. |
| (Jiang et al. 2020) |
|
Identified vaping emission product:
|
| (Lanzarotta et al. 2020) |
|
|
| (Meehan-Atrash et al. 2019) |
|
|
| (Lynch et al. 2021) |
|
|
| (Kovach et al. 2021) |
|
|
| (Mikheev and Ivanov 2022) |
|
Temperature measurement depends on chemical liquids and temperature setting.
Aerosol size distribution characterization:
|
| (Marrocco et al. 2022) |
E-liquids:
|
|
On a special note, the physical inspection of the patient-provided cartridges exhibited severe burn marks, probably due to the high operating voltage and the resulting high temperature of the e-liquid. Nickel and chromium heating coils were detected in all devices, along with other metals present in the filaments, battery contact, and ceramics. Other metals identified included Cu, Pb, Au, Fe, Zr, Si, Al, Na, K, Ni, Sn (Wagner et al. 2020; Gonzalez-Jimenez et al. 2021). Other substances also found were phosphorus (P), silicon-rich rubbers, or fluorinated microplastics. Their presence in the e-cig cartridges raises concerns in terms of potential chemicals released during the vaping phase (Wagner et al. 2020).
The first investigation on the chemical composition of e-liquids from 38 samples collected from the first 10 New York cases of EVALI showed that compared to the marijuana medical products, the illicit cartridges contained a low concentration of cannabinoids (50% vs 80–90% in marijuana medical products), along with an unusual ratio of Δ9THC/Δ8THC isomers, due to the high volume of the synthetic Δ8THC. In addition, high concentrations of diluents, such as VEA (64% of samples - concentration range 16–58%) and MCT (41% of samples - concentration range 3–24%) were also detected. (Duffy B et al. 2020) This trend was confirmed by further and later investigation nationwide, that showed the presence of additional cannabinoids in the EVALI patient-provided cartridges as well as in the aerosol generated from them, such as cannabichromene (CBC), cannabidiol (CBD) cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinol (CBN), tetrahydrocannabinolic acid (THCA) and tetrahydrocannabivarin (THCV) (Ciolino, Ranieri, et al. 2021; Duffy BC et al. 2021; Guo et al. 2021; Lu SJ et al. 2021). All the illicit/patient-ptovided cartridges were found to contain various concentration of VEA, MCT, polyethylene glycol used as diluents either in combination or alone. (Ciolino, Falconer, et al. 2021; Duffy BC et al. 2021; Guo et al. 2021; Lu SJ et al. 2021). The most common terpenes reported were caryophyllene, limonene, myrcene (Lu SJ et al. 2021) (Table 5).
Numerous chemicals were identified in the e-liquids contained in counterfeit cartridges used by EVALI patients, including pesticide residues (such as myclobutanil and piperonyl butoxide-d9, bifenazate, bifenthrin), 2,2-dimethoxybutane, tetramethyl silicate, decane, methyl esters, ethyl esters, siloxanes, and acetates, as well as pine rosin acids, pine rosin derived methyl esters, dipropylene glycol dibenzoate isomers, and sucrose acetate isobutyrate compounds, (Muthumalage, Friedman, et al. 2020; Ciolino, Falconer, et al. 2021; Lu SJ et al. 2021) (Table 5).
Chemicals detected in the emissions generated from counterfeit cartridges included n-butane, benzene, xylene, pentene, ethanol, acetone, ethylbenzene and toluene, PCP-polycaprolactone/household constituents (e.g. methacrolein, acetaldehyde, crotonaldehyde, formaldehyde etc.), other toxic compounds (e.g. acrolein, pentadiene compounds, hexane compounds, methyl vinyl ketone, etc.), and elements such as Si, Cu, Ni, and Pb (Muthumalage, Friedman, et al. 2020; Gonzalez-Jimenez et al. 2021; McGuigan et al. 2022) (Table 5).
The majority of the detected chemicals, such as hydrocarbons, silicon conjugates and derivates, and VOCs, are known to be respiratory irritants, depressants, and paralytic agents, which could potentially cause dyspnea, chest tightness, and pulmonary edema (common symptoms among EVALI patients) (FDA 2012; Muthumalage, Friedman, et al. 2020; McGuigan et al. 2022). These chemicals can also physically interact with phospholipids and surfactants, inducing chemical pneumonitis, and interstitial and alveolar alterations, such as alveolar-capillary membranes dysfunction, pulmonary edema, and surfactant alteration, representative of acute lung injury (McKee et al. 2015). In addition, the identification of solvents, such as n-butane, a gaseous petroleum compound used in the illicit cartridge to increase the amount of THC released and retained in the lung (Varlet et al. 2016; Muthumalage, Friedman, et al. 2020; Ahmed et al. 2021), could be accounted for the atypical/eosinophilic pneumonia, acute lung injury and pulmonary edema, as described in some EVALI cases (Anderson R. P. and Zechar K. 2019; Stephens et al. 2020; Ahmed et al. 2021).
FDA’s preliminary lab analysis, dated February 12, 2020, reported that among the 1090 samples collected from vaping devices and products containing liquid, packaging, or other documentation, related to the EVALI patients, 511 (50%) contained THC, 50% of which were diluted with VEA, in a concentration between 23% and 88%, while 29% of them were diluted with MCT. Moreover, through the chemical analysis of 677 out of the 1090 samples, directly linked to 95 EVALI patients identified with CDC case numbers, it was determined that 73% patients were exposed to THC, and among them, 81% were also exposed to VEA, 32% to aliphatic esters (e.g. triglycerides), and 9% to polyethylene glycol. (FDA 2020c)
Based on the presence of VEA in BAL and the liquids of THC-based e-cigs from EVALI patients (Duffy B et al. 2020; FDA 2020b; Muthumalage, Friedman, et al. 2020), the federal agencies, CDC and FDA, declared in the early 2020 THC and VEA the two most presumable causative agents of EVALI, even in the absence of strong mechanistic hypothesis of disease. Since then, few studies have investigated the physical and chemical properties of particles and gaseous byproducts generated from THC and VEA pyrolysis, summarized in Table 6. Indeed, we found only three papers attempting the analysis of the aerosol generated from VEA, THC, and their mixtures, (Mikheev et al. 2020; Marrocco et al. 2022; Mikheev and Ivanov 2022), while nine papers investigated the chemical analysis of liquid and vapors generated from various combination of THC, VEA, Terpenes (Meehan-Atrash et al. 2019; Lanzarotta et al. 2020; Lynch et al. 2021; Mikheev and Ivanov 2022), and two addressed the physical and chemical analysis of aerosol emitted by pyrolysis of VEA alone (Mikheev et al. 2020; Kovach et al. 2021) or single diluents, either as liquid or vapor (Jiang et al. 2020).
The aerosol characterization showed that on average, the emitted particle number concentration in the vapors ranged from 106 to 108 particles/cm3, while the count median diameter varied from 50 to 200 nm, depending upon the device type, heating power, and puffing topography. Interestingly, for the case of VEA 100%, as the flow rate or the voltage increased, the count median diameter decreased while the particle number concentration increased (Mikheev et al. 2020; Marrocco et al. 2022; Mikheev and Ivanov 2022). The total number concentration, mean and modal aerosol size of particles generated from different combinations of D8THC/VEA/Terpenes varied also according to the e-liquid composition and voltages, but without any apparent specific trend. The released VOC and total PM mass concentration significantly rose with increasing e-liquid VEA concentration and operational voltages. Specifically, the concentration of VOCs increased linearly or exponentially with time, within a range between 0.173 and 24.5 ppm, while the total PM mass concentration ranged widely between 67 and 910 mg/m3, with the bulk of PM mass distributed between the PM0.1 and PM0.1–2.5; in both cases, the higher number was reached by emissions from VEA 100% at 5V. (Marrocco et al. 2022) (Table 6) The only three studies addressing the physical properties of the particles emitted from the pyrolysis of e-liquids containing different concentrations of THC, VEA and Terpenes confirmed that the e-liquid composition, device type, heating power, and puffing topography influenced the aerosol particles’ size and concentration (Mikheev et al. 2020; Marrocco et al. 2022). Although these studies represent a first attempt to clarify the possible link between the nanoparticles released from e-cigs and EVALI, they highlighted the concept that there is a significant difference between vapors generated from individual e-liquid components (ie, VEA 100%) and e-liquid mixture (ie, Δ8THC + VEA + Terp): the combination of VEA with THC and terpenes would certainly affect the physical characteristics of released particles (size and number concentration) and induce chemical heterogeneity in the released particles and gaseous byproducts.
Lanzarotta et al investigated the chemical properties of vapor generated from the combination THC/VEA (~50:50 w/w) from a CCell cartridge connected to a vaping device, operated at 3.7V, with a puff duration of 4 seconds and an interval between puffs of 30 seconds, sampled at flow rate 1.0 liter/min, mimicking the real-word exposure. The main finding of the study was that the THC/VEA liquids exhibit sufficient chemical differences compared to the individual THC and VEA controls, and the chemical spectrum generated from the pure VEA vapor exhibited a carbonyl peak, similar to THC/VEA, which was absent in the case of THC-only vapor spectrum. (Lanzarotta et al. 2020) A similar study was subsequently performed by Lynch et al. Starting from the same e-liquid composition (THC/VEA ~50:50 w/w) and puffing topography (puff duration 4 sec, interval 30s, flow 1L/min), they measured the coil temperature at increasing operational voltages, from 3.0 V to 4.5 or 5V, using 6 in-house prepared cartridges, as well as one black-market cartridge and 1 “authentic” cartridge containing D9THC from EVALI investigations (Lynch et al. 2021). Regardless of the type of cartridges, the following degradant products were identified in the emitted vapors: D9THC, VEA, 1-pristene, durohydroquinone monoacetate (DHQMA), 4-acetoxy-2,3,5trimethyl-6-methylene-2,4-cyclohexadienone (ATMMC). However, as intuitively expected, they also measured a voltage-dependent increase of the coil temperature during vaping: from a range of 217–300°C at 3.0 V to 415–476° C at 5.0 V for the in-house prepared cartridges, to 454–510°C at 5.5 V and 548–632°C at 6V for black-market and authentic cartridges. (Lynch et al. 2021) This temperature trend was further confirmed by Mikheev at al, who reported a coil temperature rise dependent on chemical liquids and temperature setting. Specifically, the authors used the “Kind Dream” vape pen, loaded with combination of THC 100%, THC/VEA 50%/50% w/w or VEA 100% and operated at 2 different temperature settings, low (177°C) and high (221°C), following a puffing protocol of 5 sec puff, 60 sec interval for 8 puffs. Interestingly, they found that regardless of the e-liquid composition, when operated at low temperature (177°C), the coil temperature was stably below 250°C; increasing the operational temperature to 221°C led to a rise of coil temperature up to 500–550°C, that was faster in cartridges containing the higher concentration of VEA (50%−100%). (Mikheev and Ivanov 2022)
In order to characterize the production of VOCs and other harmful and potentially harmful constituents (HPHCs) from THC pyrolysis, Meehan-Atrash et al. investigated the chemical composition of vapors generated from dabbing pure THC or the synthetic distillate THC:terpenes 90:10 v/v, compared to the vapor generated from vaping the mixture THC/Terpenes 90:10 v/v using a CCell cartridge vaporizer, operated at 3 voltages, 3.2 V, 4.0 V, and 4.8 V, with 1 puff of 55 ml volume over 3 seconds. The adsorption/thermal desorption gas chromatography−mass spectrometry (ATD-GCMS) helped to selectively identify the following chemical species in the gas phase: methacrolein, benzene, xylenes, toluene, styrene, ethylbenzene, isoprene, other non-target hydrocarbons, and total VOCs. Interestingly, as shown also by Marrocco et al. (2022) the relative amount of each species, as well as the other hydrocarbons, and total VOCs, increased depending on e-liquid composition (THC vs THC/Terpenes) and the operating voltage (when compared among the three vaping voltage conditions) (Meehan-Atrash et al. 2019).
Jiang et al. studied the vaping emission products from commonly used liquid diluents, such as propylene glycol (PG), vegetable glycerin (VG), VEA, vitamin e (VE), MCT oil, squalane (SQL), and triethyl citrate (TEC). It is worth noting that this study does not represent the real-world human exposures (cartridges containing only diluents are not commercially available). However, it was confirmed that the chemical composition of aerosols is very different from their parent e-liquid, due to the formation of new by-products during the vaping process. The detected new products included carbonyls, alkyl alcohols, esters, carboxylic acids, and short-chain alkanes, likely resulting from thermal decomposition and oxidation of liquid diluents. In particular, VEA and VE released carbonyls, long-chain alcohols, and quinone-like products (Jiang et al. 2020).
From the analysis of the degradation products of VEA 100% or THC/VEA 50%/50% pyrolysis, several products were identified. In the vapors generated from VEA 100%, the most common by-products were 1-pristene, durohydroquinone monoacetate (DHQMA), duroquinone (DQ),, while 2,6,10,14-tetramethyl-1-pentadecene (TMPD) was not confirmed (Mikheev et al. 2020; Kovach et al. 2021); in addition, in vapor generated from combination of THC/VEA 50%/50%, but not in VEA 100%, 4-acetoxy-2,3,5trimethyl-6-methylene-2,4-cyclohexadienone (ATMMC) was also found (Lynch et al. 2021) (Table 6).
In summary, the main finding of the presented studies is that there is a substantial difference in the chemical composition and structure between the parent e-liquid and the generated vapors (Jiang et al. 2020; Mikheev et al. 2020), and between the vapors generated from a single e-cig constituent compared to the vapors from real-world e-liquid mixtures (Meehan-Atrash et al. 2019; Lanzarotta et al. 2020; Lynch et al. 2021; Marrocco et al. 2022; Mikheev and Ivanov 2022). Although the process toward understanding the possible cause of EVALI starts with the identification of the e-liquids ingredients, it is not useful, besides being unrealistic, to rely only on the e-liquids’ physicochemical properties aiming to clarify the mechanistic pathway of EVALI, since it is clear that the thermal degradation generates byproducts with substantial differences from the parental e-liquids, and increases the likelihood of having a mixture of toxic chemicals in the vapor, which can exert synergistic effects on the respiratory system, and potentially leading to the development of EVALI.
An interesting hypothesis on the causative agent of EVALI has been the possibility of the release of ketene from the thermal degradation of VEA. Ketene is a highly reactive and highly toxic molecule, produced by cleavage of the acetate group from the whole VEA molecule (Committee on Acute Exposure Guideline Level et al. ; National Institute for Occupational Safety and Health NIOSH 1994). Although very few and historic studies have documented that the minimum lethal in-air concentration of ketene is 200 ppm, causing death after single 10-min inhalation exposure in primates, and concentrations as low as 5 ppm can trigger severe alveolar damage and secondary cerebral anoxia 24 h after inhalation in humans and animals (Committee on Acute Exposure Guideline Level et al. ; Treon et al. 1949; National Institute for Occupational Safety and Health NIOSH 1994), to date, the role of ketene in the development of EVALI, its generation in the vaping process, and consequently its presence in the BAL are still unknown. Indeed, the chemical analysis of VEA and VE vaping emissions under real-world vaping conditions did not identify the presence of ketene (Mikheev et al. 2020; Wu and O’Shea 2020; Mikheev and Ivanov 2022). Recently, few studies have addressed the possibility to generate ketene in the vaping atmosphere, however many discrepancies have been characterized: 1) the difference between the VEA boiling point 220˚C, and the temperature at which e-cigs typically operate, 170°C, in a wet-through-wick condition (Chen W et al. 2018; Dibaji et al. 2018); 2) the high power (30W or 50W - 11.0 or 15.5 A, respectively) (Wu and O’Shea 2020) or high temperature (700°C-1000°C) (Narimani and da Silva 2020) of VEA pyrolysis necessary to generate ketene not comparable with the power and temperature of real-world e-cigs (3.6 V, 9.4 W, 2.5 A), at which ketene was not detectable in vaping emissions (Jiang et al. 2020). Nevertheless, Narimani et al revealed that such high temperatures could be reached in “dry-hits” conditions, i.e. in those devices where the temperature is not automatically adjusted based on the e-liquid level, and lower e-liquid levels increase the operating temperature (Narimani and da Silva 2020). This information is particularly important if related to the fact that THC counterfeit vaping cartridges from EVALI patients showed severe burn marks (extensive charred, blackened material on the inside and outside of the oil-soaked ceramics and insulation), distinctive signs of devices that were operating at very high internal temperatures (Jiang et al. 2020).
To better understand and predict the lung response to the e-cig emissions, it is of great importance to understand the chemical and physical properties of vapors, including both the gaseous and particulate phase, and their diffusion/deposition patterns in the various regions of the respiratory tract, that can help explain the distinctive health effects from such complex exposures. The lack of standardized methodologies and platforms to generate and characterize vaping emissions under real-world consumer vaping conditions prevents the generation of reliable and generalizable physicochemical data, which are necessary to understand the etiopathogenesis of EVALI.
3.5. Toxicological studies related to EVALI
While the toxicological properties of aerosols emitted from nicotine-based e-cigs have been under investigation in the last decade, there is still a limited number of studies focusing on the in vivo/in vitro toxicity of vapors generated from THC/VEA e-cigs associated with EVALI syndrome. Indeed, very few studies have focused on the toxicity of aerosols emitted from the use of pure VEA or other diluents, while only one study has investigated the effect of THC/VEA pyrolysis byproducts (including both particles and vapors) on lung epithelial cells, thus highlighting a major knowledge gap preventing the understanding of the mechanistic pathways leading to EVALI.
Table 7 summarizes the most relevant studies published since 2019 focusing on the in vitro/in vivo toxicological characterization of the aerosols generated from e-liquids containing THC/VEA, CBD, and other common diluents, aiming to find a causative link to EVALI. Among them, five studies assessed the acute cytotoxic effect of counterfeit CBD or commonly used liquid diluents, including PG, VG, MCT, VEA, as either e-liquids or vapors, either in vivo (C57BL/6NCr mice) (Bhat et al. 2020; Matsumoto et al. 2020; Muthumalage, Lucas, et al. 2020a; Matsumoto et al. 2022) or in vitro (human bronchial epithelial cells, human monocytes, human lung fibroblasts cells, human primary AT-II cells) (Muthumalage and Rahman 2019; Bhat et al. 2020; Jiang et al. 2020; Matsumoto et al. 2020; Muthumalage, Lucas, et al. 2020a). Their findings revealed that the aerosols could induce a varying degree of cytotoxicity, barrier dysfunction, and inflammation in vitro and in vivo depending on e-liquid composition, puffing protocol, operational voltage, and cell lines. Acute (24 h) in vitro exposure of human bronchial epithelial cells (BEAS-2B or 16-HBE) or human monocytes cells (MM6) to aerosols generated from MCT, VEA or CBD, induced a substantial secretion of pro-inflammatory cytokines such as IL-6, IL-8, Eotaxin, MCP-1, CXCL1, and CXCL2, massive generation of reactive oxygen species (ROS), increased cytotoxicity and lactate dehydrogenase (LDH) release (Muthumalage and Rahman 2019; Jiang et al. 2020; Muthumalage, Lucas, et al. 2020a).
Table 7.
Summary of the in vivo/in vitro toxicological experiments conducted on various e-liquids or the generated aerosols/vapors.
| AUTHOR | Cell/Animal model | EXPOSURE | FINDINGS: | COMMENT: |
|---|---|---|---|---|
| (Muthumalage, Lucas, et al. 2020b) |
|
Aerosols generated from:
Operated voltages: 3.8V 70 mL puffs ×10 minutes in air-liquid interface. Time-point 24 hours |
|
|
|
6 Cartridges 70 ml puff, 2 puff/min, for 1 h/day × 3 consecutive days |
|
||
| VOCs release: CBD =20.03 ppm, MCT= 10.33 ppm, VEA= 9.67 ppm. | ||||
| Human Plasma | E-cig users vs non-smokers |
|
||
| (Muthumalage and Rahman 2019) |
|
|
|
|
|
|
|||
| (Bhat et al. 2020) |
|
|
|
Limitation of the study:
|
| (Jiang et al. 2020) | Human bronchial epithelial cells (BEAS-2B) |
|
|
|
| (Matsumoto et al. 2020) | C57BL6 mice Human primary AT-II cells (from 1 single adult human lung donor) |
|
VEA aerosol 1-hour × 2/day for 6 or 15 days:
15 days of VEA exposure:
|
|
| (Marrocco et al. 2022) | Human lung epithelial cell line (Calu-3) Human peripheral blood monocytes (THP-1) |
E-liquids:
|
Cell viability
ROS
Apoptosis
Inflammatory response
|
|
| (Matsumoto et al. 2022) | C57BL6 mice Primary human alveolar macrophages from adult human lungs |
|
|
|
Mice challenged with VEA, MCT or CBD e-cig vapors from 3 to 15 or 28 days also exhibited increased inflammatory markers, such as IL-6, IL-8, Eotaxin, G-CSF, and MCP-3, and reduction of RANTES, IL-4, IL-17A, and IL-12p40, accompanied by the presence of VEA in the BAL (only in the VEA-treated mice), the disruption of alveolar-capillary barrier, progressive increase of BAL total fluid volume, total cell count (mono/macrophages and neutrophils), increased total protein (including albumin), presence of large vacuolated macrophages, decreased lung surfactant protein A or increased surfactant protein-D, and alteration of lipidomic profile (Bhat et al. 2020; Matsumoto et al. 2020; Muthumalage, Lucas, et al. 2020a; Matsumoto et al. 2022). The lung parenchymal alteration was represented by alveolar and parenchymal inflammation in a bronchiolocentric pattern with an increased number of monocytes and neutrophils, and large, foamy and vacuolated macrophages, also associated with alveolar septal thickening and pulmonary blood vessels surrounded by lymphocyte-rich cell aggregates (Bhat et al. 2020; Matsumoto et al. 2022). (Table 7)
We found only one research study that systematically investigated the in vitro toxicity of aerosol generated from real-world combination of D8THC/VEA/Terpenes, operated at 2 different voltages (3.7 and 5V). Using 2 physiologically relevant cell lines, Calu 3 human lung epithelial cells and THP-1 human monocytes, Marrocco et al investigated the cytotoxic effect of 2 doses of the collected vapors, representative of 1 and 3 months vaping exposure. Overall, the aerosol generated from D8THC 36% + VEA 54% + Terpenes 10% was the most bioactive, on both cell lines, as demonstrated by the increased LDH release, increased ROS generation (only in THP-1), significant decrease in mitochondrial membrane potential, and increase in caspase 3 activation, and upregulation of a limited number of pro-inflammatory markers, while suppressing the majority of them. (Marrocco et al. 2022)
From the studies analyzed, while it is clear that the injury of the alveolar epithelium is crucial in the pathogenesis of EVALI, it is still difficult to delineate a precise cascade of events. The only one study, performed by Matsumoto et al, approaching the identification of the specific mechanistic pathway through the RNA sequencing on two VEA-exposed alveolar epithelial (AT-II) cells from a single donor, revealed that the VEA-induced severe inflammatory status was correlated to the enrichment in the IL-17, MAPK and TNF signaling pathways (Matsumoto et al. 2020).
A common feature between the in vivo toxicology studies and the clinical reports was the presence of lipid-laden macrophages in the airspace, which is a non-specific marker of EVALI. Yet, since lipid-laden macrophages were characterized in mice exposed to e-cig vapors generated from PG and VG regardless of the presence of nicotine or VEA as a result of the alteration of lipid homeostasis (Madison M. C. et al. 2019), as well as in lungs of individuals exposed to other chemicals and healthy smokers (Maddock et al. 2019; Christiani 2020; Jonas A 2020; Shields P. G. et al. 2020), it raises questions about the possible role of these macrophages on lung injury development and progression. The involvement of alveolar and interstitial macrophages is crucial both in the recognition, activation, and reaction against a foreign body or pathogenic factors at early stages (Higgins et al. 2008) and in the resolution of inflammation, regulation of fibro-proliferative response, and wound healing in the late stage of disease (Bellingan 2002; Gordon 2003; Huang X et al. 2018; Matsumoto et al. 2022).
The detection of ROS in MCT, VEA, and CBD e-cig vapors has also been demonstrated (Muthumalage and Rahman 2019; Muthumalage, Lucas, et al. 2020a; Marrocco et al. 2022). Previous studies have already identified the presence of ROS in conventional tobacco smoke and nicotine e-cig emissions (Goel et al. 2015; Lerner et al. 2015; Tierney et al. 2016; Zhao, Zhang, et al. 2018; Son et al. 2019), and their role as mediators both in vivo and in vitro of oxidative stress, cell death, DNA damage, and lung inflammation, underlying also the pathogenesis of chronic obstructive pulmonary disease and lung cancer (Anderson et al. 2016; Yu et al. 2016; Rouabhia et al. 2017). Even though the generation of ROS by pyrolysis of e-liquids cannot be directly accounted as a specific cause or marker of EVALI, the simultaneous release of heavy metals and organic compounds in the e-liquid vapor can increase the generation of ROS, thus potentiating their dangerous health effects.
Even though these results highlight a certain correlation between the nature of vaping exposures (mainly VEA) and EVALI, major limitations still need to be addressed to understand the mechanistic pathophysiological pathway underlying EVALI.
The major limitation consist on the fact that among the available toxicological studies only one has tested the effect of vapors generated from combination D8THC/VEA/Terpenes on the human lung epithelial cells in vitro, and none has tested D9THC either in vitro or in vivo, which is mostly due to ongoing strict federal research restrictions on D9THC; moreover the majority of the studies focused on the cytotoxicity of pure VEA e-liquid or its vapor, which is unrealistic, and not representative of complex mixtures containing VEA. Although VEA serves mainly as a diluent of the active agent THC, the mixture of distinct chemicals in the combination THC/VEA vapor can exert synergistic effects on bioactivity and toxicity, which can further be modulated by the relative composition of ingredients and e-cig operating conditions. Moreover, there is no consistency in the puffing topography, cartridges’ operational voltage, and vapor sampling method among the studies, as well as the dose ranges and time-points assessed for toxicity, leading to inconsistencies in the physicochemical characterization of vapors and incomparable biological endpoints between different studies. These issues prevent the generalizability of the data that could be used to explain the EVALI-related health effects observed in the general population. Finally, as mentioned before, in vitro or in vivo exposure to e-liquids obtained as-is does not help to understand if the aerosols generated from them during vaping will be harmful to the alveolar epithelial cells, because pyrolysis involves drastic changes in physicochemical properties during the transformation from the e-liquid to the vapor phase and thus they can have significantly different toxicological profiles.
In the absence of strong and reliable data on the mechanism of toxicity of THC/VEA vapor, to date many hypotheses on the pathogenesis of EVALI have been proposed, mostly correlating to the presence of VEA, such as the longer residence of un-hydrolyzed VEA in the lung airspace, due to the absence of pancreatic carboxyl ester hydrolase and cholesteryl ester hydrolase. (Hybertson et al. 1998; Jensen et al. 1999; Hybertson et al. 2005; Desmarchelier et al. 2013; Lee H 2020) Moreover, the hydrophobic nanoparticles potentially generated by VEA aerosolization could reach the alveoli surface and directly interact with the lipid monolayer or the liquid crystalline phase of the pulmonary surfactant (Lee H 2020; Mikheev et al. 2020), leading to increased surface tension (Blount et al. 2020; DiPasquale et al. 2020), impairment of alveolar-capillary function of gas exchange (DiPasquale et al. 2020), and respiratory compression-expansion cycling (Lee H 2020), consequently inducing acute lung injury.
As mentioned before, the role of ketene in the development of EVALI has also been supposed. The acute respiratory distress syndrome manifested by acute occupational intoxication with a mixture of ketene and crotonaldehyde, consisting in respiratory failure and ground-glass opacities presented 12 hours post-5-minutes exposure (Huang J-F et al. 2013; Attfield et al. 2020), was consistent with the small number of young EVALI patients who developed life-threatening symptoms literally within hours after initial constitutional, respiratory, and gastrointestinal symptoms (Layden J. E. et al. 2020). However, this hypothesis was not supported by the in vivo acute exposure of mice to the aerosol generated by pure VEA under real-world vaping conditions (Bhat et al. 2020; Matsumoto et al. 2020). Besides these speculations, the exclusive correlation between EVALI and VEA has failed to be proven (Kleinman et al. 2020), while many other toxicants contained in THC-based aerosol (for example, silica and silicon-derivates) are already known to react with alveolar surfactant and induce respiratory failure due to alveolar damage (McKee et al. 2015; Christiani 2020).
Other authors have considered that either inhalation of a single chemical contained in the e-cig vapor, such as diacetyl, chlorine, VEA, can be directly cytotoxic to certain lung cells, leading to cellular necrosis, neutrophilic inflammation, collateral damage, or inhalation of the base ingredients of e-liquids (PG and VG) from the e-cigs vapor can alter the physiologic state of the immune system, making the lung sensitive to any other inhalants that are normally well tolerated (Alexander et al. 2020).
However, it is also reasonable to speculate that the mixture of chemicals and particles released in the THC/VEA e-cigs vapors can exert a synergistic and direct cytotoxic effect on the alveolar epithelial cells, inducing cells membrane damages, cellular necrosis, and impairment of the alveolar-capillary barrier leading to increased permeability, pulmonary edema, and recruitment of inflammatory cells. In alternative, it is also possible that alveolar macrophages can recognize and engulf the particles and give rise to the cytokine storm and ROS generation, which induces a strong pro-inflammatory phenotype, leading to cytotoxicity in the alveolar epithelial cells, impairment of the alveolar-capillary barrier, and in turn acute lung injury pattern.
Given the multitude of unanswered questions, further and more comprehensive molecular biology and toxicological studies are needed to investigate the mechanism of immune response to vapors generated from THC/VEA e-cigs and the resulting acute, sub-acute, and chronic health effects.
Besides the cytokine/chemokine profile assessment, previous studies on nicotine e-cig exposure have also focused on the membrane pattern recognition receptors and cellular protein expression. For example, Singh et al described alteration of proteins related to cellular processes including cell adhesion, cell migration, membrane trafficking, cell communication, apoptosis, and transcriptional regulation. In particular, they illustrated an overexpression of TLR-4 (toll-like receptor 4) and cytosolic receptor NOD-1 (nucleotide-binding oligomerization domain-containing protein-1), and a lipid raft-associated protein caveolin-1, which governed the amplified downstream signaling cascade, leading to the inflammatory response to the nicotine e-cig vapors in vitro (Singh DP et al. 2021). If it is clear that EVALI is driven by a severe alveolar pro-inflammatory status, the precise cytokines/chemokine profile is still unknown, and many inconsistencies are reported in the literature. Therefore, a more systematic proteomic approach can help elucidate the trigger event, and subsequently the signaling cascade leading to the diffuse and massive alveolar damage.
In addition to the protein profile, transcriptomic RNA-sequencing analysis would be of great help in elucidating the alteration in the expression of key genes involved in the pathogenesis of EVALI, as already tentatively shown for the VEA treated cells by Matsumoto et al (Matsumoto et al. 2020). Previous investigation on the effect of nicotine e-cigs vapors on gene expression and subsequent molecular pathways of vapers’ oral epithelium have shown a significant number of aberrantly expressed transcripts, mostly related to regulatory non-coding RNAs associated with the development of cancer (Tommasi et al. 2019). More importantly, Park et al reported significant transcriptomic changes in pathways related to downregulation of ciliogenesis, leading to a decreased number of ciliated cells, downregulation of new protein synthesis, and upregulation of inflammatory response, in normal human bronchial epithelial cells treated with nicotine e-cigs vapors which can ultimately impair the immune response against foreign bodies and pathogens (Park H-R et al. 2019; Park HR et al. 2021).
A preliminary study on the lipidomic profile alteration induced by pure VEA or counterfeit CBD e-cig vapors in mice was proposed by Muthumalage et al. They reported an increased level of leukotrienes in mice, and increased hydroxyeicosatetraenoic acids (HETEs) in plasma of e-cigs users, both of which are implicated in oxidative stress and inflammatory response in lungs (Muthumalage, Lucas, et al. 2020a). Many studies have reported the dysregulation of lung lipid homeostasis in response to e-cigs vapors (Madison Matthew C et al. 2020; Singh DP et al. 2021), however, Moshensky et al. reported that mice exposed to nicotine e-cigs vapors for 1 h daily for 12 days exhibited changes in circulating metabolites depending on the type of device, e-liquid composition, puffing protocol, operational voltage and temperature (Moshensky et al. 2021). This study is particularly relevant because it supports the need for a systematic and standardized vapor generation and sampling methodology and also highlights the need for studies addressing the potential health effects of real-world THC/VEA and nicotine e-cigs vapors.
A comprehensive genomic, proteomic and metabolomic approach would help to elucidate crucial processes of lung inflammation, cell damage, and death, aiming to understand the mechanistic pathways underlying EVALI.
3.6. Regulations
E-cigs and their components and parts have been under the jurisdiction of the Food and Drug Administration since May 2016 (Register 2016), when they were classified under the definition of “tobacco products”, and consequently subjected to the Tobacco Control Act provisions, addressing advertising/promotion, child safety, health warning labeling, restriction of marketing and sales to youth (of minimum age), and reporting/notification. In more detail, the regulation includes 1. Enforcement action against adulterated and misbranded products; 2. Disclosure of ingredient listing, including Harmful and Potentially Harmful Constituents (HPHCs); 3. Registration of manufacturers and product listings; 4. Restrictions on sale and distribution of products with mislabeled risk description; 5. Prohibition on sales or distribution of free samples; 6. Premarket review of tobacco products. In addition, the FDA established 3 further restrictions, concerning the minimum age of purchase, the health warning labeling on packages and advertisements, and the prohibition on vending machine distribution.
In 2018, in an attempt to mitigate the expansion of youth sales, the FDA began to regulate e-liquid packaging to make them less appealing to minors. (FDA 2018) Following the FDA provision, on December 20, 2019, a federal law raised the federal minimum legal sales age for all tobacco products, including e-cigarettes, from 18 to 21 across the United States. (Congress 2019) The legislation was passed in all 50 states on December 31, 2020. (CDC 2020b)
In conjunction with all the efforts taken to limit and constrain the spread of e-cigs especially among the young population, in September 2019, the President of the United States announced his plan to clear the market of unauthorized, non-tobacco-flavored e-cigs products. (FDA 2020a), which was finalized in January 2020 by the FDA through the enforcement of the policy on unauthorized flavored cartridge-based e-cigarettes that appealed to children, including fruit and mint flavorings. (FDA 2020b) It is also worth mentioning that although flavors were not found to be correlated to the development of EVALI, the flavor contribution to the vapor toxicity has been already recognized, and correlated either to the presence of toxic ingredients in the parent e-liquid, or the release of toxic chemicals after vaporization (Behar et al. 2014; Clapp et al. 2017; Hua My et al. 2019; Rowell et al. 2020; Salam et al. 2020).
Subsequently, in December 2019, due to the EVALI outbreak, the FDA and Drug Enforcement Administration (DEA) started a law enforcement response against the sales of illicit THC-containing products, and the elimination of VEA from vaping products (FDA 2019; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington 2020).
In February 2020, the U.S. House of Representatives approved the “Protecting American Lungs and Reversing the Youth Tobacco Epidemic Act”, to prohibit all flavored tobacco products, among the other restrictions.
In addition to the federal measures, state governors have enacted measures to prevent the escalation of EVALI cases. For example, in 2019 many states like Washington and Colorado banned the use of vitamin E acetate in vaping products, while the State of Oregon only issued a recommendation for cannabis retailers to carefully review their vaping products for potential safety concerns. The Governor of Massachusetts declared a public health emergency in September 2019 due to the increased number of vaping-related illnesses and deaths, with a moratorium on vaping produced, and two months later, in November 2019, the Massachusetts House Bill No. 4196 (“An act Modernizing Tobacco control”) imposed a 75% excise tax on nicotine-containing vaping products, temporary banning all flavors and flavored products from the market, except in licensed smoking bars starting on June 1, 2020 (Massachusetts 2019). Similarly, the Governor of New York State prohibited the sale of flavored e-cigs and e-liquids (NewYorkState 2020), while the Governor of California proposed a 12.5% increase in excise taxes on e-cigs (Senate Bill No.395 signed in October 2021 (California 2021).
It is also important to highlight that until 2019, only 7 states had legalized cannabis and THC-containing products for recreational use, while only medical marijuana was allowed in 26 States, and the remaining 18 states prohibited all cannabis use. (Wing et al. 2020) Many pitfalls are strictly correlated to the legalization of cannabis. While some studies have speculated a higher incidence of EVALi in the States where THC is prohibited (Wing et al. 2020), the legalization of cannabis has led to an expansion of the uncontaminated and un-adulterated THC products in the legal market, as well as of contaminated e-liquids and counterfeit cartridges both in the states where the THC-e-cigs are prohibited and in more liberal states, due to the trafficking across the States. (Cirulis et al. 2020; Wing et al. 2020; Hall et al. 2021b, 2021a) Although more accurate surveys, data reports and new study designs design are necessary to confirm these hypotheses, the Governments should put into policies that discourage illicit trade market, and estabilish laws to protect the THC-users rather than just banning THC products. To date, in fact, there are very limited existing policies, regulations, and standards at the local, state, and federal level that address permissible or recommended volumes and/or concentrations of ingredients (including nicotine, THC, flavors, and diluents) and safety/hygiene parameters of e-liquids and cartridges (e.g., standardization and quality control for liquids and vaporizers, disclosure of ingredients in liquids).
4. Conclusions and the way forward
“E-cigs, or vaping, associated acute lung injury” is characterized by an acute inflammatory process of the lungs that disrupts the lung endothelial and epithelial barriers (alveolar-capillary membrane damage), leading to increased permeability, excessive transudation of fluid, recruitment of neutrophils and monocytes in the alveoli, and release of pro-inflammatory cytokines (Johnson and Matthay 2010). This acute inflammation, which results in collapse of alveoli and severe impairment of gas exchange, has been presumably attributed in the e-cig or vaping product users to the presence of THC and VEA in the e-liquids, due to their detection in the majority of patients’ biological samples and vaping products. However, scant, non-standardized and inconclusive studies have been performed to assess the physical-chemical and toxicological properties of vaping aerosols and to delineate the possible pathophysiological mechanisms leading to acute lung injury. Consequently, big knowledge gaps still exist at multiple levels, such that the mechanistic pathway(s) that lead to respiratory failure in e-cig users are still unknown.
The very few vaping atmospheres examined in the current literature are not always representative of the real-world e-cigs aerosols, thus are not comparable. Subsequently, the in vivo/in vitro toxicological studies performed are based on variable experimental approaches, due to the lack of standardized methodologies to generate and characterize controlled real-world e-cigs aerosols. In the absence of sufficient reliable data on the physico-chemical and toxicological properties of THC/VEA aerosol, it is therefore difficult to draw specific conclusions on the etiopathogenesis of EVALI.
More studies are warranted to fill in the existing gaps: a comprehensive analytical assessment of the VOC, hydrocarbons, ROS, elements, and other organic constituents of the THC/VEA emissions, along with an extensive physicochemical characterization of the aerosol particulates, and exhaustive in vitro/in vivo toxicological investigations, through a multi-omics approach, would help to delineate the cascade of events leading to the acute lung injury, to detect pathognomonic signs or biomarkers of disease, and also characterize long-term cardiopulmonary consequences of the EVALI patients and asymptomatic users. Such a multi-disciplinary approach would also help the federal regulatory agencies in future decisions on the regulation of e-cigs or vaping products.
Besides the prompt law enforcement response to the illicit products, and the elimination of VEA from vaping products (FDA 2019; Krishnasamy, Hallowell, Ko, Board, Hartnett, Salvatore, Danielson, Kite-Powell, Twentyman, Kim, Cyrus, Wallace, Melstrom, Haag, King, Briss, Jones, Pollack, Ellington 2020), which helped to dampen the EVALI outbreak, to date, no other measure has been taken to prevent future outbreaks. Indeed, the possibility of a resurgence of the EVALI crisis may still resurface given the lack of measures against the use of illicit or widely customizable e-cigs products. In addition to dismantling the illicit market and increasing the minimum age from 18 to 21 years old, there are still more actions that need to be taken. For example, the prohibition of flavoring sales should be applied also to the disposable and large cartridges, as well as pods, flavored with tobacco or menthol. Moreover, limiting the parameters easily customizable by the user, such as e-liquid ingredient proportions, voltage, and temperature, can greatly help toward the prevention of a future EVALI epidemic or other accidental health hazards. In addition, the identification of released harmful chemical compounds in the e-cig vapors and available information on their individual toxicological dose parameters (such as lethal dose, lethal concentration, no/lowest-observed adverse effect level) can be a useful tool for risk assessors and legislators to implement e-cig restrictions based on evidence of toxicity.
Human epidemiological studies, based on standardized and more comprehensive surveys or interviews along with regular follow-ups and clinical testing, could also be beneficial in gathering pertinent information on the e-cigs or vaping product use (such as type of device, source, brand, composition, operating conditions) and vapers’ behavioral patterns (such as frequency of use), and linking them to any observed pulmonary abnormalities to prevent future outbreaks.
Supplementary Material
Acknowledgment
The authors gratefully acknowledge all the past and present members of the Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, including Jeff Rawson Ph.D., Postdoctoral Fellow from Prof. George M. Whitesides Laboratory, Department of Chemistry and Chemical Biology, Harvard University, for helpful discussions and comments; Professor Dhimiter Bello, Department of Public Health, UMass Lowell, and Professor Ilias Kavouras, Environmental, Occupational, and Geospatial Health Sciences, CUNY Graduate School of Public Health and Health Policy, for the internal review of the manuscript; the Editor in Chief and the anonymous peer-reviewers selected by the editor for their suggestions and comments that helped to improve the quality of this manuscript.
Footnotes
Declaration of Interest
This review aims to provide a comprehensive and critical appraisal of existing literature on clinical/epidemiological features and physicochemical-toxicological characterization of vaping emissions associated with EVALI. The authors believe that highlighting the knowledge gaps in the current literature and the limitations in the e-cigs regulations is necessary for the development of new study designs and for the federal regulatory agencies in future decisions on the regulation of e-cigs or vaping products, to prevent future outbreaks.
This review was made possible by the T32 Grant No. HL007118 from NIH. The authors have not participated in and do not anticipate participation in any legal, regulatory, or advocacy proceedings related to the contents of the paper.
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