Edited by: Paolo Montuschi, Catholic University of the Sacred Heart, Italy
Reviewed by: Dhyan Chandra, University at Buffalo, United States; Narasaiah Kolliputi, University of South Florida, United States; Monica Goldklang, Columbia University, United States
*Correspondence: Irfan Rahman,
This article was submitted to Respiratory Pharmacology, a section of the journal Frontiers in Pharmacology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
New emerging tobacco products, especially electronic cigarettes (E-Cig) or electronic nicotine delivery systems (ENDS), have gained a huge popularity, particularly in younger populations. The lack of sufficient evidence-based health effect studies has promoted widespread use/abuse with the assumption that E-Cig or ENDS and/or vaping products are safer and less toxic than conventional tobacco smoking. However, the recent escalation in acute lung injuries and their associated fatalities among ENDS or vaping product users has now brought attention to this silent epidemic
The use of electronic cigarettes (E-Cig) or electronic nicotine delivery systems (ENDS) has reached epidemic levels among young adults in the US. Currently, an estimated 10 million US adults and over three million high school adolescents are active ENDS users (including e-juices and pod based systems) with as high as 27.5% of high school students in 2019 (
ENDS products encompass all the E-Cigs, vapes, e-hookahs, vape pens, tank systems, pods, and mods used at high temperatures. Using ENDS products is commonly referred to as vaping. ENDS products work by heating the e-liquid or e-oil provided in cartridges to produce an aerosol/vapor that users inhale into their lungs. The e-liquid or e-oil may contain nicotine, tetrahydrocannabinol (THC) and/or cannabinoid (CBD), and other substances and additives (flavors), that has hugely contributed to the popularity of ENDS use. There are more than 7,000 flavors including fruit or candy essences added to enhance the “experience”.
Effective delivery of nicotine in the form of a vapor utilizes vehicle solvents like propylene glycol (PG) and vegetable glycerin (VG), which are generally regarded safe by the FDA as food additives. Little is known about how ENDS constituents, e.g. PG and VG, affect the respiratory tract and its local immune-inflammatory functions. Emerging evidence indicates that the acute effects of ENDS or vaping products use on the respiratory system are of particular concern (
Among EVALI affected subjects where the lung samples were available, abnormal lipid-laden macrophages that are associated with lipoid and other forms of pneumonia were observed. The presenting symptoms include cough, shortness of breath/dyspnea, chest pain, nausea, vomiting/diarrhea, fatigue, fever, and/or weight loss. The fast development of this clinical entity suggests that some subclinical reactions with unknown long term health implications are taking place in the lungs of most ENDS/THC products’ (including wax and dabs) users, with EVALI cases representing the tip of the iceberg. Indeed, sporadic cases of EVALI had been reported in the UK, EU, and elsewhere, despite highly variable public health policies and also in many places there is no clearly identified reporting system for such cases (
Most of the subsequent analysis has been geared towards the constituents of E-liquids/E-juice or vaping products like Vitamin-E (alpha-tocopherol) acetate (VEA) which is being implicated as the likely ‘exogenous’ source of lipids in these ENDS-user subjects (
Recent histopathological reports showed the presence of burnt/blackened lungs, suggesting that aromatic/volatile hydrocarbons, including terpenes (diluent) and oils, are involved in EVALI (
In contrast to the e-liquid constituents, the lipid derivatives from the ‘endogenous’ source such as the epithelial lining fluid (ELF) and/or lung surfactants and their constituents, i.e. phospholipids, including dipalmitoylphosphatidylcholine (DPPC), could also be associated with the inflammatory responses of innate immune cells of ENDS users. Hence, the airway lipid dysregulation might also be contributing to the ENDS use associated inflammatory responses and perhaps is involved in EVALI as well. Therefore, the rapid and mass spread of ENDS among US young adults, and the seriousness of potentially acute lung reactions (including fatality), calls for a systematic investigation of ENDS use inflammatory responses (
Besides the source of the lipid dysregulation, there is an urgent need to establish the biomarkers that correlate with the acute response to ENDS use or EVALI as recommended by recent CDC guidelines (
Certain mechanistic approaches can be presented to understand the mechanisms of EVALI. These biochemical, cellular, and molecular changes are known to occur by e-cig vaping. The following sections provide some of the interesting current hallmarks on the observed mechanisms of lung injuries caused by ENDS use.
Several physiologic mechanisms, including lung surfactants, mucociliary clearance, and phagocytosis of the inhaled particulates, are paramount in maintaining the airway homeostasis. The airway epithelial cells (AECs), including alveolar type I (AT-I) and type II (AT-II) cells, alveolar macrophages (AMs), and the granulocytes or polymorphonuclear cells (PMNs) are the prominent airway innate immune cells driving these physiological functions and are among the first responders following the ENDS aerosol/vape exposure, as depicted in
Interaction of ENDS use or vaping generated aerosols/lipids with the airway innate immune cells. The inhaled vapors/aerosols from ENDS use that consists of the hydrocarbons like oil and lipids, vitamin E acetate (VEA) and heavy metals end up in the alveolar regions where active efferocytosis of these aerosolized constituents leads to accumulation of lipid-laden AMs (Lipoid AMs or Foam cells) and the NET-release from the PMNs. The oxidative damage also the leads to the aggregation of oxidative derivatives of the cellular lipids and the surfactants. The AT-II cells secrete inflammatory factors and lung surfactants in the ELF, AMs, alveolar macrophages; AT-1, Alveolar type-1 cells; AT-2, Alveolar type-2 cells; PMNs, polymorphonuclear cells; NETs, neutrophil extracellular traps.
Several pathophysiological alterations in the lung functions have been associated with E-Cig exposure both in humans and in animal model studies with the reported effects on the airway mucociliary clearance and dysreglated repair mechanisms. In E-Cig users a reduced pulmonary function is often observed that is evaluated by the forced expiratory volume in one second (FEV1) and the ratio of forced expiratory volume to forced vital capacity (FEV/FVC) (
In a limited clinical study, higher serum club cell protein 16 (CC16) levels were strongly correlated in frequent E-Cig users compared to occasional smokers, reflecting epithelial dysfunction/injury in the lungs (
Clinical data, comprehensive or restrictive, on pulmonary toxicity are lacking; therefore, most of the understanding of the inhalational toxicity of E-Cig aerosol exposure comes from animal studies. In an acute (3 d) exposure mouse model of E-cig exposure, Lerner et al. demonstrated increased BALF IL-6 and CCL2 levels following Blu side-stream aerosol exposure (
Granulocytes, especially PMNs or neutrophils recruited to the injury site rapidly undergo degranulation and set extracellular traps (ETs) to curb the insult. Neutrophil-derived ETs (NETs) are extracellular fibers composed of DNA, histones, and granule-derived proteins such as elastase or myeloperoxidase derived by a process referred to as NETosis (
In summary, the following high priority questions should be probed in the ongoing and future research efforts and directions on understanding EVALI pathophysiologies: The most compelling question is to delineate whether the observed EVALI in the reported cases is due to e-cig nicotine/flavor of vaping products in addition to the combined THC oils, or both. Longitudinal studies of ENDS users of nicotine, THC, or the combination of nicotine/THC products can help answer this question. Clinical manifestations following vaping/aerosol exposure are known in all the reported cases, which included inflammation, lipoid- or eosinophilic pneumonia or hypersensitive pneumonitis with a typical ground-glass opacity on the lung CT scans, and the oxygen supplementation along with steroid therapy was able contain the analyzed pathological symptoms. Some patients received prophylactic antibiotics, however, no infection was detected in these patients with EVALI. As EVALI is a manifestation of several components, accordingly the clinical characteristics, diagnosis, and therapeutic interventions are evolving ( There are no reports on other potentially harmful ingredients besides VEA, which is in fact protective in the lungs as discussed earlier. All the recent reports that implicate VEA to EVALI are based on its detection in the users’ lungs and the e-liquid usage history, but none of the studies provide direct evidence that VEA is the causative agent. All the oils contain VEA and it is very commonly used to dilute the THC oil or is used as a cutting/diluting agent. Other studies have implicated the E-cig flavors with the compromised lung functions, but the etiology so far has prominently pointed towards THC oil containing cartridges. There are several other compounds and ingredients that could be potentially harmful when inhaled as vapors/aerosol and thus, there is an urgent need to analyze the cartridges used and study the pulmonary toxicology, including chemistry, aerosol physico-biological interactions, and pathophysiological mechanisms of counterfeit/bootleg cartridges versus medical dispensary products. Further understanding the chemistry (e.g. chemical compounds, heavy metals, and hydrocarbons), toxicology, and the lung cellular/molecular mechanisms of patients will EVALI could provide much needed information on mechanisms of the disease ultimately leading to regulation of these products, and therapeutic interventions. These studies should be supplemented with thorough chemical analyses specifically for the aerosolization process and its resulting emissions under different conditions, as well as formation of secondary products. It also should include the forensic chemical and the toxicological studies using cell- and animal-based models along with the Identification of non-invasive biomarkers of ENDS/vaping exposure (plasma/serum, EBC, sputum) and injury progression could provide helpful indicators for early signs of lung damage by these products. Finally, susceptibility factors to EVALI should be researched including genetic and environmental factors, immunocompromising treatments, comorbidities and certain lifestyle choice confounding factors, could also render subjects vulnerable to EVALI and associated pathologies.
Thus, understanding the cause, toxicity and mechanisms of EVALI due to e-cig and/or THC-oil based products vaping will provide the information on regulation of these products and timely therapeutic interventions.
All authors wrote and revised/edited the manuscript. HC and IR conceptualized the theme and reviewed the literature. HC and IR wrote and edited the manuscript. TM and WM edited the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors acknowledge the support by NIH R21 AI144374, FIU HWCOM and ORED Start-Up Funds (to HC); by NIH R01 DA042477 and R01 TW010654 (to WM); and by NIH R01 HL135613, and U54CA228110 (IR).