The relationship between the use of electronic nicotine delivery systems (ENDS) and effects on pulmonary immune responses—a literature review

Abstract

Introduction:

The use of electronic nicotine delivery systems (ENDS), or vaping, is a relatively recent phenomenon, and there are various gaps in our current knowledge regarding the specific effects of e-cigarettes, such as their immunological effects. The importance of this question became even more relevant in light of the COVID-19 pandemic.

Objective:

This literature review examines the relationship between the use of electronic nicotine delivery systems (ENDS) and immunological effects to examine available information and identify gaps in the current knowledge. Our search strategy included studies focusing on the effects of ENDS on the immune response during infectious respiratory diseases such as COVID-19 and pneumonia.

Methods:

Peer-reviewed studies presenting quantitative data published from 2007, the year that e-cigarettes were introduced to the US market until 2022 have been included. All studies were indexed in PubMed. We excluded papers on THC and EVALI (E-cigarette, or Vaping Product, Use Associated Lung Injury) as we wanted to focus on the effects of nicotine devices.

Results:

Among the 21 articles that assessed the relationship between ENDS and immunological health effects, we found eight studies based on cell models, two articles based on both cell and mouse models, five articles based on mouse models, and six studies of human populations. Most of the articles identified in our review demonstrated a potential association between vaping and adverse immunological health effects.

Discussion:

Overall, the evidence from the cell and animal studies indicates that there is a positive, statistically significant association between vaping and adverse immune response during infectious respiratory diseases. The evidence from human studies is not conclusive.

1. Introduction

Since 2014, the use of electronic nicotine delivery systems (ENDS or e-cigarettes) has grown extensively in various age groups (Cooper et al., 2022), with the highest increase found among young adults and teenagers who have never smoked before. According to the CDC (Cooper et al., 2022), since 2017, the number of e-cigarette users aged 18–24 has grown by 7.6%, while the number grew by 2.1% among adults aged 25–44. Additionally, more than 2 million middle and high school students reported using e-cigarettes in 2022, comprising 14.1% of all high school students and 3.3% of middle school students in the US, few of whom, based on smoking trends in the past 30 years, would be expected to have experience with smoking (American Lung Association, 2022a,b; Cooper et al., 2022; Friend, 2002).

The rapid growth of e-cigarette use among the young population is of concern since e-cigarette aerosols contain toxic compounds such as metals, aldehydes, and other compounds that may interfere with the immune system (National Academies of Science Engineering and Medicine (NASEM), 2018). This increase in e-cigarette use may be attributed to various marketing strategies implemented by e-cigarette companies who promote their devices as harmless alternatives to combustible cigarettes, giving the young population the impression that their products have little to no harm (U.S. Department of Health and Human Services, 2022). In addition, the use of celebrity endorsements, social media campaigns, and the addition of sweet flavors such as bubble gum, strawberry crunch, and fruity flavors (Grand View Research, 2021), make their products appealing to young adults and teens.

Whether the companies are targeting the young population intentionally or not, the age statistics of current e-cigarette users show that young adults are more susceptible to using these devices than older adults. Furthermore, the long-term effects of ENDS are still unknown, and more research is needed to determine the potential health risks of e-cigarettes, especially for never-smokers.

Using the marketing strategies described above, the global e-cigarette market reached a value of $18.47 billion in 2021, and despite the COVID-19 pandemic, from 2021 to 2028, its compound annual growth rate is expected to hit 27.3% (Grand View Research, 2021).

E-cigarettes are battery-powered devices that heat and aerosolize a liquid (e-liquid) containing nicotine and flavorings in a solution of propylene glycol (PG) and vegetable glycerin (VG) (National Academies of Sciences, 2018; American Lung Association, 2022a,b). When the device heats the e-liquid, the resulting aerosol delivers nicotine into the lungs, giving a similar effect people can obtain from combustible cigarettes since nicotine is highly addictive (Marques et al., 2021). ENDS devices come in different shapes, designs, and sizes. Some of them include a tank or cartridge that users can refill with e-liquid from a small bottle sold separately, other devices come with pre-filled “pods” that users can simply attach and detach from their devices, and newer devices are completely disposable (Cooper et al., 2022). Many constituents that have been found in e-cigarette aerosols have the potential to be toxic or carcinogenic (Goniewicz et al., 2013; Pankow et al., 2015; Olmedo et al., 2018).

A literature review by Keith and Bhatnagar (2021) concluded there was a relationship between e-cigarette use and cardiovascular, respiratory, and immunological effects on healthy individuals. Signs such as increases in blood pressure, heart rate, arterial stiffness, and resistance to airflow in the lungs have been observed in a healthy population of adults using e-cigarettes. Genotoxic and inflammatory effects in the lungs were also noted.

E-cigarette use has become closely linked to numerous respiratory diseases such as asthma, pneumonia (Allergy and Asthma Network, 2022), and even COVID-19 (Mayo Foundation for Medical Education and Research, 2022). According to a survey conducted by Yale Medicine, among individuals who were 13–24 years old, “COVID-19 diagnosis was five times more likely among those who vaped and seven times more likely among those who vaped and smoked” (MacMillan, 2021). Additionally, several studies report the relationship between vaping and asthma and pneumonia, supporting that the immune system is affected by exposure to e-cigarette aerosol, making users more susceptible to respiratory disease (Culpitt et al., 2005; Frey et al., 2020).

The recent COVID-19 pandemic has increased the urgency of investigating the effects of e-cigarettes on pulmonary immune responses and underscored their potential impacts on the public, highlighting the need to regulate the use and sale of these devices (MacMillan, 2021). The purpose of this review was to summarize the state of the knowledge and identify gaps in the literature regarding the relationship between the use of Electronic Nicotine Delivery Systems (ENDS) and their effects on pulmonary immune responses.

2. Methods

A review of publications from 2005 to 2022 regarding the immunological effects of e-cigarettes was conducted using PubMed to obtain articles relevant to our research question, based on Medical Subject Headings (MeSH terms) and free text terms based on title or abstracts (tiab) to maximize the likelihood of finding all relevant articles. The search strategy included the following terms:

(“Electronic Nicotine Delivery Systems" [Mesh] OR Vaping [Mesh] OR e-cigarette vapor [Mesh] OR E-cigarette*[tiab] OR E-cig*[tiab] OR Juuling [tiab] OR pod systems [tiab] OR pod mods [tiab] OR pod vape [tiab]) AND (immune system diseases [Mesh] OR communicable diseases [Mesh] OR respiratory tract diseases [Mesh] OR “Influenza, Human" [Mesh] OR influenza*[tiab] OR respiratory infectious disease* [tiab] OR respiratory tract disease*[tiab] OR lung damage*[tiab] OR lung injur*[tiab] OR “COVID-19" [Mesh] OR “SARS-CoV-2" [Mesh] OR COVID-19 [tiab] OR COVID19 [tiab] OR airway resistance [Mesh] OR respiratory function tests [Mesh] OR “pulmonary function*" [tiab] OR “respiratory impedance*" [tiab] OR “respiratory resistance*" [tiab] OR “Epithelial Cells" [Mesh] OR “endothelial cell*" [tiab] OR “epithelial cell*" [tiab] OR “Inflammation" [Mesh] OR inflammat*[tiab] OR immun*[tiab] OR “Cytokines" [Mesh] OR Cytokine*[tiab])

This PubMed search strategy resulted in 1624 articles. After screening and applying our inclusion and exclusion criteria, 21 articles were selected. Articles were compiled and organized using the software Zotero, which made it efficient to identify common information and key terms found in different articles. After utilizing our search strategy, papers that met our inclusion criteria were selected using a screening software for academic journals called “Covidence.”

2.1. Exclusion criteria and decision flowchart

We decided to exclude studies of “E-cigarette or Vaping Use-Associated Lung Injury (EVALI)” because we wanted to focus on ENDS devices, and the CDC determined EVALI to be strongly linked to vitamin-E-acetate found mainly in THC products, and not found in nicotine-delivery e-cigarettes (Centers for Disease Control and Prevention, 2021). We also excluded industry studies that have been conducted by organizations or companies involved in the manufacture and sale of vaping devices in order to minimize observer bias. Articles that were not published in English or were not geographically relevant to the US were excluded. Finally, articles primarily dealing with subjects not relevant to our topic of interest or that have already been extensively reviewed elsewhere have been excluded. For example, articles investigating the relationship between asthma and e-cigarette use (without a specific focus on the effects on the immune responses) were excluded because it has already been extensively investigated by other authors such as Li et al. (2022). The details of our screening process can be found in the flowchart below (Fig. 1) to make our screening process transparent and specific.

Fig. 1.

Flowchart describing PubMed search and exclusion criteria.

3. Results

Among the 21 articles obtained that assessed the relationship between vaping and immunological health effects, we found eight studies based exclusively on cell models, five articles based on mouse models, two articles based on both cell and mouse models, and six studies based on human populations. Common toxic compounds of e-cigarette aerosols, their potential sources, and known health effects found in our literature review are presented in Table 1. A summary of all the articles that have been reviewed by this paper has been included in Table 2.

Table 1.

Toxic compounds of e-cigarette aerosols, potential sources, and known health effects identified.

Toxic Compound	Potential Source of Compound	Toxic effect	References
Acetaldehyde	E-liquid	Irritant to eye, skin, respiratory tract. Associated with coughing, erythema. Potential carcinogen	(Kaur et al., 2018; Pankow et al., 2015; Goniewicz et al., 2013; Martin et al., 2016)
Acetone	Flavoring chemicals	Irritant to respiratory system. Associated with nausea, depression, cardiorespiratory failure	Kaur et al. (2018)
Acrolein	Flavoring chemical	Toxicant to respiratory and cardiovascular systems	(Yeager et al., 2016; DeJarnett et al., 2014)
Propylene Glycol (PG)	E-liquid	Associated with seizure, neurological symptoms, nausea, irregular sensations	Misra et al. (2014)
Vegetable Glycerin (VG)	E-liquid	Associated with headaches, excessive thirst, vomiting	Misra et al. (2014)
Diethylene glycol	E-liquid	Associated with renal and neurological and liver toxicity, and metabolic acidosis	(Landry et al., 2015; Hahn et al., 2014; Agency for Toxic Substances and Disease Registry, 2014)
Metals (arsenic, cadmium, lead, nickel, chromium)	Coil, e-liquid, and other components of the device	Potential carcinogens; toxic to the lungs, brain, liver, kidney; immunological effects	(Misra et al., 2014; Olmedo et al., 2018; Scott et al. (2018)
Formaldehyde	E-liquid	Irritant to respiratory system; associated with asthma; potential carcinogen	Jensen et al. (2015)

Table 2.

Paper Summaries.

Title	Authors	Method	Exposure source, duration, dosage at the point of change (when provided by authors)	Summary	Immunological effects observed
“Electronic Cigarette Liquid Increases Inflammation and Virus Infection in Primary Human Airway Epithelial Cells.”	Wu et al. (2014)	Cell model Human tracheobronchial epithelial cells: hTBE	E-cigarette e-liquid 24 h	Human tracheobronchial epithelial cells were grown in submersion culture and exposed to e-liquids diluted with cell culture media. Epithelial cells that were exposed to e-liquids showed decrease in production of antiviral proteins and increased viral load (human rhinovirus) that usually causes lung infection. The results show that e-liquids inhibited the expression of SPLUNC1 (short palate and nasal epithelial clone 1), a host defense molecule against bacterial infection, while causing an increase in level of inflammation and IL-6 cytokine production.	Decrease in production of antiviral proteins Increased susceptibility to human rhinovirus (HRV) infection Decrease in SPLUNC1 expression Increase in pro-inflammatory IL-6 cytokine production
“E-Cigarette Affects the Metabolome of Primary Normal Human Bronchial Epithelial Cells.”	Aug et al. (2015)	Cell model Human bronchial epithelial cells	E-cigarette e-liquid 7 h, 13 h 100 μL of e-liquid	The study utilized cultured primary human bronchial epithelial cells and exposed them to e-liquids. The results showed that cells exposed to e-liquids led to a significant decrease in cell viability and increase in oxidative stress compared to cells of the control group which were only exposed to air.	Decrease in human bronchial epithelial cell viability and increase in necrotic cell death
“Phagocytosis and Inflammation: Exploring the effects of the components of E-cigarette vapor on macrophages”	Ween et al. (2017)	Cell model Alveolar macrophage	E-cigarette e-liquid 24 h 250 μL of e-liquid	The study utilized differentiated THP-1 macrophages and exposed them to e-liquids. Macrophages that were exposed to e-liquids, compared to the control group, were found to be less effective in phagocytosing bacteria and found to have fewer pathogen recognition receptors.	Decrease in pro-inflammatory cytokines released by macrophages (TNF-α, IL-1β, and IL-6, MIP-1α, MIP-1β, MCP-1) Reduction in macrophage pathogen recognition receptor levels (SR-A1 and TLR-2), resulting in decreased level of phagocytosis
“Electronic Cigarette Exposure Triggers Neutrophil Inflammatory Responses.”	Higham et al. (2016)	Cell model Human neutrophils	E-cigarette aerosol 10 s and 30 s puffs Aerosol generated by e-cigarette containing 24 mg of nicotine	Neutrophils were exposed to e-cigarette vapor extracts and the expression of leukocyte-specific receptor markers (CD11b and CD66b), neutrophil elastase level, and p38 MAPK activation level were measured. In addition, the activity of neutrophil elastase and the activation of inflammatory signaling pathways were measured. The paper concluded that e-cigarette vapor extracts can cause pro-inflammatory response for neutrophils.	Increased expression of MMP-9 and CXCL8, as well as increased activity of neutrophil elastase and MMP-9 Increased level of leukocyte specific receptor markers (CD11b and CD66b), a sign of neutrophil activation Increase in p38 MAPK activation level, which promotes inflammation
“Effects of E-Cigarette Flavoring Chemicals on Human Macrophages and Bronchial Epithelial Cells”	Morris et al. (2021)	Cell model Human bronchial epithelial cells, naïve and activated macrophages: THP-1	E-cigarette e-liquid 1000 μM of flavoring chemical	The study utilized human bronchial epithelial cells and naïve and activated macrophages, which were exposed to different concentrations of 30 different flavoring chemicals contained in e-cigarette liquid. Cellular viability, cell membrane change, reactive oxygen species production, and inflammatory cytokine release were measured. The results of the study were mixed. Some flavoring chemicals decreased cell viability, while others did not influence either viability or cell membrane disruption. In addition, some chemicals produced pro-inflammatory effects, while others produced anti-inflammatory effects or none. Even the degree to which each chemical produced a pro- or anti-inflammatory effect varied. Overall, the study concluded that there may be a potential lung cytotoxicity, inflammation, and oxidative stress that can be caused by e-cigarettes.	Increased levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 Decrease in cell viability and increase in necrotic cell death Potential lung cytotoxicity, inflammation, and oxidative stress
“JUUL e-liquid exposure elicits cytoplasmic Ca2+ responses and leads to cytotoxicity in cultured airway epithelial cells”	Zhang et al. (2021)	Cell model human airway epithelial cells)	E-cigarette e-liquid 24–48 h	Two types of airway epithelial cells were exposed to different flavored e-liquids of JUUL, such as “mint”, “Virginia Tobacco”, and “Menthol.” Intracellular Ca2+ levels, their viability, and pro-inflammatory cytokine levels were measured. The study found that exposure to JUUL e-liquid led to decrease in cell viability and increase in inflammatory response and apoptosis.	Increased level of pro-inflammatory cytokine IL-6 Increase in early apoptotic marker Annexin V Elevation of intracellular cytoplasmic Ca2+, a sign of cytotoxicity
“Inflammatory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavoring Chemicals and Flavored e-Liquids without Nicotine”	Muthumalage et al. (2018)	Cell model Monocytic cells: MM6, U937	E-cigarette aerosol 24 h 1000 μM of flavoring chemical	Two monocytic cell types were exposed to different flavored e-liquids of e-cigarettes. Cell viability, cytotoxicity, and concentrations of secreted inflammatory cytokine were measured. The study concluded that exposure to e-liquid led to dose-dependent cytotoxicity in monocytic cells. In addition, researchers observed an increase in the level of hydrogen peroxide in these cells and free oxygen species, which is indicative of high cytotoxicity and elevated level of inflammation.	Increased level of pro-inflammatory cytokine IL-8 Increased level of hydrogen peroxide, a sign of oxidative stress and cytotoxicity
“Effect of e-cigarettes on nasal epithelial cell growth, Ki67 expression, and pro-inflammatory cytokine secretion”	Rouabhia et al. (2020)	Cell model Human primary nasal epithelial cells	E-cigarette aerosol 6 h 2 puffs every 60sec lasting 5 s followed by a 25–30s pause	The study utilized human primary nasal epithelial cells to determine the effect of e-cigarette aerosol on cell growth and pro-inflammatory cytokine secretion. Cell viability and lactate dehydrogenase (LDH) activity were measured. Cells that were exposed to the aerosol demonstrated greater levels of inflammation, higher pro-inflammatory cytokine levels, and reduced proliferation rate.	Increased levels of pro-inflammatory cytokines IL-6. IL-8, TNF-α, and MCP-1
“Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria”	Hwang et al. (2016)	Cell model Human epithelial cells, macrophages, netruophils Mice model Female CD-1 mice	E-cigarette aerosol 1 h per day, 5 days per week for 4 weeks total	Human cells, including epithelial cells, macrophages, and neutrophils, were used to investigate the immunological effect of e-cigarette aerosol. These cells were then exposed to the aerosol and subsequently exposed to a bacterial colony to measure the cells’ antimicrobial activity. The results of the study demonstrated an overall decrease in the cells’ antibacterial function. Upon investigation of the bacteria, researchers observed an increase in growth, biofilm formation, and the ability of the bacteria to adhere to neighboring epithelial cells. Furthermore, exposure to aerosol led to an increase in makers of inflammation.	Increased level of acute phase reactant (Pentraxin), which suggests systemic inflammation Increased pro-inflammatory cytokines KC, IL-1ra, and TREM-1 in bronchoalveolar lavage fluid (BALF) Reduced level of cytokines (GM-CSF, IL-3) important for rapid activation of host defense during early stages of infection in BALF Increased susceptibility to MRSA (methicillin-resistant S-aureus) infection Decreased antimicrobial activity among macrophages and neutrophils
“Vapors Produced by Electronic Cigarettes and E-Juices with Flavorings Induce Toxicity, Oxidative Stress, and Inflammatory Response in Lung Epithelial Cells and in Mouse Lung”	Lerner et al. (2015)	Cell model Human bronchial airway epithelial cells: H292, human fetal lung fibroblasts: HFL1 Mice model C57BL/6 J mice	E-cigarette aerosol 24 h 10 μg/mL	The study focused on whether e-liquid aerosol could lead to oxidative stress and inflammatory response in human lung epithelial cells and in the lungs of mice. The researchers of the study observed increased secretion of inflammatory cytokines (IL-6, IL-8) among epithelial cells that were exposed to the aerosol, as well as increased stress and morphological changes among lung fibroblasts—indicating increased inflammatory response. Furthermore, mice that were exposed to the aerosol also exhibited an increase in pro-inflammatory cytokines and decreased ability to maintain cellular redox homeostasis, indicating high levels of oxidative stress and reactive oxygen species. Overall, the result concluded that e-cigarette exposure is highly correlated with oxidative stress and harmful inflammatory responses.	Increased secretion of pro-inflammatory cytokines IL-6 and IL-8 Increase in reactive oxygen species (ROS) levels, indicative of oxidative stress at a cellular level
“Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine”	Madison et al. (2019)	Mice model C57BL/6 J mice	E-cigarette aerosol 24 h	Mice were exposed to electronic nicotine delivery system (ENDS) vapor for 4 months. These mice, just like the control, did not develop pulmonary inflammation or emphysema. After extracting the lungs of the mice, it was found that ENDS exposure led to the disruption of lung lipid homeostasis in alveolar macrophages and epithelial cells of the mice. In addition, when mice with influenza were exposed to ENDS vapor, they demonstrated enhanced lung inflammation and tissue damage, while the control group did not. Overall, the study concluded that chronic exposure to ENDS vapor leads to dysfunction of lung epithelial cells and immune cells that makes the lung vulnerable to infectious diseases.	Enhanced lung inflammation and tissue damage observed in mice exposed to e-cigarette aerosol Disruption of lung lipid homeostasis in mice alveolar macrophages and epithelial cells
“Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner”	Garcia-Arcos et al. (2016)	Mice model A/J mice	E-cigarette aerosol 8 h , 12 h 36 puffs of vapor containing 18 mg/mL of nicotine	The study investigated the effects of e-cigarette aerosol, with and without nicotine, on mouse lungs. The paper found that the mice that inhaled aerosol containing nicotine, as opposed to nicotine free aerosol, demonstrated increased reactivity of the airway, enlargement of the distal airspace, increased mucin production, and increased cytokine and protease expression, which are all signs of inflammatory responses and symptoms associated with the development of COPD.	Increased levels of pro-inflammatory cytokines IL-6 and IL-8 Observation of symptoms associated with the development of COPD (increased cytokine expression, airway hyper-reactivity, lung tissue destruction) in mice exposed to e-cigarette aerosol
“Exposure to Electronic Cigarettes Impairs Pulmonary Anti-Bacterial and Anti-Viral Defenses in a Mouse Model”	Sussan et al. (2015)	Mice model C57BL/6 J mice	E-cigarette aerosol 2 weeks 2 puffs per day with each puff lasting 2 s	The study investigated the level of anti-bacterial and anti-viral activity in mice when exposed to e-cigarette aerosol. Mice that have been exposed to the aerosol demonstrated high levels of oxidative stress and inflammation in the airway compared to the control group only exposed to air. When both groups of mice, experimental and control, were exposed to a bacterial and viral strain, the experimental group exhibited enhanced illness and mortality. Overall, the study demonstrated that both immunological and pulmonary dysfunction are highly correlated with exposure to e-cigarette aerosol in mice.	Increased susceptibility to S. pneumoniae infection Increased susceptibility to influenza caused by decreased level of cytokine IL-17, which plays role in defending against influenza infection
“Time course of changes in inflammatory and oxidative biomarkers in lung tissue of mice induced by exposure to electronic cigarette aerosol”	Alzoubi et al. (2022)	Mice model Balb/c mice	E-cigarette aerosol 1 week, 2 weeks, 4 weeks One 4 s puff every 10s of the exposure period everyday	Mice were exposed to e-cigarette aerosols. Lung samples were then collected after the exposure and biomarkers for inflammatory cells, tumor necrosis factor, and reactive oxygen species were measured. The study showed that exposure of e-cigarette aerosol to the mice resulted in significant increase in total inflammatory cells and other immune cells, such as eosinophils, macrophages, and tumor necrosis factors—indicating that inhalation of the aerosol is positively associated with inflammation in lung tissues.	Statistically significant increase (p < 0.05) in total inflammatory cells, eosinophils, macrophages, and pro-inflammatory cytokine TNFα—observed in lung tissues of mice exposed to e-cigarette aerosol Increased levels of neutrophils and basophils
“Comparison of the effects of e-cigarette vapor with cigarette smoke on lung function and inflammation in mice”	Glynos et al. (2018)	Mice model C57BL/6 J mice	E-cigarette aerosol 15 puffs over 2-min period everyday	The study compared the immunological effects of e-cigarette aerosol with the effects of cigarette smoke on lung function and inflammation in mice. Mice that were used as models of the study were exposed to either e-cigarette aerosol or cigarette smoke. The paper found that e-cigarette vapor, similar to cigarette smoke, can adversely affect the immunological and respiratory system, leading to greater inflammatory response.	Increased levels of pro-inflammatory cytokine IL-1β and IL-6 for mice exposed to e-cigarette aerosol Increased airway resistance, tissue elasticity, and static compliance due to inflammation observed in lungs of mice exposed to e-cigarette aerosol
“E-cigarette use results in suppression of immune and inflammatory response genes in nasal epithelial cells similar to cigarette smoke”	Martin et al. (2016)	Human (cross-sectional study)	E-cigarette aerosol	The authors of the paper utilized prospective, cross-sectional study to determine how exposure to e-cigarette aerosol impacts the expression of immune inflammatory-response genes in nasal epithelial cells. They studied nonsmokers, self-described active cigarette smokers, and self-described, active e-cigarette smokers. RNA extracted from these cells was used to determine the immune gene expression level. The study found that both groups exposed to cigarette and e-cigarette demonstrated a decrease in the number of immune-related genes that are normally expressed in non-smokers. It also found that e-cigarettes suppress immune function at a greater level than cigarettes.	Suppression of genes related to immune responses, such as EGR1—which directly regulates the transcription of various immune genes to make cytokines, chemokines, adhesion molecules, proteases, and autophagy Decreased gene expression of CSF-1 and CCL26 - CSF 1: plays crucial role for innate immunity and defends against fungal, bacterial, and viral infections - CCL26: recruits immune cells to the site of infection, such as eosinophils, basophils, T cells, and natural killer cells
“Association Between Youth Smoking, Electronic Cigarette Use, and COVID-19″	Gaiha et al. (2020)	Human (cross-sectional study)	E-cigarette aerosol	The study investigated the association between youth e-cigarette use and COVID-19 symptoms, testing, and diagnosis by conducting a national cross-sectional online survey for adolescents and young adults aged 13–24 years old. The sample size of the population was 4351.Using multivariable logistic regression, the association of interest was determined. The authorsof the paper determined that COVID-19 diagnosis were 5 times more likely among users of e-cigarettes compared to individuals who have never used e-cigarette or traditional cigarette. In addition, users of both cigarette and e-cigarette were 7 times more likely. These results of the study were statistically significant.	Ever-users of e-cigarettes five times more likely to be diagnosed with COVID-19 infection than individuals who never used e-cigarettes - (95% CI: 1.82–13.96) Ever-dual-users of e-cigarettes and cigarettes seven times more likely to be diagnosed with COVID-19 infection than individuals who never used e-cigarettes or cigarettes - (95% CI: 1.19–21.39)
“Short-term Pulmonary Effects of Using an Electronic Cigarette Impact on Respiratory Flow Resistance, Impedance, and Exhaled Nitric Oxide”	Vardavas et al. (2012)	Human (experimental study)	E-cigarette aerosol 5 min	The study, with the permission of the ethics committee, recruited 30 adults for an experimental study regarding the short-term immunological and pulmonary effects of e-cigarettes. The experimental group was given an e-cigarette with cartridge to use for 5 min, while the control group was given a device without the cartridge. Investigators measured exhaled nitric oxide, which plays a crucial role in various physiologic processes, including the regulation of immunity and cytotoxicity. The study found that even after a 5-min exposure to e-cigarette aerosol, the experimental group showed statistically significant and immediate decrease in exhaled nitric oxide level.	Decrease in of exhaled Nitric Oxide Increased susceptibility to asthmatic symptoms for e-cigarette users, such as bronchoconstriction, airway impedance, and peripheral airway flow resistance—which are strongly correlated with bronchial hyperreactivity
Electronic cigarette use and risk of COVID-19 among young adults without a history of cigarette smoking	Young-Wolff et al. (2022)	Human (cohort study)	E-cigarette aerosol	The study utilized a retrospective cohort study to investigate whether the use of e-cigarette increases the susceptibility to COVID-19. After examining medical records of 74,853 young adults, authors found that former e-cigarette use was associated with greater risk of COVID-19 (aOR = 1.39, 95% CI: 0.98–1.96). However, no statistically significant association was found between current e-cigarette use and risk of COVID-19 (aOR = 1.12, 95%:0.77–1.62).	Higher susceptibility to COVID-19 for former e-cigarette users than non-users of e-cigarettes (OR = 1.39, 95% CI: 0.98–1.96)
The Association of Electronic Cigarette Use With SARS-CoV-2 Infection and COVID-19 Disease Severity	Burnett-Hartman et al. (2022)	Human (cohort study)	E-cigarette aerosol	The study collected self-report of COVID-19 infection and the history of e-cigarette use from 126,475 sample patients across the US. After analyzing results through a multivariable logistic regression and controlling for confounding variables, authors found no association with COVID-19 hospitalization and death with former (OR = 1.19) and current e-cigarette use (OR = 1.02).	No statistically significant association found between COVID-19 hospitalization and death with former (OR = 1.19) and current e-cigarette use (OR = 1.02)
Electronic Cigarette Use Is Not Associated with COVID-19 Diagnosis	Jose et al. (2021)	Human (cohort study)	E-cigarette aerosol	The study tested the hypothesis whether current e-cigarette use is associated with COVID-19 infections among patients seeking medical care. Data was collected from patients seeking medical care at the Mayo Clinic, US. The authors found that patients using e-cigarettes were not more likely to have a COVID-19 diagnosis (OR = −0.93) and e-cigarette use did not appear to increase susceptibility to COVID-19 infection.	No statistically significant association found between COVID-19 susceptibility and e-cigarette uses (OR = −0.93)

3.1. Cell models

Overall, papers based on cell models only or both cell and mouse models demonstrated an association between vaping and negative immunological health effects, which was supported by p-values produced by statistical analyses. Six papers focused on cell exposure to e-liquids or e-liquid components, while four articles focused on cell exposure to e-cigarette aerosols.

In a study conducted by Wu et al. (2014), human tracheobronchial epithelial cells, which play a critical role in the host’s defense system against pathogens, but also in immune-mediated inflammatory diseases (IMIDs) such as asthma (Frey et al., 2020) were grown in culture and exposed to e-liquids diluted with cell culture media. The cells were later examined for the production of the proinflammatory cytokine IL-6, human rhinovirus (HRV) infection, as well as the level of host defense molecules by the cells, such as SPLUNC1. The result of the study aligned with Wu’s initial hypothesis that e-liquids would lead to detrimental effects on human airway epithelial functions. Their main findings indicate that e-liquid exposure causes an increase in IL-6 cytokine production as well as increased HRV infection and HRV-induced IL-6 expression. These findings also suggest that e-liquid exposure may promote respiratory viral infections and exaggerate airway inflammation. Consistent with these observations, the study further found that e-liquid exposure to tracheobronchial epithelial cells diminishes lung innate immunity against pathogens such as HRV by inhibiting the expression levels of SPLUNC1, an important antimicrobial protein (Chu et al., 2007).

A study by Aug et al. (2015), who similarly used cultured human bronchial epithelial cells, found that the exposure of cells to e-liquids resulted in a significant decrease in cell viability and an increase in oxidative stress. This finding was supported by changes in intracellular metabolome that occurred after exposure. Furthermore, Ween et al. (2017), who used differentiated THP-1 macrophages, showed that exposure to e-liquids could lead to severe immune deficiencies. For example, the author’s study illustrated that the exposure led to a very high level of lactate dehydrogenase (LDH) production—which usually occurs when tissues or cells are damaged by bacterial or viral infections. In addition, Ween and colleagues revealed that e-liquid exposure led to a drastic reduction in the expression of pattern recognition receptors (PRRs), such as scavenger receptor A1 (SR-A1) and toll-like receptor-2 (TLR-2), which could potentially lead to a reduced immune response against pathogens. In concert with these observations, they also found that e-liquid exposed macrophages expressed lower levels of the proin-flammatory cytokines TNF-α, IL-1β, and IL-6, which activated macrophages usually produce to promote the adaptive immune system, for example during an infection (Arango Duque and Descoteaux, 2014). Interestingly, they observed an increase in IL-8, which is a proinflammatory cytokine that is important for the recruitment and activation of neutrophils and therefore plays an important role in lung inflammation and injury (Cesta et al., 2022). Together, their results thus suggest that e-liquid exposure alters macrophage function potentially leading to increased lung injury and reduced immunity against pathogens. Similarly, Higham et al. (2016) exposed neutrophils to e-liquids and observed changes in neutrophil morphology, increased expression of CD11b and CD66b (integrins that play a role in inflammatory responses), increased expression levels of MMP-9 and CXCL8, as well as increased neutrophil elastase and MMP-9 activity. Mechanistically, these neutrophil activation changes were correlated with an increase in p38 MAPK activation. Together these findings indicate that exposure to e-liquids leads to pro-inflammatory responses from human neutrophils.

Some researchers conducted their studies in a more systematic manner than others. For example, Morris et al. (2021) examined the effects of individual components in e-liquids. The human bronchial epithelial cell line (BEAS-2B) and the macrophage cell line (THP-1) were exposed to different chemicals contained in e-liquids, such as ethyl maltol, hexanal, diketones, and vanillin. While ethyl maltol and hexanal increased inflammatory cytokine production (IL-1β, IL-8, and TNF-α) by THP-1 macrophage cells, most other compounds had an apparent suppressive effect on the release of inflammatory cytokines by activated macrophages. Furthermore, vanillin, ethyl maltol, and the diketones (2, 3-pentanedione, 2,3-heptanedione, and 2,3-hexanedione), increased the production of reactive oxygen species (ROS) in both the human bronchial epithelial cell line as well as the macrophage cell line. Similar to Morris et al. (2021) investigated the immunological effects of various e-liquid flavors, such as “Mint,” “Virginia Tobacco,” and “Menthol.” When airway epithelial cells were exposed to these different e-liquids, the researchers found an increase in intracellular Ca2+ levels, pro-inflammatory cytokine levels, and a decrease in cell viability. Muthumalage et al. (2018) took on a similar approach to investigate the effects of different flavoring chemicals (diacetyl, cinnamaldehyde, acetoin, pentanedione, o-vanillin, maltol and coumarin) in monocytic cell lines, finding increased levels of IL-8 and increased production of cell-free ROS by cells that have been exposed to each type of flavoring chemical tested. Interestingly, mixing a variety of flavors resulted in greater cytotoxicity and cell-free ROS levels compared to the treatments with individual flavors.

Three cell-based studies utilized e-cigarette aerosols to show the relationship between vaping and immunological impact on cells. In a study conducted by Hwang et al. (2016), human epithelial cells were exposed to e-cigarette aerosols and methicillin-resistant S-aureus (MRSA) bacteria, or only to MRSA; after exposure, the number of MRSA in exposed and unexposed cells was compared. The result showed a 25% greater concentration of MRSA, as well as significantly greater levels of cell death and lactate dehydrogenase (LDH production indicating necrosis), in the exposed group than in the control. When the group exposed a mouse macrophage cell line (MH-S cells) to e-cigarette aerosols, this led to a reduction in antimicrobial activity. Moreover, blood-derived human neutrophils also displayed decreased antimicrobial activity after e-cigarette aerosol exposure, in a nicotine concentration-dependent manner. Rouabhia et al. (2020) utilized human primary nasal epithelial cells to determine how e-cigarette aerosol exposure impacts their cell viability and function. E-cigarette exposure led to a reduced cell proliferation rate and eventually to a higher level of LDH, indicating necrosis. In addition, e-cigarette aerosol exposure to these nasal epithelial cells increased their production of pro-inflammatory cytokines (L-6, IL-8, TNF-α, and MCP-1). Another study by Lerner et al. (2015) demonstrated that ENDS aerosol exposure to human airway epithelial cells (H292) leads to increased expression of pro-inflammatory cytokines (IL-6 and IL-8). Moreover, they found that human lung fibroblasts displayed loss of cell viability and secreted increased levels of IL-8 in response to a cinnamon-flavored e-liquid aerosol.

Overall, all cell-based papers mentioned above showed that the exposure of cells to e-liquids or e-cigarette aerosol has the potential to lead to immunotoxic effects, often involving immune cell death, impaired antimicrobial function of innate immune cells and the overproduction of pro-inflammatory cytokines and reactive oxygen species by both innate immune cells as well as airway epithelial cells indicating that e-cigarettes can lead to increased airway inflammation.

3.2. Mouse models

A total of seven studies, five of them based on mouse models only and two studies based on cell and mouse models (Hwang et al. and Lerner et al.), investigated the immunological effects of e-cigarette aerosol exposure. All of them showed associations between exposure and negative immunological effects. Hwang et al. (2016) who utilized both cell and mouse models to assess the effect of e-cigarette aerosols, found that inhalation of aerosol led to an elevation of an acute phase reactant (Pentraxin 3) in their serum, suggesting systemic inflammation, and increased expression of select pro-inflammatory markers (KC, IL-1ra, and TREM-1) in bronchoalveolar lavage fluid (BALF), whereas other cytokines (GM-CSF, IL-3) that are important for rapid activation of host defenses during early stages of infection were reduced in BALF from exposed mice. In line with these findings, Staphylococcus aureus infections became more virulent upon exposure to e-cigarette aerosol in a murine pneumonia model (Hwang et al., 2016). These results indicate that e-cigarettes are cytotoxic to animal airway cells, leading to both local airway as well as systemic inflammation, while simultaneously suppressing the host immune defenses against pathogenic infections.

In another study, Lerner et al. (2015) exposed 8-week-old mice to e-cigarette aerosols generated by TE-10 and Blu e-cigarettes. After conducting a bronchoalveolar lavage (BAL) on the mice 3 days after exposure, Lerner found increased concentrations of inflammatory cytokines in the sample BALF, such as IL-6, MCP-1, IL-1α, and IL-13, showing activation of mice’s immune system upon e-cigarette aerosol exposure. They also observed diminished expression of lung glutathione levels upon e-cigarette aerosol exposure, which is critical in maintaining cellular redox balance. A reduction in glutathione levels could implicate oxidative stress culminating in an inflammatory response. Lerner’s findings were confirmed by Garcia-Arcos et al. (2016), who also showed an increase in inflammatory cytokines such as MCP-1 and IL-6 after exposing 12-week-old mice to aerosolized vegetable glycerin (VG) and propylene glycol (PG), two of the main components of e-liquids. This study also found an increase in airway resistance in the mice as well as widespread apoptosis of their airway and alveolar cells. Inflammatory and oxidative stress biomarkers were assessed by Alzoubi et al. (2022). They observed that mice exposed to e-cigarette aerosol resulted in a statistically significant increase in both pro-inflammatory cytokine (TNF-α) and ROS expression in the lungs compared to the control, as well as an influx of inflammatory immune cells such as eosinophils and macrophages in the lungs. This was also reported by Glynos et al. (2018) who showed that mice that have been exposed to e-cigarette aerosols, compared to the control, demonstrated higher levels of oxidative stress in lung tissue and pro-inflammatory cytokine (IL-1β and IL-6) levels in BALF.

In a study by Sussan et al. (2015), mice exposed to e-cigarette aerosol, demonstrated higher levels of macrophages and neutrophils in their BALF, and also showed increased percentage weight loss, mortality rate, and susceptibility to influenza.

The link between e-cigarette aerosol exposure and respiratory immunological effects in mice was also studied by Madison et al. (2019). When mice infected with influenza were exposed to e-cigarette aerosol, the experimental group demonstrated higher levels of lung inflammation and tissue damage than the control group. When their lungs were extracted for closer investigation, it was found that ENDS exposure led to the disruption of lung lipid homeostasis in alveolar macrophages and epithelial cells.

Overall, the results from studies based on murine models provided similar results as studies based on cell models, confirming an association between vaping and negative immunological pulmonary effects.

3.3. Human populations

Six studies based on human populations resulted from our literature search strategy, all of which indicate a statistically significant relationship between vaping and immunological respiratory effects; four of them relate to COVID-19. Vardavas et al. (2012) found e-cigarettes to have adverse effects to a similar extent to combustible cigarettes. Thirty healthy smokers were recruited for the study. All 30 were exposed to e-cigarettes, while 10 from the group were evaluated as non-exposed controls prior to their participation in the experimental group. The study concluded that compared to the control group, the exposed group had a statistically significant increase in airway impedance of lungs and peripheral airway flow resistance, which are strongly correlated with bronchial hyperreactivity. They also observed a decreased fraction of exhaled nitric oxide (FeNO) associated with e-cigarette use, similar to what is known for cigarette use (Malinovschi et al., 2006). Normally, increased levels of FeNO serve as a useful biomarker of eosinophilic airway inflammation associated with asthma (Ahovuo-Saloranta et al., 2019), however in smokers with asthma the overall increase in FeNO may be due to the effect of smoking. FeNO is lower in smoking than in non-smoking asthmatics, whereas FeNO is still higher in untreated smoking asthmatics than in healthy smokers (Ahovuo-Saloranta et al., 2019). Currently, there are no specific guidelines on using FeNO for asthma phenotyping in smoking subjects (Ahovuo-Saloranta et al., 2019). Therefore, we interpret the net decrease in FeNO observed upon e-cigarette use as most likely indicating the absence of eosinophilic airway inflammation or asthma in the study subjects. Instead, it is more likely that the observed FeNO reduction in e-cigarette smoking asthmatics is caused by the mechanical effect of bronchoconstriction (ATS/ERS 2005; Landry et al., 2015). Furthermore, a prospective, observational cross-sectional study conducted by Martin et al. (2016) showed a statistically positive association between vaping and a decrease in the number of immune-related expressed genes vital for the function of the immune system. One group consisted of 13 nonsmokers who were not exposed to any forms of tobacco products, another group consisted of 14 active cigarette smokers, and the final group consisted of 12 active ENDS users. Subjects’ superficial nasal scrape biopsies, nasal lavage, urine, and serum were analyzed to confirm the smoking status and assessed for changes in immune gene expression profiles. The study showed that compared to the nonsmoker group, the e-cigarette group showed an overall suppression of immune-related genes (amongst which the cytokine-cytokine receptor interaction pathway was most significantly affected). Importantly, the extent of suppression and the number of suppressed immune-related genes was six times greater in the e-cigarette user group than in the combustible cigarette user group. These findings suggest that, more so than cigarette smoking, e-cigarette use is associated with decreased expression of innate immune-related genes in the nasal mucosa, thereby potentially enhancing the susceptibility to lung tissue injury and microbial infections.

The link between vaping and COVID-19 was investigated by four population-based studies, which provided varying conclusions regarding the relationship. Gaiha et al. (2020) conducted an online national investigation of adolescents and young adults, by surveying 4351 participants aged 13–24 regarding their COVID-19 status and their e-cigarette use. Utilizing multivariable logistic regression, Gaiha et al. (2020) showed that e-cigarette users were five times more likely to test positive for COVID-19 (95% CI: 1.82–13.96), showing a potential association between vaping and increased susceptibility to COVID-19. However, it should be noted that this study is based on self-report only, is a cross-sectional study which limits the interpretation of causality, and although the association was found to be statistically significant, confounding variables such as demographic factors (including race and socioeconomic status), were not considered. Similar results were found in a study conducted by Young-Wolff et al. (2022). After obtaining medical data from 395,114 people from Kaiser Permanente Hospital in California, Young-Wolff and colleagues found that former e-cigarette use was positively associated with risk for COVID-19 (aOR = 1.39, 95% CI: 0.98–1.96). However, despite using proper sample size and statistical analysis, no association was found between the current use of e-cigarettes and the susceptibility to COVID-19.

Contrary to Gaiha et al. and Young-Wolff et al., some studies found no association between e-cigarette use and risk for COVID-19. In a study conducted by Burnett-Hartman et al. (2022), a survey was given to adult patients hospitalized in Kaiser Permanente hospital across the US regarding their COVID-19 infection and COVID-related risk factors such as e-cigarette use. After controlling for confounding factors such as demographic, behavioral, and clinical factors and conducting a multivariable logistic regression, the author concluded that there was no association between e-cigarette use and increased risk or severity of COVID-19 infection. Similarly, in a study conducted by Jose et al. (2021), the authors found no evidence for the relationship between former or current e-cigarette use and the risk of getting COVID-19 (OR 0.67, p = 0.013). These results were derived using logistic regression models performed on answers to a survey that was given to 69,264 patients in the Mayo Clinic in Minnesota.

4. Discussion

Our literature review of studies published from 2005 to 2022 yielded 21 papers on the immunological effects of e-cigarette use beyond asthma (reviewed extensively elsewhere, i.e. Li et al., 2022). Overall, the majority of studies indicate that e-cigarette use causes increased airway inflammation, for example by increased proinflammatory cytokine release (mainly IL-1β, IL-6, IL-8, Trem-1) in the lung and nasal passages (Sussan et al., 2015; Lerner et al., 2015), by airway epithelial cells (Wu et al., 2014; Hwang et al., 2016), lung fibroblasts (Lerner et al., 2015) and neutrophils (Higham et al., 2016), as well as systemic inflammation as indicated by elevated pro-inflammatory cytokine levels in serum (Rouabhia et al., 2020). The inflammatory immune response upon e-cigarette exposure is also characterized by neutrophil activation and in particular an associated increase in MMP-9 (Culpitt et al., 2005) and neutrophil elastase activation (Yoshioka et al., 1995), which is a characteristic feature of chronic obstructive pulmonary disease (COPD) (Pesci et al., 1998). Necrotic cell death in epithelial airway cells upon e-cigarette aerosol exposure (Hwang et al., 2016), which could potentially be mediated by elevated expression of Trem-1 in BALF from e-cigarette-exposed mice (El Mezayen et al., 2007), can also lead to strong inflammatory responses (Kaczmarek et al., 2013).

In addition, several studies found a clear association between e-cigarette exposure and oxidative stress, as indicated by increased expression of ROS (Morris et al., 2021; Alzoubi et al., 2022; Muthumalage et al., 2018) and decreased glutathione levels in the lung, suggestive of an imbalance of the cellular redox balance (Lerner et al., 2015). It is well known that oxidative stress and inflammation are tightly entwined, promoting each other’s production and activation (Hasnain et al., 2012); Chen et al. (2018). Moreover, airway inflammation associated with increased pro-inflammatory cytokine expression, oxidative stress and neutrophil activation can eventually lead to exacerbation of respiratory diseases such as asthma and COPD (Rahman, 2006; Drost, 2005; Mishra et al., 2018; Pesci et al., 1998). E-cigarette use may therefore lead to airway inflammation and eventually asthma (Li et al., 2022) and COPD, similar to conventional cigarette smoking (Zuo et al., 2014).

In parallel to inducing airway and systemic inflammation, e-cigarette use also causes an impairment of the antimicrobial responses by airway epithelial cells and innate immune cell types in the lung, and increased pathogenic respiratory infections (Denney and Ho, 2018). For example, e-liquid exposed tracheobronchial epithelial cells express reduced levels of SPLUNC-1, an important antimicrobial protein (Chu et al., 2007), whereas neutrophils (Hwang et al.) and macrophages (Ween et al., 2017) demonstrated reduced antimicrobial function. In macrophages, e-cigarette exposure caused a disruption of lung lipid homeostasis (Madison et al., 2019; Culpitt et al., 2005; Yoshioka et al., 1995; Pesci et al., 1998), reduced expression of pattern recognition receptors (SR-A1 and TLR-2) (Ween et al., 2017), and lower levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) (Ween et al., 2017; Hwang et al., 2016) all necessary for the responsiveness to pathogenic infections. These findings thus suggest that ENDS use alters the host defenses and may increase the susceptibility to pathogenic infections. Indeed, numerous studies indicated that e-cigarette use is associated with increased susceptibility to pathogenic infections such as influenza, MRSA and HRV (Wu et al., 2014; Sussan et al., 2015; Hwang et al., 2016).

In summary, the studies captured by this literature review indicate that e-cigarette use triggers several different mechanisms that contribute to airway inflammation, thereby increasing the risk of chronic respiratory diseases such as asthma (Li et al., 2022) and COPD, while simultaneously suppressing key processes that are important for proper antimicrobial immune responses in the lung, thus increasing susceptibility to infectious respiratory diseases. In Fig. 2, we provide a summary of the findings of this review to more easily navigate the results (Fig. 2).

Fig. 2.

Summary of the relationship between exposure to electronic nicotine delivery systems (ENDS) and immunological effects on the respiratory system found in this review.

Several limitations are noted. First, some articles (Higham et al., 2016; Sussan et al., 2015) failed to provide the name of the e-cigarettes used in their study or explain the reasons for choosing a specific device. This is important since different devices, though they are all categorized as “e-cigarettes,” function differently with different heating mechanisms and compounds contained in the e-liquids and aerosols (Misra et al., 2014).

Second, human studies investigating the relationship between ENDS and COVID-19 failed to reach similar conclusions, with one finding no association between e-cigarette use and COVID-19 (Gaiha et al., 2020) whereas others found an association (Burnett-Hartman et al., 2022; Jose et al., 2021; Young-Wolff et al., 2022). Since COVID-19 is a very recent occurrence, we believe more population studies, especially longitudinal or randomized clinical trials with larger sample sizes, are needed to obtain enough data to make a more definitive and accurate conclusion regarding the relationship than before.

Finally, all studies that have been included in the literature review focused primarily on the short-term effects of vaping on the immune system. For example, studies conducted by Gaiha et al. (2020) and Young-Wolff et al. (2022) do not take into account the length of the period each individual has been vaping. Therefore, their results may not accurately represent the true immunological effects for individuals who have been vaping for many years. Since vaping is still a recent trend, it is currently difficult to evaluate the long-term effects of e-cigarette use.

Notwithstanding those limitations, the main strength of this literature review is that similar conclusions were reached by most cell and murine model studies, even when different methods were used, which enhances the overall reliability of their findings. The main gaps in research that were identified by our literature review include the need for longitudinal human studies and randomized clinical trials, with large sample sizes to establish a causal relationship between vaping and immunological deficiencies. Further research is also needed into the potential effects of ENDS use and COVID-19 to help elucidate the contradictory results found in our review and to understand the long-term immune effects of the use of ENDS.

5. Conclusion

Based on most of the studies that are included in this paper, there seems to be a positive association between e-cigarette use and harmful immunological effects, such as increased pro-inflammatory cytokine and oxidative stress production, indicating that the use of electronic nicotine delivery systems can be considered a risk factor for immunological (e.g., asthma and COPD) and infectious respiratory diseases. The COVID-19 pandemic has highlighted the importance of investigating risk factors that influence pulmonary immune responses to infectious diseases such as the use of ENDS.

Data availability

No data was used for the research described in the article.