Methods

Design

We conducted a three-layer systematic review of the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [8]. This review was not pre-registered, and the study results should be considered exploratory.

Search Strategy

The search on PubMed was performed in three layers: the first layer, the effect of vaping on lung function; the second layer, the effect of vaping on lung structure and inducing lung injury; and the third layer, the physiopathologic effect of vaping on lung and possible carcinogenic effect (Figure 1).

First layer: This layer is concerned with the association between vaping and lung function. We used keywords including ((("ERV"[Title/Abstract] OR "expiratory reserve volume" [Title/Abstract] OR "FEFmax"[Title/Abstract]) AND ("FRC"[Title/Abstract] OR "functional residual capacity"[Title/Abstract])) OR ("FVC"[Title/Abstract] OR "forced vital capacity"[Title/Abstract])) AND ("IC"[Title/Abstract] OR "inspiratory capacity"[Title/Abstract]) to find all available evidence on the effect of vape or electronic cigarette on lung function and capacities.

Second layer: This layer was about the association between vaping and lung injury. The search was performed using specific keywords (((((vape [Title/Abstract]) OR (electronic cigarette [Title/Abstract])) OR (vaping [Title/Abstract])) OR (e-cigarette [Title/Abstract])) AND ((lung [Title/Abstract]) AND (injury [Title/Abstract]))), covering the period from July 15, 2015, to December 2023, without any language limitations. EVALI cases were first reported to the Centres for Disease Control and Prevention (CDC) in August 2019 and rapidly increased thereafter, suggesting new or increased exposure to one or more toxicants from the use of e-cigarette products [9].

Third layer: This layer was about the association between vaping and lung cancer. We also used keywords such as ("vape"[Title/Abstract] OR "electronic cigarette"[Title/Abstract] OR "vaping"[Title/Abstract] OR "e-cigarette"[Title/Abstract]) AND ("cancer"[Title/Abstract] OR "neoplasm"[Title/Abstract] OR "tumorigenic"[Title/Abstract]) to find all available evidence on the effect of vape or electronic cigarette on pathology or physiology and ultimately possible inducing cancer.

The inclusion criteria were as follows: (i) Study types included are original research articles, including observational studies (cohort, case-control, and cross-sectional), randomized controlled trials, and case reports that investigate the effects of vaping on lung health; (ii) subjects: studies involving humans of any age, sex, and health status; (iii) measured parameter: articles that assess lung function, structural lung injury, physiopathological effects, and potential carcinogenic outcomes related to vaping; (iv) publication language: studies published in English; (v) date of publication: studies published between July 15, 2015, and December 2023.

The exclusion criteria were as follows: (i) study types: reviews, editorials, commentaries, and letters to the editor; (ii) subjects: studies on animals, unless the findings are directly related to human health implications and are used to supplement human data; (iii) measured parameters: articles that do not directly assess the impact of vaping on lung health, such as those focusing solely on the chemical composition of e-liquids without linking to health outcomes; (4) duplicate studies and studies with incomplete data or those lacking clear methodology and results.

Results

We found 1365 articles in a three-layer search, including 415 on the association between vaping and lung function, 625 on the association between vaping and lung injury, and 330 on the association between vaping and lung cancer (Figure 2). Finally, after removing duplicates, reviews, and letters, 19 articles were selected, including two on the association between vaping and lung function, 14 on the association between vaping and lung injury, and 3 on the association between vaping and lung cancer.

Vape and Lung Capacity

Four studies investigated the association between vaping and lung function overall (Table 1). In a study by Stokes and Fisher, adult male Long-Evans rats exposed to e-cigarette vapour for ten minutes exhibited a reduction in both inhaled and exhaled air per minute, indicating a decrease in overall lung ventilation [10]. This reduction in tidal volume might be attributed to protective bronchoconstriction, as observed by Khosravi et al. in adult guinea pigs exposed to vapour [11]. Furthermore, Odish et al. reported the case of a 19-year-old man with EVALI, where the history and imaging findings were consistent with lung injury caused by e-cigarette use, emphasizing the negative effects of vapour on lung function [12]. Lee et al. conducted a study on young, male Hartley guinea pigs [13]. They revealed that vaping induced acute bronchoconstriction, contributing to the impairment of lung function. Yanina et al. observed changes in the morphological and optical properties of lung tissue in male Wistar rats, further supporting the notion that vaping leads to reduced lung function [14].

Vape and Lung Injury

Our search returned 14 studies that discussed the association between vaping and lung injury (Table 2). Research indicates that e-cigarettes, especially those containing nicotine, disturb mitochondrial membrane potential, release ATP and mitochondrial DNA (mtDNA), and trigger inflammatory responses [15]. Vitamin E acetate (VEA) is implicated in EVALI. It has been discovered to be a diluting agent in illegal vapour pens. In contrast, nicotine is typically diluted with equal amounts of propylene glycol (PG) and vegetable glycerine (VG) [16]. Vaping has become the preferred method of nicotine consumption among young adults (15-24 years old), surpassing traditional cigarettes [17]. Studies conducted in a laboratory setting have shown that the survival of normal human bronchial epithelial cells decreases in a manner that is dependent on the dosage when exposed to vapour emitted by electronic vapour devices [18]. In 2018, the National Youth Tobacco Survey found that 4.9% of students in middle school and 20.8% of students in high school had used e-cigarettes within the past 30 days [18].

We reviewed various data regarding the possible effects of vaping/e-cigarettes on lung injury. And as it turned out, in 2019 in the USA, there was an epidemic of EVALI (e-cigarette, or vaping, product use-associated lung injury). Most researchers and doctors agree on the toxic composition of these devices. Vitamin E acetate and/or tetrahydrocannabinol can affect the appearance of pneumonia, broncho-centric bilateral ground glass opacities, and general deterioration of lung function. It is important to note that a clear link has been established between the use of tetrahydrocannabinol in e-cigarettes and EVALI. In addition, as a result of the disease, some patients developed complications in the form of other diseases, such as invasive pulmonary aspergillosis and acute eosinophilic pneumonia. The CDC emphasizes bronchoalveolar lavage (BAL) fluid analysis to detect harmful substances at the presumed site of lung injury [9]. Vitamin E acetate in vapes/e-cigarettes presumably enters the respiratory epithelial-lining fluid, which is a suspected site for lung injury. Its effect is established by the method of detecting vitamin E acetate in BAL. Blount et al. found that 48 out of 51 patients with lung injuries had vitamin E acetate present in the BAL fluid [9]. It is important to note that 99 healthy participants, according to Blount et al., did not find vitamin E acetate in the BAL liquid [9]. Itoh et al. diagnosed e-cig-induced acute lung injury (ALI) caused by using e-cigarettes [19]. A 46-year-old man was diagnosed with ALI due to e-cig use [19]. Lung histological examination revealed lesions with acute changes, alveolar septum swelling, and eosinophil and neutrophil invasion, with intra-alveolar invasion of eosinophils and neutrophils; in addition, abundant macrophages containing blackish-brown pigment, multinucleated foreign-body giant cells, and intra-alveolar organization [19]. It is considered that these changes are due to the ingestion of foreign substances in the composition of the e-cigarette into the respiratory system. Layden et al. presented the results: of the 91 patients who underwent CT imaging, 6 cases of pneumomediastinum, 11 cases of pleural effusion, and 2 cases of pneumothorax were present (in 15 patients) [20]. Two patients had both a pneumomediastinum and a pneumothorax, and two patients had both a pneumomediastinum and pleural effusion [20]. Adhikari et al., in the case report, presented the results of a 23-year-old man [21]. A chest X-ray showed bilateral pneumonia, and a computed tomography (CT) scan of the chest showed bilateral lung infiltrates [4]. In another case report described by Sharma et al., a chest X-ray of a 35-year-old man was examined, which showed a right-sided pneumothorax with a slight displacement of the structures of the heart and mediastinum to the left [22]. Szafran et al. did a study on mice, and it showed that exposure to only e-cig delivery vehicles, VG/PG, without nicotine, affects the lungs and that the addition of vanilla flavouring may enhance the lung responses [23]. There was also a case in the Wolf and Richards et al. report where attention was drawn to acute eosinophilic pneumonia as a potential consequence of lung injury associated with vaping with THC [24]. It is worth mentioning another case report where a teenager was diagnosed with invasive pulmonary aspergillosis as a complication after EVALI. Kupelian et al. reported the first case, most likely related to the use of tetrahydrocannabinol and/or vaping [25]. In the case report of Stein et al., an interesting case was written about a man with testicular cancer who, during the course of the disease, had bilateral opacities of the "frosted glass" type and intrathoracic adenopathy revealed on a CT scan [26]. Later, it turned out that the patient smoked THC three times a day. As mentioned, the epidemic of EVALI is associated with the use of tetrahydrocannabinol and vitamin E acetate (VEA) in e-cigarettes. Heinzerling et al. point out that most foods that contain THC also contain VEA, which reinforces the link between these chemicals and the outbreak [27]. Vaping with tetrahydrocannabinol significantly increases the risk of lung injury and complications after e-cigarette or vaping product use-associated lung injury (EVALI). Besides the above-mentioned EVALI outcomes, other complications may occur, such as pneumothorax and acute respiratory distress syndrome (ARDS). They are mentioned in the case reports by Smith et al. [28] and Yingchoncharoen et al. [29]. ARDS is a life-threatening lung injury characterized by the rapid onset of widespread inflammation in the lungs. Multiple risk factors, including pneumonia, non-pulmonary sepsis, aspiration of gastric contents, or inhalation injury, have been reported to cause ARDS [29]. Currently, unfortunately, some women use e-cigarettes during pregnancy with the opinion that they are harmless. However, due to the similar development and physiology of sheep and human lungs, Berkelhamer et al. conducted a test on adult sheep and their two-day-old lambs in their study [30]. Their data show that foetal and newborn lungs may have increased susceptibility to toxicity when exposed to flavoured e-cigarette solutions and that physiological responses to these common additives may also be altered in immature lungs. We concluded that the use of electronic cigarettes in the foetal period carries a high risk to the foetus. Also, many articles note the bilateral infiltrates, bilateral opacities, and/or ground glass opacity (GGO) in the lungs as a result of smoking e-cigarettes and/or vaping [31,32]. The frightening thing is that in addition to this, the disease is accompanied by various respiratory symptoms and other functional abnormalities with frequent sub-pleural sparing, and small pleural effusions may also be detected. After studying all these articles to identify the link between vaping and lung injury, we conclude that e-cigarette smokers and/or vapers are susceptible to various lung diseases. In particular, due to the legalization of THC in some US states, the situation has accepted and is accepting severe outcomes of smoking electronic cigarettes as well as vaping, which contains vitamin E acetate. Currently, the vaping situation is deteriorating, and it may be a new pandemic, especially among young people and adolescents. Despite the law on the sale of smoking systems only after adulthood, vape shops are not limited to them. Many people mistakenly think that e-cigarettes and vaping are harmless compared to tobacco. However, as can be seen from our review article, the impact is significant and may increase.

Vaping and Lung Cancer

Only two studies were about the association between vaping and lung cancer (Table 3 [PNLP1] and [PNLP2]). Lung cancer (LC) is a diverse disease with different clinical and pathological features. It can be histologically classified into two groups: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) [33]. The diagnostic rate for NSCLC is 85%, while for SCLC it is only 15% [34]. Concerning the hereditary predisposition to lung cancer (LC), it has been acknowledged that around 85% of the risk of developing LC is associated with cigarette smoking. Therefore, lung cancer develops in 15% of smokers, suggesting a varying vulnerability to the harmful effects of tobacco carcinogens. Research has indicated that electronic cigarettes (ECs) cause harm to DNA in the lungs and hinder the process of DNA repair in lung tissues. This implicates ECs as a potential cause of lung cancer in mice.

Every year, about 2.2 million cases of lung cancer are diagnosed in the world, and it ranks second after breast cancer. Electronic cigarettes have risen in popularity in recent years as a means of consuming nicotine or simulating tobacco smoking without carcinogenic combustion products [35]. Most vapers consider smoking electronic cigarettes and/or vaping harmless. Also, some use this type of smoking to reduce the use of tobacco cigarettes. In particular, these smoking systems are common among adolescents and young people due to the availability and lack of regulation of vaping sales. However, are they harmless, and do they affect lung cancer? In 2019, Tang et al. found that exposure to electronic cigarette smoke (ECS) induced lung adenocarcinoma in six- to eight-week-old male mice, suggesting a potential link between ECs and lung cancer [36]. As a result of the study, it was noted that exposure to ECS induces the formation of lung tumours in mice. In the same year, Zahedi et al. demonstrated an epithelial-to-mesenchymal transition (EMT) in lung cancer cells during exposure to e-cigarette products, indicating a possible contribution to cancer progression for those at risk for lung cancer [37].

While studying the effects of vaping on the lungs, we saw a study where smoking e-cigarettes with nicotine was used to reduce the smoking of conventional cigarettes and improve lung health among chronic smokers undergoing a cancer screening programme [38]. Lucchiari et al. showed that 20% of 210 smokers stopped smoking after six months [38]. Surprisingly, there were no side effects at the end of the study, but symptoms such as burning in the throat were found in the subjects after smoking electronic cigarettes. The best preventative measure to curb the adverse health effects associated with smoking is abstaining from smoking or tobacco cessation [39]. Most cancer patients who persist in smoking already recognize the adverse health effects and the importance of stopping smoking [39]. The effects of shaping and e-cigarettes on lung cancer have not been studied as much, although the outcomes can only be guessed. One of the important points is that these types of smoking significantly reduce the functionality of the lungs. As written earlier, exposure to e-cigarettes affects the development of lung adenocarcinoma. Although the carcinogenicity of these tobacco systems has not been fully studied, one can only assume their effect on human health.

Discussion

In recent times, the widespread adoption of vaping, particularly among youth, has been fueled by enticing advertisements, an array of flavours, and aesthetically pleasing designs. Positioned as a tool for quitting traditional smoking, vaping has indeed facilitated smoking cessation for many over the past few decades. However, the ongoing research into the harms of vaping suggests that, while potentially less harmful than traditional cigarettes, vaping is far from being considered a completely safe practice. This discussion sheds light on the adverse effects of vaping on lung health, emphasizing the need for preventive measures.

Pulmonary Impact of Vaping

The impact of vaping on lung health remains an evolving area of investigation, with conclusive results yet to be established. Nonetheless, the documented harm to the lungs associated with vaping is cause for concern. Studies have indicated potential links between vaping and pneumonia, shortness of breath, increased risk of respiratory infections, asthma and bronchitis, and effects on lung tissue [40]. Some studies have shown that vaping or e-cigarettes have the potential to increase susceptibility to pneumococcal infection [41-43]. This inflammation may manifest in symptoms akin to respiratory conditions such as asthma and bronchitis. One of the suggested reasons was the effect of vapour on oxidative stress-induced, PAFR-dependent pneumococcal adhesion to airway epithelial cells and pneumococcal colonization in the mouse nasopharynx [41]. An alarming observation is the onset of lipoid pneumonia in an otherwise healthy patient using cannabis-containing e-cigarettes, suggesting that the composition of vape liquids plays a crucial role in respiratory complications [42]. Some people feel shortness of breath after using a vape [44]. This may be a sign of lung irritation and airway obstruction. Research indicates that vaping may compromise the lung's immune system, heightening the risk of respiratory infections [45]. Some studies have shown that the use of vaping can cause or affect complications such as exacerbations of asthma and bronchitis in some people [46]. Continuous and long-term use of vape may lead to changes in lung tissue. These changes may include inflammation and the destruction of lung tissue.

Risks Associated With Vape Liquid Components

The composition of vape liquids introduces additional considerations for lung health. The inclusion of vitamin E in vape liquids, while commonly used to create vapour in a vape, poses potential risks [47]. The 2019 surge in severe lung diseases reported in individuals using vape liquids containing THC and vitamin E underscores the need for scrutiny [48]. However, the use of vitamin E in vape liquids does not apply to all vape products. These risks are especially related to the use of vitamin E extracted from natural oils that have been illegally added to vape liquids. High-quality, properly refined vitamin E is suggested to pose fewer risks and may even be used as a dietary supplement for lung health. However, research on the long-term effects of PG and glycerin vaporization is inconclusive, raising questions about the safety of these components, especially with excessive or prolonged use [49,50]. This damage can include lung inflammation, increased lung secretions, cough and sputum, lung infection, and respiratory problems such as bronchitis and asthma.

Global Concerns and Regulatory Considerations

In a report, the World Health Organization (WHO) expressed reservations about the widespread use of e-cigarettes, citing concerns about efficacy in smoking cessation and potential harm, especially among youth [PNLP1] [51]. Despite having fewer toxic substances than traditional cigarettes, e-cigarettes are considered harmful. The WHO emphasizes that the high-temperature vaporization of liquid nicotine in e-cigarettes can lead to addiction, warranting vigilant monitoring of these devices.

Long-Term Effects and Comparisons With Smoking

The long-term effects of smoking, including a high risk of stroke, heart disease, and various types of cancer, have been well established [52-54]. According to the report published by the Committee for Disease Control and Prevention (CDC), one out of five people dies due to smoking [55]. Meanwhile, e-cigarettes seem to be a less risky option for people who want to quit smoking. Using an electronic cigarette to quit smoking does not mean that it is safe. Even if the vape liquid does not contain nicotine, its adverse effects may bother the user. To date, little evidence has been provided about the long-term effects of vaping, as it will take at least 10 years to determine the effects of vaping on the lungs. But experience with smoking shows that vaping has similar negative health effects, such as chronic obstructive pulmonary disease (COPD), heart disease, and cancer. Inhaling vape vapour may lead to inflammation in the lungs and cause complications such as cough, phlegm, chest pain, and lung infection [44, 56]. Also, some research has shown that continuous use of vaping may increase the risk of developing lung diseases such as bronchitis and asthma [57]. Some studies have shown that using vapes can increase heart rate, increase blood pressure, and cause heart problems [58]. The use of vape liquids containing nicotine may lead to side effects such as addiction, an increased risk of cardiovascular diseases, nerve disorders, breathing problems, sleep disorders, and an increased risk of cancer such as lung, pancreatic, and brain cancer [58]. The use of vaping by young people and teenagers can lead to the development of nicotine addiction, psychological and cognitive risks, and harmful effects on growth and the brain [59].

Strengths and Limitations

Strengths: The article presents a comprehensive review of existing evidence on the adverse effects of vaping on lung health following PRISMA and Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines and the multi-layered approach to searching, which should lend credibility to the methods used. It synthesizes findings from various studies, offering a holistic view of the current state of knowledge on this topic.

The discussion on public health implications goes beyond the scientific findings to highlight the urgent need for public health interventions. This adds a practical dimension to the research by emphasizing the importance of regulatory measures and awareness campaigns.

We made evidence-based recommendations for public health efforts that focused on dispelling misconceptions about the safety of vaping and promoting proven smoking cessation methods. This adds a pragmatic and actionable dimension to the discussion.

We acknowledge the current lack of conclusive evidence on the long-term effects of vaping. This recognition of uncertainty adds credibility to the review and emphasizes the importance of continued research in this evolving field.

By stressing the need for ongoing research to capture emerging trends, the study demonstrates a forward-looking approach. This is crucial in a field where new vaping products and formulations are continuously introduced.

Limitations: Despite the compelling evidence presented, this review acknowledges certain limitations. The review highlights a limitation in the predominantly experimental and case-report nature of the studies reviewed, involving animal or cell line models. While these studies are crucial for understanding biological mechanisms, their findings may not always directly translate to human populations due to species differences in metabolism and physiology. This variability in study designs may pose challenges in establishing causation and generalizing findings to broader populations.

There is a predominance of short-term studies and case reports, which limits the ability to make definitive conclusions about the long-term carcinogenic effects of vaping. Long-term studies are essential to assess the cumulative effects of vaping on lung cancer risk.

Many studies do not adequately control for confounding factors such as concurrent tobacco use, environmental exposures, and genetic predispositions that might influence lung cancer risk, which could lead to conflicting results. Also, significant variability in the types of vaping devices and liquids and the presence of potential contaminants complicate the establishment of a standardized exposure assessment and may lead to conflicting evidence regarding the association between vaping and lung cancer.

Some studies may have small sample sizes, reducing the power to detect significant effects or associations and limiting the generalizability of the findings to a broader population. The studies discuss the use of e-cigarettes as a method to reduce or quit tobacco cigarette smoking, as seen in the study by Lucchiari et al. [38]. However, these findings could be in conflict with the potential harmful effects of vaping, as vaping is sometimes initiated as an alternative to smoking without a full understanding of its risks.

The vaping product market is rapidly evolving, with new products and formulations constantly emerging. This means that the substances and exposures being studied may quickly become outdated, and the findings may not apply to the products currently in use.

Future Directions

Given the points above, future research should prioritize long-term, longitudinal human studies with large and diverse populations, consider the rapidly changing landscape of e-cigarette products, and focus on comprehensive exposure assessments to elucidate the potential risks of vaping, particularly concerning lung cancer. Additionally, clear communication to the public regarding the current understanding and unknowns of vaping risks is important to address misconceptions and inform behaviour.