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Impact of vaping on respiratory health

Linked editorial.

Protecting children from harms of vaping

• Related content
• Peer review
• Andrea Jonas , clinical assistant professor
• Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Stanford University, Stanford, CA, USA
• Correspondence to A Jonas andreajonas{at}stanford.edu

Widespread uptake of vaping has signaled a sea change in the future of nicotine consumption. Vaping has grown in popularity over the past decade, in part propelled by innovations in vape pen design and nicotine flavoring. Teens and young adults have seen the biggest uptake in use of vape pens, which have superseded conventional cigarettes as the preferred modality of nicotine consumption. Relatively little is known, however, about the potential effects of chronic vaping on the respiratory system. Further, the role of vaping as a tool of smoking cessation and tobacco harm reduction remains controversial. The 2019 E-cigarette or Vaping Use-Associated Lung Injury (EVALI) outbreak highlighted the potential harms of vaping, and the consequences of long term use remain unknown. Here, we review the growing body of literature investigating the impacts of vaping on respiratory health. We review the clinical manifestations of vaping related lung injury, including the EVALI outbreak, as well as the effects of chronic vaping on respiratory health and covid-19 outcomes. We conclude that vaping is not without risk, and that further investigation is required to establish clear public policy guidance and regulation.

Abbreviations

BAL bronchoalveolar lavage

CBD cannabidiol

CDC Centers for Disease Control and Prevention

DLCO diffusing capacity of the lung for carbon monoxide

EMR electronic medical record

END electronic nicotine delivery systems

EVALI E-cigarette or Vaping product Use-Associated Lung Injury

LLM lipid laden macrophages

THC tetrahydrocannabinol

V/Q ventilation perfusion

Introduction

The introduction of vape pens to international markets in the mid 2000s signaled a sea change in the future of nicotine consumption. Long the mainstay of nicotine use, conventional cigarette smoking was on the decline for decades in the US, 1 2 largely owing to generational shifts in attitudes toward smoking. 3 With the advent of vape pens, trends in nicotine use have reversed, and the past two decades have seen a steady uptake of vaping among young, never smokers. 4 5 6 Vaping is now the preferred modality of nicotine consumption among young people, 7 and 2020 surveys indicate that one in five US high school students currently vape. 8 These trends are reflected internationally, where the prevalence of vape products has grown in both China and the UK. 9 Relatively little is known, however, regarding the health consequences of chronic vape pen use. 10 11 Although vaping was initially heralded as a safer alternative to cigarette smoking, 12 13 the toxic substances found in vape aerosols have raised new questions about the long term safety of vaping. 14 15 16 17 The 2019 E-cigarette or Vaping product Use-Associated Lung Injury (EVALI) outbreak, ultimately linked to vitamin E acetate in THC vapes, raised further concerns about the health effects of vaping, 18 19 20 and has led to increased scientific interest in the health consequences of chronic vaping. This review summarizes the history and epidemiology of vaping, and the clinical manifestations and proposed pathophysiology of lung injury caused by vaping. The public health consequences of widespread vaping remain to be seen and are compounded by young users of vape pens later transitioning to combustible cigarettes. 4 21 22 Deepened scientific understanding and public awareness of the potential harms of vaping are imperative to confront the challenges posed by a new generation of nicotine users.

Sources and selection criteria

We searched PubMed and Ovid Medline databases for the terms “vape”, “vaping”, “e-cigarette”, “electronic cigarette”, “electronic nicotine delivery”, “electronic nicotine device”, “END”, “EVALI”, “lung injury, diagnosis, management, and treatment” to find articles published between January 2000 and December 2021. We also identified references from the Centers for Disease Control and Prevention (CDC) website, as well as relevant review articles and public policy resources. Prioritization was given to peer reviewed articles written in English in moderate-to-high impact journals, consensus statements, guidelines, and included randomized controlled trials, systematic reviews, meta-analyses, and case series. We excluded publications that had a qualitative research design, or for which a conflict of interest in funding could be identified, as defined by any funding source or consulting fee from nicotine manufacturers or distributors. Search terms were chosen to generate a broad selection of literature that reflected historic and current understanding of the effects of vaping on respiratory health.

The origins of vaping

Vaping achieved widespread popularity over the past decade, but its origins date back almost a century and are summarized in figure 1 . The first known patent for an “electric vaporizer” was granted in 1930, intended for aerosolizing medicinal compounds. 23 Subsequent patents and prototypes never made it to market, 24 and it wasn’t until 1979 that the first vape pen was commercialized. Dubbed the “Favor” cigarette, the device was heralded as a smokeless alternative to cigarettes and led to the term “vaping” being coined to differentiate the “new age” method of nicotine consumption from conventional, combustible cigarettes. 25 “Favor” cigarettes did not achieve widespread appeal, in part because of the bitter taste of the aerosolized freebase nicotine; however, the term vaping persisted and would go on to be used by the myriad products that have since been developed.

Timeline of vape pen invention to widespread use (1970s-2020)

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The forerunner of the modern vape pen was developed in Beijing in 2003 and later introduced to US markets around 2006. 26 27 Around this time, the future Juul Laboratories founders developed the precursor of the current Juul vape pen while they were students at the Stanford Byers-Center for Biodesign. 28 Their model included disposable cartridges of flavored nicotine solution (pods) that could be inserted into the vape pen, which itself resembled a USB flash drive. Key to their work was the chemical alteration of freebase nicotine to a benzoate nicotine salt. 29 The lower pH of the nicotine salt resulted in an aerosolized nicotine product that lacked a bitter taste, 30 and enabled manufacturers to expand the range of flavored vape products. 31 Juul Laboratories was founded a decade later and quickly rose to dominate the US market, 32 accounting for an estimated 13-59% of the vape products used among teens by 2020. 6 8 Part of the Juul vape pen’s appeal stems from its discreet design, as well as its ability to deliver nicotine with an efficiency matching that of conventional cigarettes. 33 34 Subsequent generations of vape pens have included innovations such as the tank system, which allowed users to select from the wide range of different vape solutions on the market, rather than the relatively limited selection available in traditional pod based systems. Further customizations include the ability to select different vape pen components such as atomizers, heating coils, and fluid wicks, allowing users to calibrate the way in which the vape aerosol is produced. Tobacco companies have taken note of the shifting demographics of nicotine users, as evidenced in 2018 by Altria’s $12.8bn investment in Juul Laboratories. 35

Vaping terminology

At present, vaping serves as an umbrella term that describes multiple modalities of aerosolized nicotine consumption. Vape pens are alternatively called e-cigarettes, electronic nicotine delivery systems (END), e-cigars, and e-hookahs. Additional vernacular terms have emerged to describe both the various vape pen devices (eg, tank, mod, dab pen), vape solution (eg, e-liquid, vape juice), as well as the act of vaping (eg, ripping, juuling, puffing, hitting). 36 A conventional vape pen is a battery operated handheld device that contains a storage chamber for the vape solution and an internal element for generating the characteristic vape aerosol. Multiple generations of vape pens have entered the market, including single use, disposable varieties, as well as reusable models that have either a refillable fluid reservoir or a disposable cartridge for the vape solution. Aerosol generation entails a heating coil that atomizes the vape solution, and it is increasingly popular for devices to include advanced settings that allow users to adjust features of the aerosolized nicotine delivery. 37 38 Various devices allow for coil temperatures ranging from 110 °C to over 1000 °C, creating a wide range of conditions for thermal degradation of the vape solution itself. 39 40

The sheer number of vape solutions on the market poses a challenge in understanding the impact of vaping on respiratory health. The spectrum of vape solutions available encompasses thousands of varieties of flavors, additives, and nicotine concentrations. 41 Most vape solutions contain an active ingredient, commonly nicotine 42 ; however, alternative agents include tetrahydrocannabinol (THC) or cannabidiol (CBD). Vape solutions are typically composed of a combination of a flavorant, nicotine, and a carrier, commonly propylene glycol or vegetable glycerin, that generates the characteristic smoke appearance of vape aerosols. Some 450 brands of vape now offer more than 8000 flavors, 41 a figure that nearly doubled over a three year period. 43 Such tremendous variety does not account for third party sellers who offer users the option to customize a vape solution blend. Addition of marijuana based products such as THC or CBD requires the use of an oil based vape solution carrier to allow for extraction of the psychoactive elements. Despite THC vaping use in nearly 9% of high schoolers, 44 THC vape solutions are subject to minimal market regulation. Finally, a related modality of THC consumption is termed dabbing, and describes the process of inhaling aerosolized THC wax concentrate.

Epidemiology of vaping

Since the early 2000s, vaping has grown in popularity in the US and elsewhere. 8 45 Most of the 68 million vape pen users are concentrated in China, the US, and Europe. 46 Uptake among young people has been particularly pronounced, and in the US vaping has overtaken cigarettes as the most common modality of nicotine consumption among adolescents and young adults. 47 Studies estimate that 20% of US high school students are regular vape pen users, 6 48 in contrast to the 5% of adults who use vape products. 2 Teen uptake of vaping has been driven in part by a perception of vaping as a safer alternative to cigarettes, 49 50 as well as marketing strategies that target adolescents. 33 Teen use of vape pens is further driven by the low financial cost of initiation, with “starter kits” costing less than $25, 51 as well as easy access through peer sales and inconsistent age verification at in-person and online retailers. 52 After sustained growth in use over the 2010s, recent survey data from 2020 suggest that the number of vape pen users has leveled off among teens, perhaps in part owing to increased perceived risk of vaping after the EVALI outbreak. 8 53 The public health implications of teen vaping are compounded by the prevalence of vaping among never smokers (defined as having smoked fewer than 100 lifetime cigarettes), 54 and subsequent uptake of cigarette smoking among vaping teens. 4 55 Similarly, half of adults who currently vape have never used cigarettes, 2 and concern remains that vaping serves as a gateway to conventional cigarette use, 56 57 although these results have been disputed. 58 59 Despite regulation limiting the sale of flavored vape products, 60 a 2020 survey found that high school students were still predominantly using fruit, mint, menthol, and dessert flavored vape solutions. 48 While most data available surround the use of nicotine-containing vape products, a recent meta-analysis showed growing prevalence of adolescents using cannabis-containing products as well. 61

Vaping as harm reduction

Despite facing ongoing questions about safety, vaping has emerged as a potential tool for harm reduction among cigarette smokers. 12 27 An NHS report determined that vaping nicotine is “around 95% less harmful than cigarettes,” 62 leading to the development of programs that promote vaping as a tool of risk reduction among current smokers. A 2020 Cochrane review found that vaping nicotine assisted with smoking cessation over placebo 63 and recent work found increased rates of cigarette abstinence (18% v 9.9%) among those switching to vaping compared with conventional nicotine replacement (eg, gum, patch, lozenge). 64 US CDC guidance suggests that vaping nicotine may benefit current adult smokers who are able to achieve complete cigarette cessation by switching to vaping. 65 66

The public health benefit of vaping for smoking cessation is counterbalanced by vaping uptake among never smokers, 2 54 and questions surrounding the safety of chronic vaping. 10 11 Controversy surrounding the NHS claim of vaping as 95% safer than cigarettes has emerged, 67 68 and multiple leading health organizations have concluded that vaping is harmful. 42 69 Studies have demonstrated airborne particulate matter in the proximity of active vapers, 70 and concern remains that secondhand exposure to vaped aerosols may cause adverse effects, complicating the notion of vaping as a net gain for public health. 71 72 Uncertainty about the potential chronic consequences of vaping combined with vaping uptake among never smokers has complicated attempts to generate clear policy guidance. 73 74 Further, many smokers may exhibit “dual use” of conventional cigarettes and vape pens simultaneously, further complicating efforts to understand the impact of vape exposure on respiratory health, and the role vape use may play in smoking cessation. 12 We are unable to know with certainty the extent of nicotine uptake among young people that would have been seen in the absence of vaping availability, and it remains possible that some young vape pen users may have started on conventional cigarettes regardless. That said, declining nicotine use over the past several decades would argue that many young vape pen users would have never had nicotine uptake had vape pens not been introduced. 1 2 It remains an open question whether public health measures encouraging vaping for nicotine cessation will benefit current smokers enough to offset the impact of vaping uptake among young, never smokers. 75

Vaping lung injury—clinical presentations

Vaping related lung injury: 2012-19.

The potential health effects of vape pen use are varied and centered on injury to the airways and lung parenchyma. Before the 2019 EVALI outbreak, the medical literature detailed case reports of sporadic vaping related acute lung injury. The first known case was reported in 2012, when a patient presented with cough, diffuse ground glass opacities, and lipid laden macrophages (LLM) on bronchoalveolar lavage (BAL) return in the context of vape pen use. 76 Over the following seven years, an additional 15 cases of vaping related acute lung injury were reported in the literature. These cases included a wide range of diffuse parenchymal lung disease without any clear unifying features, and included cases of eosinophilic pneumonia, 77 78 79 hypersensitivity pneumonitis, 80 organizing pneumonia, 81 82 diffuse alveolar hemorrhage, 83 84 and giant cell foreign body reaction. 85 Although parenchymal lung injury predominated the cases reported, additional cases detailed episodes of status asthmaticus 86 and pneumothoraces 87 attributed to vaping. Non-respiratory vape pen injury has also been described, including cases of nicotine toxicity from vape solution ingestion, 88 89 and injuries sustained owing to vape pen device explosions. 90

The 2019 EVALI outbreak

In the summer of 2019 the EVALI outbreak led to 2807 cases of idiopathic acute lung injury in predominantly young, healthy individuals, which resulted in 68 deaths. 19 91 Epidemiological work to uncover the cause of the outbreak identified an association with vaping, particularly the use of THC-containing products, among affected individuals. CDC criteria for EVALI ( box 1 ) included individuals presenting with respiratory symptoms who had pulmonary infiltrates on imaging in the context of having vaped or dabbed within 90 days of symptom onset, without an alternative identifiable cause. 92 93 After peaking in September 2019, EVALI case numbers steadily declined, 91 likely owing to identification of a link with vaping, and subsequent removal of offending agents from circulation. Regardless, sporadic cases continue to be reported, and a high index of suspicion is required to differentiate EVALI from covid-19 pneumonia. 94 95 A strong association emerged between EVALI cases and the presence of vitamin E acetate in the BAL return of affected individuals 96 ; however, no definitive causal link has been established. Interestingly, the EVALI outbreak was nearly entirely contained within the US with the exception of several dozen cases, at least one of which was caused by an imported US product. 97 98 99 The pattern of cases and lung injury is most suggestive of a vape solution contaminant that was introduced into the distribution pipeline in US markets, leading to a geographically contained pattern of lung injury among users. CDC case criteria for EVALI may have obscured a potential link between viral pneumonia and EVALI, and cases may have been under-recognized following the onset of the covid-19 pandemic.

CDC criteria for establishing EVALI diagnosis

Cdc lung injury surveillance, primary case definitions, confirmed case.

Vape use* in 90 days prior to symptom onset; and

Pulmonary infiltrate on chest radiograph or ground glass opacities on chest computed tomography (CT) scan; and

Absence of pulmonary infection on initial investigation†; and

Absence of alternative plausible diagnosis (eg, cardiac, rheumatological, or neoplastic process).

Probable case

Pulmonary infiltrate on chest radiograph or ground glass opacities on chest CT; and

Infection has been identified; however is not thought to represent the sole cause of lung injury OR minimum criteria** to exclude infection have not been performed but infection is not thought to be the sole cause of lung injury

*Use of e-cigarette, vape pen, or dabbing.

†Minimum criteria for absence of pulmonary infection: negative respiratory viral panel, negative influenza testing (if supported by local epidemiological data), and all other clinically indicated infectious respiratory disease testing is negative.

EVALI—clinical, radiographic, and pathologic features

In the right clinical context, diagnosis of EVALI includes identification of characteristic radiographic and pathologic features. EVALI patients largely fit a pattern of diffuse, acute lung injury in the context of vape pen exposure. A systematic review of 200 reported cases of EVALI showed that those affected were predominantly men in their teens to early 30s, and most (80%) had been using THC-containing products. 100 Presentations included predominantly respiratory (95%), constitutional (87%), and gastrointestinal symptoms (73%). Radiological studies mostly featured diffuse ground glass opacities bilaterally. Of 92 cases that underwent BAL, alveolar fluid samples were most commonly neutrophil predominant, and 81% were additionally positive for LLM on Oil Red O staining. Lung biopsy was not required to achieve the diagnosis; however, of 33 cases that underwent tissue biopsy, common features included organizing pneumonia, inflammation, foamy macrophages, and fibrinous exudates.

EVALI—outcomes

Most patients with EVALI recovered, and prognosis was generally favorable. A systematic review of identified cases found that most patients with confirmed disease required admission to hospital (94%), and a quarter were intubated. 100 Mortality among EVALI patients was low, with estimates around 2-3% across multiple studies. 101 102 103 Mortality was associated with age over 35 and underlying asthma, cardiac disease, or mental health conditions. 103 Notably, the cohorts studied only included patients who presented for medical care, and the samples are likely biased toward a more symptomatic population. It is likely that many individuals experiencing mild symptoms of EVALI did not present for medical care, and would have self-discontinued vaping following extensive media coverage of the outbreak at that time. Although most EVALI survivors recovered well, case series of some individuals show persistent radiographic abnormalities 101 and sustained reductions in DLCO. 104 105 Pulmonary function evaluation of EVALI survivors showed normalization in FEV 1 /FVC on spirometry in some, 106 while others had more variable outcomes. 105 107 108

Vaping induced lung injury—pathophysiology

The causes underlying vaping related acute lung injury remain interesting to clinicians, scientists, and public health officials; multiple mechanisms of injury have been proposed and are summarized in figure 2 . 31 109 110 Despite increased scientific interest in vaping related lung injury following the EVALI outbreak, the pool of data from which to draw meaningful conclusions is limited because of small scale human studies and ongoing conflicts due to tobacco industry funding. 111 Further, insufficient time has elapsed since widespread vaping uptake, and available studies reflect the effects of vaping on lung health over a maximum 10-15 year timespan. The longitudinal effects of vaping may take decades to fully manifest and ongoing prospective work is required to better understand the impacts of vaping on respiratory health.

Schematic illustrating pathophysiology of vaping lung injury

Pro-inflammatory vape aerosol effects

While multiple pathophysiological pathways have been proposed for vaping related lung injury, they all center on the vape aerosol itself as the conduit of lung inflammation. Vape aerosols have been found to harbor a number of toxic substances, including thermal degradation products of the various vape solution components. 112 Mass spectrometry analysis of vape aerosols has identified a variety of oxidative and pro-inflammatory substances including benzene, acrolein, volatile organic compounds, and propylene oxide. 16 17 Vaping additionally leads to airway deposition of ultrafine particles, 14 113 as well as the heavy metals manganese and zinc which are emitted from the vaping coils. 15 114 Fourth generation vape pens allow for high wattage aerosol generation, which can cause airway epithelial injury and tissue hypoxia, 115 116 as well as formaldehyde exposure similar to that of cigarette smoke. 117 Common carrier solutions such as propylene glycol have been associated with increased airway hyper-reactivity among vape pen users, 31 118 119 and have been associated with chronic respiratory conditions among theater workers exposed to aerosolized propylene glycol used in the generation of artificial fog. 120 Nicotine salts used in pod based vape pen solutions, including Juul, have been found to penetrate the cell membrane and have cytotoxic effects. 121

The myriad available vape pen flavors correlate with an expansive list of chemical compounds with potential adverse respiratory effects. Flavorants have come under increased scrutiny in recent years and have been found to contribute to the majority of aldehyde production during vape aerosol production. 122 Compounds such as cinnamaldehyde, 123 124 2,5-dimethylpyrazine (chocolate flavoring), 125 and 2,3-pentanedione 126 are common flavor additives and have been found to contribute to airway inflammation and altered immunological responses. The flavorant diacetyl garnered particular attention after it was identified on mass spectrometry in most vape solutions tested. 127 Diacetyl is most widely associated with an outbreak of diacetyl associated bronchiolitis obliterans (“popcorn lung”) among workers at a microwave popcorn plant in 2002. 128 Identification of diacetyl in vape solutions raises the possibility of development of a similar pattern of bronchiolitis obliterans among individuals who have chronic vape aerosol exposure to diacetyl-containing vape solutions. 129

Studies of vape aerosols have suggested multiple pro-inflammatory effects on the respiratory system. This includes increased airway resistance, 130 impaired response to infection, 131 and impaired mucociliary clearance. 132 Vape aerosols have further been found to induce oxidative stress in lung epithelial cells, 133 and to both induce DNA damage and impair DNA repair, consistent with a potential carcinogenic effect. 134 Mice chronically exposed to vape aerosols developed increased airway hyper-reactivity and parenchymal changes consistent with chronic obstructive pulmonary disease. 135 Human studies have been more limited, but reveal increased airway edema and friability among vape pen users, as well as altered gene transcription and decreased innate immunity. 136 137 138 Upregulation of neutrophil elastase and matrix metalloproteases among vape users suggests increased proteolysis, potentially putting those patients at risk of chronic respiratory conditions. 139

THC-containing products

Of particular interest during the 2019 EVALI outbreak was the high prevalence of THC use among EVALI cases, 19 raising questions about a novel mechanism of lung injury specific to THC-containing vape solutions. These solutions differ from conventional nicotine based products because of the need for a carrier capable of emulsifying the lipid based THC component. In this context, additional vape solution ingredients rose to attention as potential culprits—namely, THC itself, which has been found to degrade to methacrolein and benzene, 140 as well as vitamin E acetate which was found to be a common oil based diluent. 141

Vitamin E acetate has garnered increasing attention as a potential culprit in the pathophysiology of the EVALI outbreak. Vitamin E acetate was found in 94% of BAL samples collected from EVALI patients, compared with none identified in unaffected vape pen users. 96 Thermal degradation of vitamin E acetate under conditions similar to those in THC vape pens has shown production of ketene, alkene, and benzene, which may mediate epithelial lung injury when inhaled. 39 Previous work had found that vitamin E acetate impairs pulmonary surfactant function, 142 and subsequent studies have shown a dose dependent adverse effect on lung parenchyma by vitamin E acetate, including toxicity to type II pneumocytes, and increased inflammatory cytokines. 143 Mice exposed to aerosols containing vitamin E acetate developed LLM and increased alveolar protein content, suggesting epithelial injury. 140 143

The pathophysiological insult underlying vaping related lung injury may be multitudinous, including potentially compound effects from multiple ingredients comprising a vape aerosol. The heterogeneity of available vape solutions on the market further complicates efforts to pinpoint particular elements of the vape aerosol that may be pathogenic, as no two users are likely to be exposed to the same combination of vape solution products. Further, vape users may be exposed to vape solutions containing terpenes, medium chain triglycerides, or coconut oil, the effects of which on respiratory epithelium remain under investigation. 144

Lipid laden macrophages

Lipid laden alveolar macrophages have risen to prominence as potential markers of vaping related lung injury. Alveolar macrophages describe a scavenger white blood cell responsible for clearing alveolar spaces of particulate matter and modulating the inflammatory response in the lung parenchyma. 145 LLM describe alveolar macrophages that have phagocytosed fat containing deposits, as seen on Oil Red O staining, and have been described in a wide variety of pulmonary conditions, including aspiration, lipoid pneumonia, organizing pneumonia, and medication induced pneumonitis. 146 147 During the EVALI outbreak, LLM were identified in the alveolar spaces of affected patients, both in the BAL fluid and on both transbronchial and surgical lung biopsies. 148 149 Of 52 EVALI cases reported in the literature who underwent BAL, LLM were identified in over 80%. 19 100 101 148 149 150 151 152 153 Accordingly, attention turned to LLM as not only a potential marker of lung injury in EVALI, but as a possible contributor to lung inflammation itself. This concern was compounded by the frequent reported use of oil based THC vape products among EVALI patients, raising the possibility of lipid deposits in the alveolus resulting from inhalation of THC-containing vape aerosols. 154 The combination of LLM, acute lung injury, and inhalational exposure to an oil based substance raised the concern for exogenous lipoid pneumonia. 152 153 However, further evaluation of the radiographic and histopathologic findings failed to identify cardinal features that would support a diagnosis of exogenous lipoid pneumonia—namely, low attenuation areas on CT imaging and foreign body giant cells on histopathology. 155 156 However, differences in the particle size and distribution between vape aerosol exposure and traditional causes of lipoid pneumonia (ie, aspiration of a large volume of an oil-containing substance), could reasonably lead to differences in radiographic appearance, although this would not account for the lack of characteristic histopathologic features on biopsy that would support a diagnosis of lipoid pneumonia.

Recent work suggests that LLM reflect a non-specific marker of vaping, rather than a marker of lung injury. One study found that LLM were not unique to EVALI and could be identified in healthy vape pen users, as well as conventional cigarette smokers, but not in never smokers. 157 Interestingly, this work showed increased cytokines IL-4 and IL-10 among healthy vape users, suggesting that cigarette and vape pen use are associated with a pro-inflammatory state in the lung. 157 An alternative theory supports LLM presence reflecting macrophage clearance of intra-alveolar cell debris rather than exogenous lipid exposure. 149 150 Such a pattern would be in keeping with the role of alveolar macrophages as modulating the inflammatory response in the lung parenchyma. 158 Taken together, available data would support LLM serving as a non-specific marker of vape product use, rather than playing a direct role in vaping related lung injury pathogenesis. 102

Clinical aspects

A high index of suspicion is required in establishing a diagnosis of vaping related lung injury, and a general approach is summarized in figure 3 . Clinicians may consider the diagnosis when faced with a patient with new respiratory symptoms in the context of vape pen use, without an alternative cause to account for their symptoms. Suspicion should be especially high if respiratory complaints are coupled with constitutional and gastrointestinal symptoms. Patients may present with non-specific markers indicative of an ongoing inflammatory process: fevers, leukocytosis, elevated C reactive protein, or elevated erythrocyte sedimentation rate. 19

Flowchart outlining the procedure for diagnosing a vaping related lung injury

Vaping related lung injury is a diagnosis of exclusion. Chest imaging via radiograph or CT may identify a variety of patterns, although diffuse ground glass opacities remain the most common radiographic finding. Generally, patients with an abnormal chest radiograph should undergo a chest CT for further evaluation of possible vaping related lung injury.

Exclusion of infectious causes is recommended. Testing should include evaluation for bacterial and viral causes of pneumonia, as deemed appropriate by clinical judgment and epidemiological data. Exclusion of common viral causes of pneumonia is imperative, particularly influenza and SARS-CoV-2. Bronchoscopy with BAL should be considered on a case-by-case basis for those with more severe disease and may be helpful to identify patients with vaping mediated eosinophilic lung injury. Further, lung biopsy may be beneficial to exclude alternative causes of lung injury in severe cases. 92

No definitive therapy has been identified for the treatment of vaping related lung injury, and data are limited to case reports and public health guidance on the topic. Management includes supportive care and strong consideration for systemic corticosteroids for severe cases of vaping related lung injury. CDC guidance encourages consideration of systemic corticosteroids for patients requiring admission to hospital, or those with higher risk factors for adverse outcomes, including age over 50, immunosuppressed status, or underlying cardiopulmonary disease. 100 Further, given case reports of vaping mediated acute eosinophilic pneumonia, steroids should be implemented in those patients who have undergone a confirmatory BAL. 77 79

Additional therapeutic options include empiric antibiotics and/or antivirals, depending on the clinical scenario. For patients requiring admission to hospital, prompt subspecialty consultation with a pulmonologist can help guide management. Outpatient follow-up with chest imaging and spirometry is recommended, as well as referral to a pulmonologist. Counseling regarding vaping cessation is also a core component in the post-discharge care for this patient population. Interventions specific to vaping cessation remain under investigation; however, literature supports the use of behavioral counseling and/or pharmacotherapy to support nicotine cessation efforts. 66

Health outcomes among vape pen users

Health outcomes among chronic vape pen users remains an open question. To date, no large scale prospective cohort studies exist that can establish a causal link between vape use and adverse respiratory outcomes. One small scale prospective cohort study did not identify any spirometric or radiographic changes among vape pen users over a 3.5 year period. 159 Given that vaping remains a relatively novel phenomenon, many users will have a less than 10 “pack year” history of vape pen use, arguably too brief an exposure period to reflect the potential harmful nature of chronic vaping. Studies encompassing a longer period of observation of vape pen users have not yet taken place, although advances in electronic medical record (EMR) data collection on vaping habits make such work within reach.

Current understanding of the health effects of vaping is largely limited to case reports of acute lung injury, and health surveys drawing associations between vaping exposure and patient reported outcomes. Within these limitations, however, early work suggests a correlation between vape pen use and poorer cardiopulmonary outcomes. Survey studies of teens who regularly vape found increased frequencies of respiratory symptoms, including productive cough, that were independent of smoking status. 160 161 These findings were corroborated in a survey series identifying more severe asthma symptoms and more days of school missed owing to asthma among vape pen users, regardless of cigarette smoking status. 162 163 164 Studies among adults have shown a similar pattern, with increased prevalence of chronic respiratory conditions (ie, asthma or chronic obstructive pulmonary disease) among vape pen users, 165 166 and higher risk of myocardial infarction and stroke, but lower risk of diabetes. 167

The effects of vaping on lung function as determined by spirometric studies are more varied. Reported studies have assessed lung function after a brief exposure to vape aerosols, varying from 5-60 minutes in duration, and no longer term observational cohort studies exist. While some studies have shown increased airway resistance after vaping exposure, 130 168 169 others have shown no change in lung function. 137 170 171 The cumulative exposure of habitual vape pen users to vape aerosols is much longer than the period evaluated in these studies, and the impact of vaping on longer term respiratory heath remains to be seen. Recent work evaluating ventilation-perfusion matching among chronic vapers compared with healthy controls found increased ventilation-perfusion mismatch, despite normal spirometry in both groups. 172 Such work reinforces the notion that changes in spirometry are a feature of more advanced airways disease, and early studies, although inconsistent, may foreshadow future respiratory impairment in chronic vapers.

Covid-19 and vaping

The covid-19 pandemic brought renewed attention to the potential health impacts of vaping. Studies investigating the role of vaping in covid-19 prevalence and outcomes have been limited by the small size of the populations studied and results have been inconsistent. Early work noted a geographic association in the US between vaping prevalence and covid-19 cases, 173 and a subsequent survey study found that a covid-19 diagnosis was five times more likely among teens who had ever vaped. 174 In contrast, a UK survey study found no association between vaping status and covid-19 infection rates, although captured a much smaller population of vape pen users. 175 Reports of nicotine use upregulating the angiotensin converting enzyme 2 (ACE-2) receptor, 176 which serves as the binding site for SARS-CoV-2 entry, raised the possibility of increased susceptibility to covid-19 among chronic nicotine vape pen users. 177 178 Further, vape use associated with sharing devices and frequent touching of the mouth and face were posited as potential confounders contributing to increased prevalence of covid-19 in this population. 179

Covid-19 outcomes among chronic vape pen users remain an open question. While smoking has been associated with progression to more severe infections, 180 181 no investigation has been performed to date among vaping cohorts. The young average age of chronic vape pen users may prove a protective factor, as risk of severe covid-19 infection has been shown to increase with age. 182 Regardless, a prudent recommendation remains to abstain from vaping to mitigate risk of progression to severe covid-19 infection. 183

Increased awareness of respiratory health brought about by covid-19 and EVALI is galvanizing the changing patterns in vape pen use. 184 Survey studies have consistently shown trends toward decreasing use among adolescents and young adults. 174 185 186 In one study, up to two thirds of participants endorsed decreasing or quitting vaping owing to a combination of factors including difficulty purchasing vape products during the pandemic, concerns about vaping effects on lung health, and difficulty concealing vape use while living with family. 174 Such results are reflected in nationwide trends that show halting growth in vaping use among high school students. 8 These trends are encouraging in that public health interventions countering nicotine use among teens may be meeting some measure of success.

Clinical impact—collecting and recording a vaping history

Vaping history in electronic medical records.

Efforts to prevent, diagnose, and treat vaping related lung injury begin with the ability of our healthcare system to identify vape users. Since vaping related lung injury remains a diagnosis of exclusion, clinicians must have a high index of suspicion when confronted with idiopathic lung injury in a patient with vaping exposure. Unlike cigarette use, vape pen use is not built into most EMR systems, and is not included in meaningful use criteria for EMRs. 187 Retrospective analysis of outpatient visits showed that a vaping history was collected in less than 0.1% of patients in 2015, 188 although this number has been increasing. 189 190 In part augmented by EMR frameworks that prompt collection of data on vaping history, more recent estimates indicate that a vaping history is being collected in up to 6% of patients. 191 Compared with the widespread use of vaping, particularly among adolescent and young adult populations, this number remains low. Considering generational trends in nicotine use, vaping will likely eventually overcome cigarettes as the most common mode of nicotine use, raising the importance of collecting a vaping related history. Further, EMR integration of vaping history is imperative to allow for retrospective, large scale analyses of vape exposure on longitudinal health outcomes at a population level.

Practical considerations—gathering a vaping history

As vaping becomes more common, the clinician’s ability to accurately collect a vaping history and identify patients who may benefit from nicotine cessation programs becomes more important. Reassuringly, gathering a vaping history is not dissimilar to asking about smoking and use of other tobacco products, and is summarized in box 2 . Collecting a vaping history is of particular importance for providers caring for adolescents and young adults who are among the highest risk demographics for vape pen use. Adolescents and young adults may be reluctant to share their vaping history, particularly if they are using THC-containing or CBD-containing vape solutions. Familiarity with vernacular terms to describe vaping, assuming a non-judgmental approach, and asking parents or guardians to step away during history taking will help to break down these barriers. 192

Practical guide to collecting a vaping history

Ask with empathy.

Young adults may be reluctant to share history of vaping use. Familiarity with vaping terminology, asking in a non-judgmental manner, and asking in a confidential space may help.

Ask what they are vaping

Vape products— vape pens commonly contain nicotine or an alternative active ingredient, such as THC or CBD. Providers may also inquire about flavorants, or other vape solution additives, that their patient is consuming, particularly if vaping related lung injury is suspected.

Source— ask where they source their product from. Sources may include commercially available products, third party distributors, or friends or local contacts.

Ask how they are vaping

Device— What style of device are they using?

Frequency— How many times a day do they use their vape pen (with frequent use considered >5 times a day)? Alternatively, providers may inquire how long it takes to deplete a vape solution cartridge (with use of one or more pods a day considered heavy use).

Nicotine concentration— For individuals consuming nicotine-containing products, clinicians may inquire about concentration and frequency of use, as this may allow for development of a nicotine replacement therapy plan.

Ask about other inhaled products

Clinicians should ask patients who vape about use of other inhaled products, particularly cigarettes. Further, clinicians may ask about use of water pipes, heat-not-burn devices, THC-containing products, or dabbing.

The following provides a practical guide on considerations when collecting a vaping history. Of note, collecting a partial history is preferable to no history at all, and simply recording whether a patient is vaping or not adds valuable information to the medical record.

Vape use— age at time of vaping onset and frequency of vape pen use. Vape pen use >5 times a day would be considered frequent. Alternatively, clinicians may inquire how long it takes to deplete a vape solution pod (use of one or more pods a day would be considered heavy use), or how frequently users are refilling their vape pens for refillable models.

Vape products— given significant variation in vape solutions available on the market, and variable risk profiles of the multitude of additives, inquiring as to which products a patient is using may add useful information. Further, clinicians may inquire about use of nicotine versus THC-containing vape solutions, and whether said products are commercially available or are customized by third party sellers.

Concurrent smoking— simultaneous use of multiple inhaled products is common among vape users, including concurrent use of conventional cigarettes, water pipes, heat-not-burn devices, and THC-containing or CBD-containing products. Among those using marijuana products, gathering a history regarding the type of product use, the device, and the modality of aerosol generation may be warranted. Gathering such detailed information may be challenging in the face of rapidly evolving product availability and changing popular terminology. Lastly, clinicians may wish to inquire about “dabbing”—the practice of inhaling heated butane hash oil, a concentrated THC wax—which may also be associated with lung injury. 193

Future directions

Our understanding of the effects of vaping on respiratory health is in its early stages and multiple trials are under way. Future work requires enhanced understanding of the effects of vape aerosols on lung biology, such as ongoing investigations into biomarkers of oxidative stress and inflammation among vape users (clinicaltrials.gov NCT03823885 ). Additional studies seek to elucidate the relation between vape aerosol exposure and cardiopulmonary outcomes among vape pen users ( NCT03863509 , NCT05199480 ), while an ongoing prospective cohort study will allow for longitudinal assessment of airway reactivity and spirometric changes among chronic vape pen users ( NCT04395274 ).

Public health and policy interventions are vital in supporting both our understanding of vaping on respiratory health and curbing the vaping epidemic among teens. Ongoing, large scale randomized controlled studies seek to assess the impact of the FDA’s “The Real Cost” advertisement campaign for vaping prevention ( NCT04836455 ) and another trial is assessing the impact of a vaping prevention curriculum among adolescents ( NCT04843501 ). Current trials are seeking to understand the potential for various therapies as tools for vaping cessation, including nicotine patches ( NCT04974580 ), varenicline ( NCT04602494 ), and text message intervention ( NCT04919590 ).

Finally, evaluation of vaping as a potential tool for harm reduction among current cigarette smokers is undergoing further evaluation ( NCT03235505 ), which will add to the body of work and eventually lead to clear policy guidance.

Several guidelines on the management of vaping related lung injury have been published and are summarized in table 1 . 194 195 196 Given the relatively small number of cases, the fact that vaping related lung injury remains a newer clinical entity, and the lack of clinical trials on the topic, guideline recommendations reflect best practices and expert opinion. Further, published guidelines focus on the diagnosis and management of EVALI, and no guidelines exist to date for the management of vaping related lung injury more generally.

Summary of clinical guidelines

• View inline

Conclusions

Vaping has grown in popularity internationally over the past decade, in part propelled by innovations in vape pen design and nicotine flavoring. Teens and young adults have seen the biggest uptake in use of vape pens, which have superseded conventional cigarettes as the preferred modality of nicotine consumption. Despite their widespread popularity, relatively little is known about the potential effects of chronic vaping on the respiratory system, and a growing body of literature supports the notion that vaping is not without risk. The 2019 EVALI outbreak highlighted the potential harms of vaping, and the consequences of long term use remain unknown.

Discussions regarding the potential harms of vaping are reminiscent of scientific debates about the health effects of cigarette use in the 1940s. Interesting parallels persist, including the fact that only a minority of conventional cigarette users develop acute lung injury, yet the health impact of sustained, longitudinal cigarette use is unquestioned. The true impact of vaping on respiratory health will manifest over the coming decades, but in the interval a prudent and time tested recommendation remains to abstain from consumption of inhaled nicotine and other products.

Questions for future research

How does chronic vape aerosol exposure affect respiratory health?

Does use of vape pens affect respiratory physiology (airway resistance, V/Q matching, etc) in those with underlying lung disease?

What is the role for vape pen use in promoting smoking cessation?

What is the significance of pulmonary alveolar macrophages in the pathophysiology of vaping related lung injury?

Are particular populations more susceptible to vaping related lung injury (ie, by sex, demographic, underlying comorbidity, or age)?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: AJ conceived of, researched, and wrote the piece. She is the guarantor.

Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: AJ receives consulting fees from DawnLight, Inc for work unrelated to this piece.

Patient involvement: No patients were directly involved in the creation of this article.

Provenance and peer review: Commissioned; externally peer reviewed.

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Wednesday, October 26, 2022

NIH-funded studies show damaging effects of vaping, smoking on blood vessels

Combining e-cigarettes with regular cigarettes may increase health risks.

Long-term use of electronic cigarettes, or vaping products, can significantly impair the function of the body’s blood vessels, increasing the risk for cardiovascular disease. Additionally, the use of both e-cigarettes and regular cigarettes may cause an even greater risk than the use of either of these products alone. These findings come from two new studies supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH).  

The findings, which appear today in the journal  Arteriosclerosis, Thrombosis, and Vascular Biology , add to growing evidence that long-term use of e-cigarettes can harm a person’s health. Researchers have known for years that tobacco smoking can cause damage to blood vessels. However, the effects of e-cigarettes on cardiovascular health have been poorly understood. The two new studies – one on humans, the other on rats – aimed to change that.

“In our human study, we found that chronic e-cigarettes users had impaired blood vessel function, which may put them at increased risk for heart disease,” said Matthew L. Springer, Ph.D., a professor of medicine in the Division of Cardiology at the University of California in San Francisco, and leader of both studies. “It indicates that chronic users of e-cigarettes may experience a risk of vascular disease similar to that of chronic smokers.” 

In this first study, Springer and his colleagues collected blood samples from a group of 120 volunteers that included those with long-term e-cigarette use, long-term cigarette smoking, and those who didn't use. The researchers defined long-term e-cigarette use as more than five times/week for more than three months and defined long-term cigarette use as smoking more than five cigarettes per day.

They then exposed each of the blood samples to cultured human blood vessel (endothelial) cells in the laboratory and measured the release of nitric oxide, a chemical marker used to evaluate proper functioning of endothelial cells. They also tested cell permeability, the ability of molecules to pass through a layer of cells to the other side. Too much permeability makes vessels leaky, which impairs function and increases the risk for cardiovascular disease.

The researchers found that blood from participants who used e-cigarettes and those who smoked caused a significantly greater decrease in nitric oxide production by the blood vessel cells than the blood of nonusers. Notably, the researchers found that blood from those who used e-cigarettes also caused more permeability in the blood vessel cells than the blood from both those who smoked cigarettes and nonusers. Blood from those that used e-cigarettes also caused a greater release of hydrogen peroxide by the blood vessel cells than the blood of the nonusers. Each of these three factors can contribute to impairment of blood vessel function in people who use e-cigarettes, the researchers said.

In addition, Springer and his team discovered that e-cigarettes had harmful cardiovascular effects in ways that were different from those caused by tobacco smoke. Specifically, they found that blood from people who smoked cigarettes had higher levels of certain circulating biomarkers of cardiovascular risks, and the blood people who used e-cigarettes had elevated levels of other circulating biomarkers of cardiovascular risks.

“These findings suggest that using the two products together, as many people do, could increase their health risks compared to using them individually,” Springer said.  “We had not expected to see that.”

In the second study, the researchers tried to find out if there were specific components of cigarette smoke or e-cigarette vapor that were responsible for blood vessel damage. In studies using rats, they exposed the animals to various substances found in tobacco smoke or e-cigarettes. These included nicotine, menthol (a cigarette additive), the gases acrolein and acetaldehyde (two chemicals found in both tobacco smoke and e-cigarette vapors), and inert carbon nanoparticles to represent the particle-like nature of smoke and e-cigarette vapor.

Using special arterial flow measurements, the researchers demonstrated that blood vessel damage does not appear to be caused by a specific component of cigarette smoke or e-cigarette vapor. Instead, they said, it appears to be caused by airway irritation that triggers biological signals in the vagus nerve that somehow leads to blood vessel damage, possibly through an inflammatory process. The vagus is a long nerve extending from the brain that connects the airway to the rest of the nervous system and plays a key role in heart rate, breathing, and other functions. The researchers showed that detaching the nerve in rats prevented blood vessel damage caused by tobacco smoke, demonstrating its key role in this process. 

“We were surprised to find that there was not a single component that you could remove to stop the damaging effect of smoke or vapors on the blood vessels,” Springer said. “As long as there’s an irritant in the airway, blood vessel function may be impaired.”   

The finding has implications for efforts to regulate tobacco products and e-cigarettes, as it underscores how difficult it is to pinpoint any one ingredient in them that is responsible for blood vessel damage. “What I like to tell people is this: Just breathe clean air and avoid using these products,” Springer said.

Lisa Postow, Ph.D., an NHLBI program officer in NHLBI’s Division of Lung Diseases, agreed that the study results “provide further evidence that exposure to e-cigarettes could lead to harmful cardiovascular health effects.” She added that more data is needed to fully understand the health effects of e-cigarettes. The NIH and others are continuing to explore this area.

Research reported in the e-cigarette study was funded by NHLBI grants U54HL147127, P50HL120163, and R01HL120062 and the U.S. Food and Drug Administration Center for Tobacco Products (FDA CTP); and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. Research reported in the cigarette smoke/-vagal nerve study was supported by NHLBI grants R01HL120062 and U54HL147127 and FDA CTP and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. For additional funding details, please see the full journal articles.

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit www.nhlbi.nih.gov .   

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Chronic e-cigarette use impairs endothelial function on the physiological and cellular levels. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.121.317749

Impairment of Endothelial Function by Cigarette Smoke is not Caused by a Specific Smoke Constituent, but by Vagal Input from the Airway. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.122.318051

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• Laura Piqueras   ORCID: orcid.org/0000-0001-8010-5168 1 , 2 , 3 &
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The electronic cigarette ( e-cigarette ), for many considered as a safe alternative to conventional cigarettes, has revolutionised the tobacco industry in the last decades. In e-cigarettes , tobacco combustion is replaced by e-liquid heating, leading some manufacturers to propose that e-cigarettes have less harmful respiratory effects than tobacco consumption. Other innovative features such as the adjustment of nicotine content and the choice of pleasant flavours have won over many users. Nevertheless, the safety of e-cigarette consumption and its potential as a smoking cessation method remain controversial due to limited evidence. Moreover, it has been reported that the heating process itself can lead to the formation of new decomposition compounds of questionable toxicity. Numerous in vivo and in vitro studies have been performed to better understand the impact of these new inhalable compounds on human health. Results of toxicological analyses suggest that e-cigarettes can be safer than conventional cigarettes, although harmful effects from short-term e-cigarette use have been described. Worryingly, the potential long-term effects of e-cigarette consumption have been scarcely investigated. In this review, we take stock of the main findings in this field and their consequences for human health including coronavirus disease 2019 (COVID-19).

Electronic nicotine dispensing systems (ENDS), commonly known as electronic cigarettes or e-cigarettes , have been popularly considered a less harmful alternative to conventional cigarette smoking since they first appeared on the market more than a decade ago. E-cigarettes are electronic devices, essentially consisting of a cartridge, filled with an e-liquid, a heating element/atomiser necessary to heat the e-liquid to create a vapour that can be inhaled through a mouthpiece, and a rechargeable battery (Fig.  1 ) [ 1 , 2 ]. Both the electronic devices and the different e-liquids are easily available in shops or online stores.

Effect of the heating process on aerosol composition. Main harmful effects documented. Several compounds detected in e-cigarette aerosols are not present in e-liquid s and the device material also seems to contribute to the presence of metal and silicate particles in the aerosols. The heating conditions especially on humectants, flavourings and the low-quality material used have been identified as the generator of the new compounds in aerosols. Some compounds generated from humectants (propylene glycol and glycerol) and flavourings, have been associated with clear airways impact, inflammation, impairment of cardiovascular function and toxicity. In addition, some of them are carcinogens or potential carcinogens

The e-liquid typically contains humectants and flavourings, with or without nicotine; once vapourised by the atomiser, the aerosol (vapour) provides a sensation similar to tobacco smoking, but purportedly without harmful effects [ 3 ]. However, it has been reported that the heating process can lead to the generation of new decomposition compounds that may be hazardous [ 4 , 5 ]. The levels of nicotine, which is the key addictive component of tobacco, can also vary between the commercially available e-liquids, and even nicotine-free options are available. For this particular reason, e-cigarettes are often viewed as a smoking cessation tool, given that those with nicotine can prevent smoking craving, yet this idea has not been fully demonstrated [ 2 , 6 , 7 ].

Because e-cigarettes are combustion-free, and because most of the damaging and well-known effects of tobacco are derived from this reaction, there is a common and widely spread assumption that e-cigarette consumption or “vaping” is safer than conventional cigarette smoking. However, are they risk-free? Is there sufficient toxicological data on all the components employed in e-liquids ? Do we really know the composition of the inhaled vapour during the heating process and its impact on health? Can e-cigarettes be used to curb tobacco use? Do their consumption impact on coronavirus disease 2019 (COVID-19)? In the present review, we have attempted to clarify these questions based on the existing scientific literature, and we have compiled new insights related with the toxicity derived from the use of these devices.

Effect of e-cigarette vapour versus conventional cigarette exposure: in vivo and in vitro effects

Numerous studies have been performed to evaluate the safety/toxicity of e-cigarette use both in vivo and in in vitro cell culture.

One of the first studies in humans involved the analysis of 9 volunteers that consumed e-cigarettes , with or without nicotine, in a ventilated room for 2 h [ 8 ]. Pollutants in indoor air, exhaled nitric oxide (NO) and urinary metabolite profiles were analysed. The results of this acute experiment revealed that e-cigarettes are not emission-free, and ultrafine particles formed from propylene glycol (PG) could be detected in the lungs. The study also suggested that the presence of nicotine in e-cigarettes increased the levels of NO exhaled from consumers and provoked marked airway inflammation; however, no differences were found in the levels of exhaled carbon monoxide (CO), an oxidative stress marker, before and after e-cigarette consumption [ 8 ]. A more recent human study detected significantly higher levels of metabolites of hazardous compounds including benzene, ethylene oxide, acrylonitrile, acrolein and acrylamide in the urine of adolescent dual users ( e-cigarettes and conventional tobacco consumers) than in adolescent e-cigarette -only users (Table 1 ) [ 9 ]. Moreover, the urine levels of metabolites of acrylonitrile, acrolein, propylene oxide, acrylamide and crotonaldehyde, all of which are detrimental for human health, were significantly higher in e-cigarette -only users than in non-smoker controls, reaching up to twice the registered values of those from non-smoker subjects (Table 1 ) [ 9 ]. In line with these observations, dysregulation of lung homeostasis has been documented in non-smokers subjected to acute inhalation of e-cigarette aerosols [ 10 ].

Little is known about the effect of vaping on the immune system. Interestingly, both traditional and e-cigarette consumption by non-smokers was found to provoke short-term effects on platelet function, increasing platelet activation (levels of soluble CD40 ligand and the adhesion molecule P-selectin) and platelet aggregation, although to a lesser extent with e-cigarettes [ 11 ]. As found with platelets, the exposure of neutrophils to e-cigarette aerosol resulted in increased CD11b and CD66b expression being both markers of neutrophil activation [ 12 ]. Additionally, increased oxidative stress, vascular endothelial damage, impaired endothelial function, and changes in vascular tone have all been reported in different human studies on vaping [ 13 , 14 , 15 , 16 , 17 ]. In this context, it is widely accepted that platelet and leukocyte activation as well as endothelial dysfunction are associated with atherogenesis and cardiovascular morbidity [ 18 , 19 ]. In line with these observations the potential association of daily e-cigarettes consumption and the increased risk of myocardial infarction remains controversial but benefits may occur when switching from tobacco to chronic e-cigarette use in blood pressure regulation, endothelial function and vascular stiffness (reviewed in [ 20 ]). Nevertheless, whether or not e-cigarette vaping has cardiovascular consequences requires further investigation.

More recently, in August 2019, the US Centers for Disease Control and Prevention (CDC) declared an outbreak of the e-cigarette or vaping product use-associated lung injury (EVALI) which caused several deaths in young population (reviewed in [ 20 ]). Indeed, computed tomography (CT scan) revealed local inflammation that impaired gas exchange caused by aerosolised oils from e-cigarettes [ 21 ]. However, most of the reported cases of lung injury were associated with use of e-cigarettes for tetrahydrocannabinol (THC) consumption as well as vitamin E additives [ 20 ] and not necessarily attributable to other e-cigarette components.

On the other hand, in a comparative study of mice subjected to either lab air, e-cigarette aerosol or cigarette smoke (CS) for 3 days (6 h-exposure per day), those exposed to e-cigarette aerosols showed significant increases in interleukin (IL)-6 but normal lung parenchyma with no evidence of apoptotic activity or elevations in IL-1β or tumour necrosis factor-α (TNFα) [ 22 ]. By contrast, animals exposed to CS showed lung inflammatory cell infiltration and elevations in inflammatory marker expression such as IL-6, IL-1β and TNFα [ 22 ]. Beyond airway disease, exposure to aerosols from e-liquids with or without nicotine has also been also associated with neurotoxicity in an early-life murine model [ 23 ].

Results from in vitro studies are in general agreement with the limited number of in vivo studies. For example, in an analysis using primary human umbilical vein endothelial cells (HUVEC) exposed to 11 commercially-available vapours, 5 were found to be acutely cytotoxic, and only 3 of those contained nicotine [ 24 ]. In addition, 5 of the 11 vapours tested (including 4 that were cytotoxic) reduced HUVEC proliferation and one of them increased the production of intracellular reactive oxygen species (ROS) [ 24 ]. Three of the most cytotoxic vapours—with effects similar to those of conventional high-nicotine CS extracts—also caused comparable morphological changes [ 24 ]. Endothelial cell migration is an important mechanism of vascular repair than can be disrupted in smokers due to endothelial dysfunction [ 25 , 26 ]. In a comparative study of CS and e-cigarette aerosols, Taylor et al . found that exposure of HUVEC to e-cigarette aqueous extracts for 20 h did not affect migration in a scratch wound assay [ 27 ], whereas equivalent cells exposed to CS extract showed a significant inhibition in migration that was concentration dependent [ 27 ].

In cultured human airway epithelial cells, both e-cigarette aerosol and CS extract induced IL-8/CXCL8 (neutrophil chemoattractant) release [ 28 ]. In contrast, while CS extract reduced epithelial barrier integrity (determined by the translocation of dextran from the apical to the basolateral side of the cell layer), e-cigarette aerosol did not, suggesting that only CS extract negatively affected host defence [ 28 ]. Moreover, Higham et al . also found that e-cigarette aerosol caused IL-8/CXCL8 and matrix metallopeptidase 9 (MMP-9) release together with enhanced activity of elastase from neutrophils [ 12 ] which might facilitate neutrophil migration to the site of inflammation [ 12 ].

In a comparative study, repeated exposure of human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates led to alterations in morphology, suppression of proliferation and induction of apoptosis, with changes in all three parameters greater in cells exposed to CS condensate [ 29 ]. Likewise, both e-cigarette aerosol and CS extract increased cell death in adenocarcinomic human alveolar basal epithelial cells (A549 cells), and again the effect was more damaging with CS extract than with e-cigarette aerosol (detrimental effects found at 2 mg/mL of CS extract vs. 64 mg/mL of e-cigarette extract) [ 22 ], which is in agreement with another study examining battery output voltage and cytotoxicity [ 30 ].

All this evidence would suggest that e-cigarettes are potentially less harmful than conventional cigarettes (Fig.  2 ) [ 11 , 14 , 22 , 24 , 27 , 28 , 29 ]. Importantly, however, most of these studies have investigated only short-term effects [ 10 , 14 , 15 , 22 , 27 , 28 , 29 , 31 , 32 ], and the long-term effects of e-cigarette consumption on human health are still unclear and require further study.

Comparison of the degree of harmful effects documented from e-cigarette and conventional cigarette consumption. Human studies, in vivo mice exposure and in vitro studies. All of these effects from e-cigarettes were documented to be lower than those exerted by conventional cigarettes, which may suggest that e-cigarette consumption could be a safer option than conventional tobacco smoking but not a clear safe choice

Consequences of nicotine content

Beyond flavour, one of the major issues in the e-liquid market is the range of nicotine content available. Depending on the manufacturer, the concentration of this alkaloid can be presented as low , medium or high , or expressed as mg/mL or as a percentage (% v/v). The concentrations range from 0 (0%, nicotine-free option) to 20 mg/mL (2.0%)—the maximum nicotine threshold according to directive 2014/40/EU of the European Parliament and the European Union Council [ 33 , 34 ]. Despite this normative, however, some commercial e-liquids have nicotine concentrations close to 54 mg/mL [ 35 ], much higher than the limits established by the European Union.

The mislabelling of nicotine content in e-liquids has been previously addressed [ 8 , 34 ]. For instance, gas chromatography with a flame ionisation detector (GC-FID) revealed inconsistencies in the nicotine content with respect to the manufacturer´s declaration (average of 22 ± 0.8 mg/mL vs. 18 mg/mL) [ 8 ], which equates to a content ~ 22% higher than that indicated in the product label. Of note, several studies have detected nicotine in those e-liquids labelled as nicotine-free [ 5 , 35 , 36 ]. One study detected the presence of nicotine (0.11–6.90 mg/mL) in 5 of 23 nicotine-free labelled e-liquids by nuclear magnetic resonance spectroscopy [ 35 ], and another study found nicotine (average 8.9 mg/mL) in 13.6% (17/125) of the nicotine-free e-liquids as analysed by high performance liquid chromatography (HPLC) [ 36 ]. Among the 17 samples tested in this latter study 14 were identified to be counterfeit or suspected counterfeit. A third study detected nicotine in 7 of 10 nicotine-free refills, although the concentrations were lower than those identified in the previous analyses (0.1–15 µg/mL) [ 5 ]. Not only is there evidence of mislabelling of nicotine content among refills labelled as nicotine-free, but there also seems to be a history of poor labelling accuracy in nicotine-containing e-liquids [ 37 , 38 ].

A comparison of the serum levels of nicotine from e-cigarette or conventional cigarette consumption has been recently reported [ 39 ]. Participants took one vape from an e-cigarette , with at least 12 mg/mL of nicotine, or inhaled a conventional cigarette, every 20 s for 10 min. Blood samples were collected 1, 2, 4, 6, 8, 10, 12 and 15 min after the first puff, and nicotine serum levels were measured by liquid chromatography-mass spectrometry (LC–MS). The results revealed higher serum levels of nicotine in the conventional CS group than in the e-cigarette group (25.9 ± 16.7 ng/mL vs. 11.5 ± 9.8 ng/mL). However, e-cigarettes containing 20 mg/mL of nicotine are more equivalent to normal cigarettes, based on the delivery of approximately 1 mg of nicotine every 5 min [ 40 ].

In this line, a study compared the acute impact of CS vs. e-cigarette vaping with equivalent nicotine content in healthy smokers and non-smokers. Both increased markers of oxidative stress and decreased NO bioavailability, flow-mediated dilation, and vitamin E levels showing no significant differences between tobacco and e-cigarette exposure (reviewed in [ 20 ]). Inasmuch, short-term e-cigarette use in healthy smokers resulted in marked impairment of endothelial function and an increase in arterial stiffness (reviewed in [ 20 ]). Similar effects on endothelial dysfunction and arterial stiffness were found in animals when they were exposed to e-cigarette vapor either for several days or chronically (reviewed in [ 20 ]). In contrast, other studies found acute microvascular endothelial dysfunction, increased oxidative stress and arterial stiffness in smokers after exposure to e-cigarettes with nicotine, but not after e-cigarettes without nicotine (reviewed in [ 20 ]). In women smokers, a study found a significant difference in stiffness after smoking just one tobacco cigarette, but not after use of e-cigarettes (reviewed in [ 20 ]).

It is well known that nicotine is extremely addictive and has a multitude of harmful effects. Nicotine has significant biologic activity and adversely affects several physiological systems including the cardiovascular, respiratory, immunological and reproductive systems, and can also compromise lung and kidney function [ 41 ]. Recently, a sub-chronic whole-body exposure of e-liquid (2 h/day, 5 days/week, 30 days) containing PG alone or PG with nicotine (25 mg/mL) to wild type (WT) animals or knockout (KO) mice in α7 nicotinic acetylcholine receptor (nAChRα7-KO) revealed a partly nAChRα7-dependent lung inflammation [ 42 ]. While sub-chronic exposure to PG/nicotine promote nAChRα7-dependent increased levels of different cytokines and chemokines in the bronchoalveolar lavage fluid (BALF) such as IL-1α, IL-2, IL-9, interferon γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1/CCL2) and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), the enhanced levels of IL-1β, IL-5 and TNFα were nAChRα7 independent. In general, most of the cytokines detected in BALF were significantly increased in WT mice exposed to PG with nicotine compared to PG alone or air control [ 42 ]. Some of these effects were found to be through nicotine activation of NF-κB signalling albeit in females but not in males. In addition, PG with nicotine caused increased macrophage and CD4 + /CD8 + T-lymphocytes cell counts in BALF compared to air control, but these effects were ameliorated when animals were sub-chronically exposed to PG alone [ 42 ].

Of note, another study indicated that although RANTES/CCL5 and CCR1 mRNA were upregulated in flavour/nicotine-containing e-cigarette users, vaping flavour and nicotine-less e-cigarettes did not significantly dysregulate cytokine and inflammasome activation [ 43 ].

In addition to its toxicological effects on foetus development, nicotine can disrupt brain development in adolescents and young adults [ 44 , 45 , 46 ]. Several studies have also suggested that nicotine is potentially carcinogenic (reviewed in [ 41 ]), but more work is needed to prove its carcinogenicity independently of the combustion products of tobacco [ 47 ]. In this latter regard, no differences were encountered in the frequency of tumour appearance in rats subjected to long-term (2 years) inhalation of nicotine when compared with control rats [ 48 ]. Despite the lack of carcinogenicity evidence, it has been reported that nicotine promotes tumour cell survival by decreasing apoptosis and increasing proliferation [ 49 ], indicating that it may work as a “tumour enhancer”. In a very recent study, chronic administration of nicotine to mice (1 mg/kg every 3 days for a 60-day period) enhanced brain metastasis by skewing the polarity of M2 microglia, which increases metastatic tumour growth [ 50 ]. Assuming that a conventional cigarette contains 0.172–1.702 mg of nicotine [ 51 ], the daily nicotine dose administered to these animals corresponds to 40–400 cigarettes for a 70 kg-adult, which is a dose of an extremely heavy smoker. We would argue that further studies with chronic administration of low doses of nicotine are required to clearly evaluate its impact on carcinogenicity.

In the aforementioned study exposing human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates [ 29 ], the detrimental effects were greater in cells exposed to nicotine-rich condensate than to nicotine-free condensate, suggesting that the possible injurious effects of nicotine should be considered when purchasing e-refills . It is also noteworthy that among the 3 most cytotoxic vapours for HUVEC evaluated in the Putzhammer et al . study, 2 were nicotine-free, which suggests that nicotine is not the only hazardous component in e-cigarettes [ 24 ] .

The lethal dose of nicotine for an adult is estimated at 30–60 mg [ 52 ]. Given that nicotine easily diffuses from the dermis to the bloodstream, acute nicotine exposure by e-liquid spilling (5 mL of a 20 mg/mL nicotine-containing refill is equivalent to 100 mg of nicotine) can easily be toxic or even deadly [ 8 ]. Thus, devices with rechargeable refills are another issue of concern with e-cigarettes , especially when e-liquids are not sold in child-safe containers, increasing the risk of spilling, swallowing or breathing.

These data overall indicate that the harmful effects of nicotine should not be underestimated. Despite the established regulations, some inaccuracies in nicotine content labelling remain in different brands of e-liquids . Consequently, stricter regulation and a higher quality control in the e-liquid industry are required.

Effect of humectants and their heating-related products

In this particular aspect, again the composition of the e-liquid varies significantly among different commercial brands [ 4 , 35 ]. The most common and major components of e-liquids are PG or 1,2-propanediol, and glycerol or glycerine (propane-1,2,3-triol). Both types of compounds are used as humectants to prevent the e-liquid from drying out [ 2 , 53 ] and are classified by the Food and Drug Administration (FDA) as “Generally Recognised as Safe” [ 54 ]. In fact, they are widely used as alimentary and pharmaceutical products [ 2 ]. In an analysis of 54 commercially available e-liquids , PG and glycerol were detected in almost all samples at concentrations ranging from 0.4% to 98% (average 57%) and from 0.3% to 95% (average 37%), respectively [ 35 ].

With regards to toxicity, little is known about the effects of humectants when they are heated and chronically inhaled. Studies have indicated that PG can induce respiratory irritation and increase the probability of asthma development [ 55 , 56 ], and both PG and glycerol from e-cigarettes might reach concentrations sufficiently high to potentially cause irritation of the airways [ 57 ]. Indeed, the latter study established that one e-cigarette puff results in a PG exposure of 430–603 mg/m 3 , which is higher than the levels reported to cause airway irritation (average 309 mg/m 3 ) based on a human study [ 55 ]. The same study established that one e-cigarette puff results in a glycerol exposure of 348–495 mg/m 3 [ 57 ], which is close to the levels reported to cause airway irritation in rats (662 mg/m 3 ) [ 58 ].

Airway epithelial injury induced by acute vaping of PG and glycerol aerosols (50:50 vol/vol), with or without nicotine, has been reported in two randomised clinical trials in young tobacco smokers [ 32 ]. In vitro, aerosols from glycerol only-containing refills showed cytotoxicity in A549 and human embryonic stem cells, even at a low battery output voltage [ 59 ]. PG was also found to affect early neurodevelopment in a zebrafish model [ 60 ]. Another important issue is that, under heating conditions PG can produce acetaldehyde or formaldehyde (119.2 or 143.7 ng/puff at 20 W, respectively, on average), while glycerol can also generate acrolein (53.0, 1000.0 or 5.9 ng/puff at 20 W, respectively, on average), all carbonyls with a well-documented toxicity [ 61 ]. Although, assuming 15 puffs per e-cigarette unit, carbonyls produced by PG or glycerol heating would be below the maximum levels found in a conventional cigarette combustion (Table 2 ) [ 51 , 62 ]. Nevertheless, further studies are required to properly test the deleterious effects of all these compounds at physiological doses resembling those to which individuals are chronically exposed.

Although PG and glycerol are the major components of e-liquids other components have been detected. When the aerosols of 4 commercially available e-liquids chosen from a top 10 list of “ Best E-Cigarettes of 2014” , were analysed by gas chromatography-mass spectrometry (GC–MS) after heating, numerous compounds were detected, with nearly half of them not previously identified [ 4 ], thus suggesting that the heating process per se generates new compounds of unknown consequence. Of note, the analysis identified formaldehyde, acetaldehyde and acrolein [ 4 ], 3 carbonyl compounds with known high toxicity [ 63 , 64 , 65 , 66 , 67 ]. While no information was given regarding formaldehyde and acetaldehyde concentrations, the authors calculated that one puff could result in an acrolein exposure of 0.003–0.015 μg/mL [ 4 ]. Assuming 40 mL per puff and 15 puffs per e-cigarette unit (according to several manufacturers) [ 4 ], each e-cigarette unit would generate approximately 1.8–9 μg of acrolein, which is less than the levels of acrolein emitted by a conventional tobacco cigarette (18.3–98.2 μg) [ 51 ]. However, given that e-cigarette units of vaping are not well established, users may puff intermittently throughout the whole day. Thus, assuming 400 to 500 puffs per cartridge, users could be exposed to up to 300 μg of acrolein.

In a similar study, acrolein was found in 11 of 12 aerosols tested, with a similar content range (approximately 0.07–4.19 μg per e-cigarette unit) [ 68 ]. In the same study, both formaldehyde and acetaldehyde were detected in all of the aerosols tested, with contents of 0.2–5.61 μg and 0.11–1.36 μg, respectively, per e-cigarette unit [ 68 ]. It is important to point out that the levels of these toxic products in e-cigarette aerosols are significantly lower than those found in CS: 9 times lower for formaldehyde, 450 times lower for acetaldehyde and 15 times lower for acrolein (Table 2 ) [ 62 , 68 ].

Other compounds that have been detected in aerosols include acetamide, a potential human carcinogen [ 5 ], and some aldehydes [ 69 ], although their levels were minimal. Interestingly, the existence of harmful concentrations of diethylene glycol, a known cytotoxic agent, in e-liquid aerosols is contentious with some studies detecting its presence [ 4 , 68 , 70 , 71 , 72 ], and others finding low subtoxic concentrations [ 73 , 74 ]. Similar observations were reported for the content ethylene glycol. In this regard, either it was detected at concentrations that did not exceed the authorised limit [ 73 ], or it was absent from the aerosols produced [ 4 , 71 , 72 ]. Only one study revealed its presence at high concentration in a very low number of samples [ 5 ]. Nevertheless, its presence above 1 mg/g is not allowed by the FDA [ 73 ]. Figure  1 lists the main compounds detected in aerosols derived from humectant heating and their potential damaging effects. It would seem that future studies should analyse the possible toxic effects of humectants and related products at concentrations similar to those that e-cigarette vapers are exposed to reach conclusive results.

Impact of flavouring compounds

The range of e-liquid flavours available to consumers is extensive and is used to attract both current smokers and new e-cigarette users, which is a growing public health concern [ 6 ]. In fact, over 5 million middle- and high-school students were current users of e-cigarettes in 2019 [ 75 ], and appealing flavours have been identified as the primary reason for e-cigarette consumption in 81% of young users [ 76 ]. Since 2016, the FDA regulates the flavours used in the e-cigarette market and has recently published an enforcement policy on unauthorised flavours, including fruit and mint flavours, which are more appealing to young users [ 77 ]. However, the long-term effects of all flavour chemicals used by this industry (which are more than 15,000) remain unknown and they are not usually included in the product label [ 78 ]. Furthermore, there is no safety guarantee since they may harbour potential toxic or irritating properties [ 5 ].

With regards to the multitude of available flavours, some have demonstrated cytotoxicity [ 59 , 79 ]. Bahl et al. evaluated the toxicity of 36 different e-liquids and 29 different flavours on human embryonic stem cells, mouse neural stem cells and human pulmonary fibroblasts using a metabolic activity assay. In general, those e-liquids that were bubblegum-, butterscotch- and caramel-flavoured did not show any overt cytotoxicity even at the highest dose tested. By contrast, those e-liquids with Freedom Smoke Menthol Arctic and Global Smoke Caramel flavours had marked cytotoxic effects on pulmonary fibroblasts and those with Cinnamon Ceylon flavour were the most cytotoxic in all cell lines [ 79 ]. A further study from the same group [ 80 ] revealed that high cytotoxicity is a recurrent feature of cinnamon-flavoured e-liquids. In this line, results from GC–MS and HPLC analyses indicated that cinnamaldehyde (CAD) and 2-methoxycinnamaldehyde, but not dipropylene glycol or vanillin, were mainly responsible for the high cytotoxicity of cinnamon-flavoured e-liquids [ 80 ]. Other flavouring-related compounds that are associated with respiratory complications [ 81 , 82 , 83 ], such as diacetyl, 2,3-pentanedione or acetoin, were found in 47 out of 51 aerosols of flavoured e-liquids tested [ 84 ] . Allen et al . calculated an average of 239 μg of diacetyl per cartridge [ 84 ]. Assuming again 400 puffs per cartridge and 40 mL per puff, is it is possible to estimate an average of 0.015 ppm of diacetyl per puff, which could compromise normal lung function in the long-term [ 85 ].

The cytotoxic and pro-inflammatory effects of different e-cigarette flavouring chemicals were also tested on two human monocytic cell lines—mono mac 6 (MM6) and U937 [ 86 ]. Among the flavouring chemicals tested, CAD was found to be the most toxic and O-vanillin and pentanedione also showed significant cytotoxicity; by contrast, acetoin, diacetyl, maltol, and coumarin did not show any toxicity at the concentrations assayed (10–1000 µM). Of interest, a higher toxicity was evident when combinations of different flavours or mixed equal proportions of e-liquids from 10 differently flavoured e-liquids were tested, suggesting that vaping a single flavour is less toxic than inhaling mixed flavours [ 86 ]. Also, all the tested flavours produced significant levels of ROS in a cell-free ROS production assay. Finally, diacetyl, pentanedione, O-vanillin, maltol, coumarin, and CAD induced significant IL-8 secretion from MM6 and U937 monocytes [ 86 ]. It should be borne in mind, however, that the concentrations assayed were in the supra-physiological range and it is likely that, once inhaled, these concentrations are not reached in the airway space. Indeed, one of the limitations of the study was that human cells are not exposed to e-liquids per se, but rather to the aerosols where the concentrations are lower [ 86 ]. In this line, the maximum concentration tested (1000 µM) would correspond to approximately 80 to 150 ppm, which is far higher than the levels found in aerosols of some of these compounds [ 84 ]. Moreover, on a day-to-day basis, lungs of e-cigarette users are not constantly exposed to these chemicals for 24 h at these concentrations. Similar limitations were found when five of seven flavourings were found to cause cytotoxicity in human bronchial epithelial cells [ 87 ].

Recently, a commonly commercialized crème brûlée -flavoured aerosol was found to contain high concentrations of benzoic acid (86.9 μg/puff), a well-established respiratory irritant [ 88 ]. When human lung epithelial cells (BEAS-2B and H292) were exposed to this aerosol for 1 h, a marked cytotoxicity was observed in BEAS-2B but not in H292 cells, 24 h later. However, increased ROS production was registered in H292 cells [ 88 ].

Therefore, to fully understand the effects of these compounds, it is relevant the cell cultures selected for performing these assays, as well as the use of in vivo models that mimic the real-life situation of chronic e-cigarette vapers to clarify their impact on human health.

The e-cigarette device

While the bulk of studies related to the impact of e-cigarette use on human health has focused on the e-liquid components and the resulting aerosols produced after heating, a few studies have addressed the material of the electronic device and its potential consequences—specifically, the potential presence of metals such as copper, nickel or silver particles in e-liquids and aerosols originating from the filaments and wires and the atomiser [ 89 , 90 , 91 ].

Other important components in the aerosols include silicate particles from the fiberglass wicks or silicone [ 89 , 90 , 91 ]. Many of these products are known to cause abnormalities in respiratory function and respiratory diseases [ 89 , 90 , 91 ], but more in-depth studies are required. Interestingly, the battery output voltage also seems to have an impact on the cytotoxicity of the aerosol vapours, with e-liquids from a higher battery output voltage showing more toxicity to A549 cells [ 30 ].

A recent study compared the acute effects of e-cigarette vapor (with PG/vegetable glycerine plus tobacco flavouring but without nicotine) generated from stainless‐steel atomizer (SS) heating element or from a nickel‐chromium alloy (NC) [ 92 ]. Some rats received a single e-cigarette exposure for 2 h from a NC heating element (60 or 70 W); other rats received a similar exposure of e-cigarette vapor using a SS heating element for the same period of time (60 or 70 W) and, a final group of animals were exposed for 2 h to air. Neither the air‐exposed rats nor those exposed to e-cigarette vapor using SS heating elements developed respiratory distress. In contrast, 80% of the rats exposed to e-cigarette vapor using NC heating units developed clinical acute respiratory distress when a 70‐W power setting was employed. Thus, suggesting that operating units at higher than recommended settings can cause adverse effects. Nevertheless, there is no doubt that the deleterious effects of battery output voltage are not comparable to those exerted by CS extracts [ 30 ] (Figs.  1 and 2 ).

E-cigarettes as a smoking cessation tool

CS contains a large number of substances—about 7000 different constituents in total, with sizes ranging from atoms to particulate matter, and with many hundreds likely responsible for the harmful effects of this habit [ 93 ]. Given that tobacco is being substituted in great part by e-cigarettes with different chemical compositions, manufacturers claim that e -cigarette will not cause lung diseases such as lung cancer, chronic obstructive pulmonary disease, or cardiovascular disorders often associated with conventional cigarette consumption [ 3 , 94 ]. However, the World Health Organisation suggests that e-cigarettes cannot be considered as a viable method to quit smoking, due to a lack of evidence [ 7 , 95 ]. Indeed, the results of studies addressing the use of e-cigarettes as a smoking cessation tool remain controversial [ 96 , 97 , 98 , 99 , 100 ]. Moreover, both FDA and CDC are actively investigating the incidence of severe respiratory symptoms associated with the use of vaping products [ 77 ]. Because many e-liquids contain nicotine, which is well known for its powerful addictive properties [ 41 ], e-cigarette users can easily switch to conventional cigarette smoking, avoiding smoking cessation. Nevertheless, the possibility of vaping nicotine-free e-cigarettes has led to the branding of these devices as smoking cessation tools [ 2 , 6 , 7 ].

In a recently published randomised trial of 886 subjects who were willing to quit smoking [ 100 ], the abstinence rate was found to be twice as high in the e-cigarette group than in the nicotine-replacement group (18.0% vs. 9.9%) after 1 year. Of note, the abstinence rate found in the nicotine-replacement group was lower than what is usually expected with this therapy. Nevertheless, the incidence of throat and mouth irritation was higher in the e-cigarette group than in the nicotine-replacement group (65.3% vs. 51.2%, respectively). Also, the participant adherence to the treatment after 1-year abstinence was significantly higher in the e-cigarette group (80%) than in nicotine-replacement products group (9%) [ 100 ].

On the other hand, it is estimated that COPD could become the third leading cause of death in 2030 [ 101 ]. Given that COPD is generally associated with smoking habits (approximately 15 to 20% of smokers develop COPD) [ 101 ], smoking cessation is imperative among COPD smokers. Published data revealed a clear reduction of conventional cigarette consumption in COPD smokers that switched to e-cigarettes [ 101 ]. Indeed, a significant reduction in exacerbations was observed and, consequently, the ability to perform physical activities was improved when data was compared with those non-vapers COPD smokers. Nevertheless, a longer follow-up of these COPD patients is required to find out whether they have quitted conventional smoking or even vaping, since the final goal under these circumstances is to quit both habits.

Based on the current literature, it seems that several factors have led to the success of e-cigarette use as a smoking cessation tool. First, some e-cigarette flavours positively affect smoking cessation outcomes among smokers [ 102 ]. Second, e-cigarettes have been described to improve smoking cessation rate only among highly-dependent smokers and not among conventional smokers, suggesting that the individual degree of nicotine dependence plays an important role in this process [ 97 ]. Third, the general belief of their relative harmfulness to consumers' health compared with conventional combustible tobacco [ 103 ]. And finally, the exposure to point-of-sale marketing of e-cigarette has also been identified to affect the smoking cessation success [ 96 ].

Implication of e-cigarette consumption in COVID-19 time

Different reports have pointed out that smokers and vapers are more vulnerable to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infections or more prone to adverse outcomes if they suffer COVID-19 [ 104 ]. However, while a systematic review indicated that cigarette smoking is probably associated with enhanced damage from COVID-19, a meta-analysis did not, yet the latter had several limitations due to the small sample sizes [ 105 ].

Interestingly, most of these reports linking COVID-19 harmful effects with smoking or vaping, are based on their capability of increasing the expression of angiotensin-converting enzyme 2 (ACE2) in the lung. It is well known that ACE2 is the gate for SARS-CoV-2 entrance to the airways [ 106 ] and it is mainly expressed in type 2 alveolar epithelial cells and alveolar macrophages [ 107 ]. To date, most of the studies in this field indicate that current smokers have higher expression of ACE2 in the airways (reviewed by [ 108 ]) than healthy non-smokers [ 109 , 110 ]. However, while a recent report indicated that e-cigarette vaping also caused nicotine-dependent ACE2 up-regulation [ 42 ], others have revealed that neither acute inhalation of e-cigarette vapour nor e-cigarette users had increased lung ACE2 expression regardless nicotine presence in the e-liquid [ 43 , 110 ].

In regard to these contentions, current knowledge suggests that increased ACE2 expression is not necessarily linked to enhanced susceptibility to SARS-CoV-2 infection and adverse outcome. Indeed, elderly population express lower levels of ACE2 than young people and SARS-CoV-2/ACE2 interaction further decreases ACE2 expression. In fact, most of the deaths provoked by COVID-19 took place in people over 60 years old of age [ 111 ]. Therefore, it is plausible that the increased susceptibility to disease progression and the subsequent fatal outcome in this population is related to poor angiotensin 1-7 (Ang-1-7) generation, the main peptide generated by ACE2, and probably to their inaccessibility to its anti-inflammatory effects. Furthermore, it seems that all the efforts towards increasing ACE2 expression may result in a better resolution of the pneumonic process associated to this pandemic disease.

Nevertheless, additional complications associated to COVID-19 are increased thrombotic events and cytokine storm. In the lungs, e-cigarette consumption has been correlated to toxicity, oxidative stress, and inflammatory response [ 32 , 112 ]. More recently, a study revealed that while the use of nicotine/flavour-containing e-cigarettes led to significant cytokine dysregulation and potential inflammasome activation, none of these effects were detected in non-flavoured and non-nicotine-containing e-cigarettes [ 43 ]. Therefore, taken together these observations, e-cigarette use may still be a potent risk factor for severe COVID-19 development depending on the flavour and nicotine content.

In summary, it seems that either smoking or nicotine vaping may adversely impact on COVID-19 outcome. However, additional follow up studies are required in COVID-19 pandemic to clarify the effect of e-cigarette use on lung and cardiovascular complications derived from SARS-CoV-2 infection.

Conclusions

The harmful effects of CS and their deleterious consequences are both well recognised and widely investigated. However, and based on the studies carried out so far, it seems that e-cigarette consumption is less toxic than tobacco smoking. This does not necessarily mean, however, that e-cigarettes are free from hazardous effects. Indeed, studies investigating their long-term effects on human health are urgently required. In this regard, the main additional studies needed in this field are summarized in Table 3 .

The composition of e-liquids requires stricter regulation, as they can be easily bought online and many incidences of mislabelling have been detected, which can seriously affect consumers’ health. Beyond their unknown long-term effects on human health, the extended list of appealing flavours available seems to attract new “never-smokers”, which is especially worrying among young users. Additionally, there is still a lack of evidence of e-cigarette consumption as a smoking cessation method. Indeed, e-cigarettes containing nicotine may relieve the craving for smoking, but not the conventional cigarette smoking habit.

Interestingly, there is a strong difference of opinion on e-cigarettes between countries. Whereas countries such as Brazil, Uruguay and India have banned the sale of e-cigarettes , others such as the United Kingdom support this device to quit smoking. The increasing number of adolescent users and reported deaths in the United States prompted the government to ban the sale of flavoured e-cigarettes in 2020. The difference in opinion worldwide may be due to different restrictions imposed. For example, while no more than 20 ng/mL of nicotine is allowed in the EU, e-liquids with 59 mg/dL are currently available in the United States. Nevertheless, despite the national restrictions, users can easily access foreign or even counterfeit products online.

In regard to COVID-19 pandemic, the actual literature suggests that nicotine vaping may display adverse outcomes. Therefore, follow up studies are necessary to clarify the impact of e-cigarette consumption on human health in SARS-CoV-2 infection.

In conclusion, e-cigarettes could be a good alternative to conventional tobacco cigarettes, with less side effects; however, a stricter sale control, a proper regulation of the industry including flavour restriction, as well as further toxicological studies, including their chronic effects, are warranted.

Availability of data and materials

Not applicable.

Abbreviations

Angiotensin-converting enzyme 2

Angiotensin 1-7

Bronchoalveolar lavage fluid

Cinnamaldehyde

US Centers for Disease Control and Prevention

Carbon monoxide

Chronic obstructive pulmonary disease

Coronavirus disease 2019

Cigarette smoke

Electronic nicotine dispensing systems

e-cigarette or vaping product use-associated lung injury

Food and Drug Administration

Gas chromatography with a flame ionisation detector

Gas chromatography-mass spectrometry

Granulocyte–macrophage colony-stimulating factor

High performance liquid chromatography

Human umbilical vein endothelial cells

Interleukin

Interferon γ

Liquid chromatography-mass spectrometry

Monocyte chemoattractant protein-1

Matrix metallopeptidase 9

α7 Nicotinic acetylcholine receptor

Nickel‐chromium alloy

Nitric oxide

Propylene glycol

Regulated on activation, normal T cell expressed and secreted

Reactive oxygen species

Severe acute respiratory syndrome coronavirus 2

Stainless‐steel atomizer

Tetrahydrocannabinol

Tumour necrosis factor-α

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Acknowledgements

The authors gratefully acknowledge Dr. Cruz González, Pulmonologist at University Clinic Hospital of Valencia (Valencia, Spain) for her thoughtful suggestions and support.

This work was supported by the Spanish Ministry of Science and Innovation [Grant Number SAF2017-89714-R]; Carlos III Health Institute [Grant Numbers PIE15/00013, PI18/00209]; Generalitat Valenciana [Grant Number PROMETEO/2019/032, Gent T CDEI-04/20-A and AICO/2019/250], and the European Regional Development Fund.

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Marques, P., Piqueras, L. & Sanz, MJ. An updated overview of e-cigarette impact on human health. Respir Res 22 , 151 (2021). https://doi.org/10.1186/s12931-021-01737-5

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Studies show that about 9 percent of the population and nearly 28 percent of high school students are e-cigarette users.

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Restricted airways, scarred lung tissue found among vapers

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Small study looks at chronic e-cigarette users, seeing partial improvement once they stop

Chronic use of e-cigarettes, commonly known as vaping, can result in small airway obstruction and asthma-like symptoms, according to researchers at Harvard-affiliated Massachusetts General Hospital.

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In the first study to microscopically evaluate the pulmonary tissue of e-cigarette users for chronic disease, the team found in a small sample of patients fibrosis and damage in the small airways, similar to the chemical inhalation damage to the lungs typically seen in soldiers returning from overseas conflicts who had inhaled mustard or similar types of noxious gases. The study was published in  New England Journal of Medicine Evidence .

“All four individuals we studied had injury localized to the same anatomic location within the lung, manifesting as small airway-centered fibrosis with constrictive bronchiolitis, which was attributed to vaping after thorough clinical evaluations excluded other possible causes,” says lead author Lida Hariri, an associate professor of pathology at Harvard Medical School and a pathologist and physician investigator at MGH. “We also observed that when patients ceased vaping, they had a partial reversal of the condition over one to four years, though not complete due to residual scarring in the lung tissue.”

A huge increase in vaping, particularly among young adults and adolescents, has occurred in the United States, with studies showing about 9 percent of the population and nearly 28 percent of high school students are e-cigarette users. Unlike cigarette smoking, however, the long-term health risks of chronic vaping are largely unknown.

In order to determine the underlying pathophysiology of vaping-related symptoms, the MGH team examined a cohort of four patients, each with a three- to eight-year history of e-cigarette use and chronic lung disease. All patients underwent detailed clinical evaluation, including pulmonary function tests, high resolution chest imaging, and surgical lung biopsy. Constrictive bronchiolitis, or narrowing of the small airways due to fibrosis within the bronchiolar wall, was observed in each patient. So was significant overexpression of MUC5AC, a gel-forming protein in the mucus layer of the airway that has been seen in airway cell and sputum samples of individuals who vape. In addition, three of the four patients had evidence of mild emphysema consistent with their former combustible cigarette smoking history, though researchers concluded this was distinct from the findings of constrictive bronchiolitis seen in the patient cohort.

Because the same type of lung damage was observed in all patients, as well as partial improvement in symptoms after e-cigarette usage was stopped, researchers concluded that vaping was the most likely cause after thorough evaluation and exclusion of other possible causes. “Our investigation shows that chronic pathological abnormalities can occur in vaping exposure,” says senior author David Christiani, a professor of medicine at HMS and a physician investigator at Mass General Research Institute. “Physicians need to be informed by scientific evidence when advising patients about the potential harm of long-term vaping, and this work adds to a growing body of toxicological evidence that nicotine vaping exposures can harm the lung.”

A hopeful sign from the study was that three of the four patients showed improvements in their pulmonary function tests and high-resolution computed tomography (HRCT) chest imaging after they ceased vaping. “While there is growing evidence to show that vaping is a risky behavior with potential long-term health consequences for users,” says Hariri, “our research also suggests that quitting can be beneficial and help to reverse some of the disease.”

The study was funded by the National Institutes of Health.

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Current evidence identifies health risks of e-cigarette use, long-term research needed

by American Heart Association

Research increasingly reveals health risks of e-cigarette use, and more studies are needed about the long-term impact e-cigarettes may have on the heart and lungs, according to a new scientific statement from the American Heart Association published in the journal Circulation .

The statement, "Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products," details the latest usage data and trends, identifies current health impacts, highlights existing basic and clinical scientific evidence surrounding e-cigarettes and recommends research priorities to further understand the short- and long-term health effects of e-cigarette use.

Vaping products, also known as e-cigarettes, are battery-operated systems that heat a liquid solution, or e-liquid, to create an aerosol that is inhaled into the lungs. Most e-liquid formulations deliver nicotine, which has been established as having negative health effects as well as strong addictive properties.

The products may also contain other substances, most commonly tetrahydrocannabinol (THC), the psychoactive element of cannabis, as well as methamphetamine, methadone or vitamins. The liquids also include humectants (hygroscopic carriers such as propylene glycol and vegetable glycerol) that act as solvents and create a water aerosol or vapor, flavoring agents, cooling agents such as menthol and sweeteners, in addition to metals from the heating coil and other chemicals.

"E-cigarettes deliver numerous substances into the body that are potentially harmful, including chemicals and other compounds that are likely not known to or understood by the user. There is research indicating that nicotine-containing e-cigarettes are associated with acute changes in several hemodynamic measures, including increases in blood pressure and heart rate ," said the volunteer chair of the scientific statement writing committee Jason J. Rose, M.D., M.B.A., an associate professor of medicine at the University of Maryland School of Medicine in Baltimore.

"There has also been research indicating that even when nicotine is not present, ingredients in e-cigarettes, particularly flavoring agents, independently carry risks associated with heart and lung diseases in animals. Negative effects of e-cigarettes have been shown through in vitro studies and in studies of individuals exposed to chemicals in commercially available products."

The writing committee points to the significance of the clinical diagnosis of "E-cigarette, or Vaping, product use Associated Lung Injury" (EVALI). EVALI was first recognized as a condition by the U.S. Centers for Disease Control and Prevention in 2019, when approximately 2,800 hospitalizations occurred among e-cigarette users in less than a year. This is cited in the statement as one example that emphasizes the lack of knowledge surrounding the risks of e-cigarettes and their ingredients.

In the case of the EVALI hospitalizations, vitamin E acetate has been implicated as the ingredient likely causing illness. This substance is used as a thickening agent in some e-cigarette liquids.

Studies gauging the specific impact e-cigarettes have on heart attacks and strokes are limited. Much research on e-cigarette use has been conducted in people who have also used or were currently using traditional cigarettes. Additionally, large survey studies have focused on younger adults who have a low occurrence of heart attacks and strokes. The writing committee says longer-term studies of e-cigarettes users of all ages are needed, including among people who already have cardiovascular disease.

One recent analysis of the adult Population Assessment of Tobacco and Health (PATH) study found a statistically significant association between former or current e-cigarette use at the time participants enrolled in the study and the development of incident respiratory disease (chronic obstructive pulmonary disease/COPD, chronic bronchitis, emphysema or asthma) within the next two years. The PATH Study, an ongoing study that started in 2013, is one of the first large tobacco research efforts undertaken by the National Institutes of Health and the U.S. Food and Drug Administration.

Additional studies cited in the statement indicate a rapid increase since 2010 in the number of people who had ever used e-cigarettes or were currently using the devices, and most of those users were current or former traditional cigarette smokers. In addition, by 2016, data from the Behavioral Risk Factor Surveillance System indicated about 1.2 million adults in the U.S. who had never smoked combustible cigarettes before were currently using e-cigarettes.

The writing committee noted that e-cigarettes are reported to be the most commonly used tobacco product among youth, particularly high school and middle school students. The statement cites data showing that almost three out of four young people using e-cigarettes exclusively report using flavored e-cigarette products. This high rate of use by youth makes it critical to assess the short- and long-term health effects of these products, according to the statement.

"Young people often become attracted to the flavors available in these products and can develop nicotine dependence from e-cigarette use. There is significant concern about young people assuming e-cigarettes are not harmful because they are widely available and marketed to an age group that includes many people who have never used any tobacco products," Rose said.

"The long-term risks of using e-cigarettes are unknown, but if the risks of chronic use are like combustible cigarettes, or even if the risks are reduced but still present, we may not observe them for decades. What is equally concerning is that studies show that some youth who use e-cigarettes go on to use other tobacco products, and there is also a correlation between e-cigarette use and substance use disorders."

Given the established, high health risks of smoking combustible cigarettes, e-cigarette products have been evaluated as smoking cessation tools. The writing committee examined the limited research in this area and concluded that any benefits e-cigarettes may offer to help people stop smoking or stop using tobacco products needs to be clearly balanced alongside the products' known and unknown potential health risks, including the known risk of long-term dependence on these products.

"E-cigarette companies have suggested that their products are a way to quit smoking traditional cigarettes. There is no strong evidence to support this beyond any short-term benefit. The lack of long-term scientific safety data on e-cigarette use, along with the potential for the addiction to e-cigarette products seen among youth, are among the reasons the American Heart Association does not recommend e-cigarette use for cessation efforts," said Rose Marie Robertson, M.D., FAHA, the Association's deputy chief science and medical officer and co-director of the Association's Tobacco Center of Regulatory Science.

"It's also important to note that e-cigarette products are not approved by the U.S. Food and Drug Administration (FDA) for tobacco cessation. The Association recommends a combination of multiple-episode cessation counseling accompanied by personalized nicotine replacement therapy with FDA-approved doses and formulations, as well as medications to help control cravings, to help people who smoke combustible cigarettes with cessation. And all of this needs to be undertaken with the understanding that quitting often takes many tries, and any failures should be seen as just episodes to learn from on the road to finally beating a powerful addiction for good."

The scientific statement writing committee emphasizes a critical need for additional knowledge and research, specifically:

• Future research should focus on gaining knowledge about serious and potentially long-term effects of e-cigarettes on the heart, blood vessels and lungs.
• Studies are needed that include patients with pre-existing cardiopulmonary disease, such as coronary artery disease or chronic obstructive pulmonary disease , to evaluate and compare outcomes among e-cigarette users in comparison to traditional smokers, and those who use e-cigarettes along with traditional cigarettes (referred to as dual users) and nonsmokers.
• More in-depth research is needed about the common chemical ingredients in e-cigarettes and the effects they independently have on pulmonary and cardiac health.
• Clinical studies are needed to study the risks and potential benefits of e-cigarettes as alternatives to traditional combustible cigarettes.
• Since the long-term health impact of e-cigarettes may take decades to emerge, more molecular and laboratory studies are needed in the interim to help determine the biological implications of e-cigarette use .

"Because e-cigarettes and other vaping systems have only been in the U.S. for about 15 years, we do not yet have enough information on their long-term health effects, so we must rely on shorter term studies, molecular experiments and research in animals to try to assess the true risk of using e-cigarettes," Jason Rose added. "It is necessary for us to expand this type of research since the adoption of e-cigarettes has grown exponentially, especially in young people, many of whom may have never used combustible cigarettes."

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Environmental Factor

Your online source for niehs news, vaping’s respiratory effects traced by leading basic researcher.

I spoke with NIEHS grantee Irfan Rahman, Ph.D., about how e-cigarettes can affect lung health and increase susceptibility to disease.

By Rick Woychik

At the 2023 meeting of the Society of Toxicology (SOT), held last month in Nashville, Tennessee, I listened to a variety of exciting talks by NIEHS scientists and grant recipients. Topics ranged from how artificial intelligence and machine learning can advance research into the health effects of chemicals to how environmental factors can influence neurological diseases.

I was thrilled to see many institute-funded scientists recognized for their outstanding toxicological research, including Irfan Rahman, Ph.D. , who took home the 2023 SOT Leading Edge in Basic Science Award. He was recognized for his groundbreaking work examining the biological mechanisms involved in e-cigarette and tobacco toxicity.

Rahman is a professor at the University of Rochester Medical Center, where he directs the Center for Inhalation and Flavoring Toxicological Research, among his many other duties. Since the 1980s, he has conducted pioneering research into the negative biological changes caused by cigarettes, secondhand smoke, and, more recently, e-cigarettes.

Last month, I sat down with Dr. Rahman to learn more about his research program, what inspired him to pursue a scientific career, and why he thinks vaping and e-cigarettes represent a major public health threat. I was deeply impressed by not only Dr. Rahman’s deep scientific knowledge in this area but also his passion for protecting human health.

Rick Woychik : You have worked to advance inhalation toxicology since the late 1980s. What inspired you to conduct such research?

Irfan Rahman : I was born in the city of Bhopal, India, and in my late teens, there was a major disaster at a pesticide plant there that caused hundreds of thousands of residents to be exposed to methyl isocyanate, which is a dangerous gas. The event had a profound effect on my personal life and prompted me to understand how inhaled toxicants can affect human health.

A significant amount of the gas ended up being emitted through our railway station, and our family lived about 3-5 miles away from that area. When the gas leaked in the early morning hours, people started panicking — thousands of people died immediately, and a lot of animals were dying, too. The gas caused asphyxia, making it hard for people to inhale oxygen.

Other motivators for me to pursue a career in inhalation toxicology were air pollution — I lived in a small village, and pollution levels were very high growing up — and the fact that there was a lot of cigarette smoke on planes that I experienced when flying in the 1980s. I remember planes being filled with smoke, and even if you requested a nonsmoking section, the secondhand environmental smoke still made its way to you.

More recently, I’ve been inspired to study vaping and e-cigarettes. I remember when the first e-cigarette devices made their way to stores in the early to mid-2000s. I knew at the time that, contrary to what many people assumed, these were not harmless devices that only caused inhalation of water vapor. There were dangerous chemicals in them, and I wanted to find out how they affect health.

RW : Thank you for sharing that story. The Bhopal Disaster is considered the worst industrial accident in history, but your experience is inspiring because out of that tragedy, you found your scientific calling.

You mentioned your early interest in studying the health effects of e-cigarettes. Your outstanding work in that area is a major reason you won the 2023 SOT Leading Edge in Basic Science Award. Can you expand on your research into vaping and e-cigarette flavoring?

IR : Vaping delivers nicotine to the lungs in ways that are seemingly safe but actually quite dangerous to lung health. During vaping, e-cigarette vapors, which include toxic chemicals, are inhaled into the lungs. Beyond nicotine, vaping can deliver substances such as vegetable glycerin, propylene glycol, volatile organic chemicals, anti-freezing agents, metals, and many other compounds. There are also many flavorants [flavoring chemicals] used in various e-cigarettes . All of these substances get into users’ air sacs, where oxygen transfer occurs. The chemicals replace oxygen, and they can cause irritability in the lung as well as breathing difficulties.

Among our other projects, my team has sought to understand how flavoring agents and other e-cigarette substances can affect circadian biology . When scientists began to investigate the molecular circuitry that dictates our circadian clocks, they originally worked out the details in certain sections of the brain. However, more recently, it was discovered that these same circuits and molecules play a role in establishing a circadian rhythm in the metabolism of cells in other parts of the body, including the lung. So, we want to study how flavoring agents may disrupt circadian biology and pave the way for lung injury, lung fibrosis, or susceptibility to respiratory disease.

RW : Speaking of susceptibility to respiratory disease, I understand that you conducted important research during the COVID-19 pandemic. Can you expand on that?

IR : In 2019, the first cases of E-Cigarette or Vaping Use-Associated Lung Injury, also called EVALI, began to crop up in the U.S. EVALI is a severe and potentially lethal lung disease, and some of the same disease mechanisms are involved in COVID-19. When we went into the pandemic, we determined that exposure to nicotine through e-cigarettes and vaping can actually increase the concentration of the ACE2 receptor for the SARS-CoV-2 virus, thereby making people more susceptible to the disease.

Also, vaping can interfere with mitochondria, which play an important role in healthy lung function. Mitochondria are the building blocks of cellular energy, and vaping chemicals can reduce that energy, causing lung cells to have less power to do their jobs. Eventually, such mitochondrial disruption produces inflammatory responses that can increase lung aging, so that a 45-year-old who vapes might actually have the lung function of a 60-year-old, for example. And that kind of accelerated lung aging, or lung cellular senescence, can also make individuals more vulnerable to diseases like COVID-19.

RW : Any final thoughts for Environmental Factor readers?

IR : Vaping is a major public health problem, in my view. It is a form of self-inflicted damage, in part because many are not aware of its health effects, or perhaps because they’ve been told it is harmless. Many young people in our country are getting addicted to e-cigarettes, and companies are producing a variety of vaping products with shiny packaging and nice-sounding flavors that make them even more enticing. But work by my team and others has provided important insights into vaping, and I try to spread the word about its negative effects whenever possible.

I am proud that through NIEHS funding, my team has been able to characterize some of the major effects of vaping, and I look forward to continuing this important research in the future. There are many unanswered questions about all of the negative biological consequences of e-cigarettes, and through further research, we will be able to answer them.

(Rick Woychik, Ph.D., directs NIEHS and the National Toxicology Program.)

Mentors shape career

Rick Woychik : Can you talk about some of the mentors who inspired you early in your career?

Irfan Rahman : Sure. Dr. N. Nath, my Ph.D. mentor at Nagpur University in India, was a wonderful person. He helped me start understanding the free-radical chemistry of tobacco smoke, and I learned a lot from him during those years.

Next, I completed postdoctoral training at the University of Miami and Georgetown University. During that time, my mentor was Dr. Donald Massaro. He was a top-notch lung physiologist and considered the king of lung disease. It was an honor to work with him.

Before joining the University of Rochester Medical Center faculty, I worked at the University of Edinburgh in Scotland. I collaborated closely with Drs. William MacNee and Kenneth Donaldson. They helped me advance my research and provided strong professional encouragement in air pollution and tobacco smoke research.

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• Published: 11 April 2022

Global youth vaping and respiratory health: epidemiology, interventions, and policies

• Lynnette Nathalie Lyzwinski   ORCID: orcid.org/0000-0002-6173-4505 1 , 2 ,
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E-cigarette usage (also known as e-cigarettes or vaping products) has increasingly been recognized as a global public health problem. One challenge in particular involves their marketing to minors (teenagers and children) and the rising prevalence of use in this population. E-cigarettes unnecessarily expose minors to health risks, these include respiratory health problems, such as exacerbations of asthma, bronchitis, and respiratory-tract irritation. Nicotine, commonly found in e-cigarettes, is also associated with cognitive impairment and neurodevelopmental problems. E-cigarettes are also risk factors for downstream substance use, including cigarettes and cannabis initiation (the gateway hypothesis), which compounds health risks in dual users. Current public health preventative and intervention studies are limited, and there is a clear need for more interventions that may prevent usage and assist with cessation in this vulnerable population. Physician education and screening uptake should also be enhanced. Stricter public health policy and protection measures are also needed on a global scale to limit e-cigarette exposure in minors.

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Lijun Wang, Jianjiu Chen, … Man Ping Wang

Introduction

The use of electronic cigarettes (also known as e-cigarettes, e-cigs, or vaping products) has increasingly been recognized as a global public health problem 1 . Vaping consists of inhaling a smoke-free aerosol through a mouthpiece, which is produced through the heating of a liquid such as glycol or glycerin in an electronic device 2 , 3 . Most e-cigarettes have the shape of a pen, but others are more discrete-looking such as JUUL, which resembles a USB drive and is popular among teenagers 4 . Common terminology for e-cigarettes is summarized in Table 1 . E-cigarettes have often been used by smokers as a harm-reduction intervention aimed to assist with cigarette-smoking cessation 5 . A meta-analysis found that e-cigarette users (who received free e-cigarettes in trials) were 1.5 times more likely to quit smoking than the control group 6 . Thus, they may play a role in smoking cessation in adult smokers and the benefits of use may outweigh the risks from a public health-harm reduction perspective as they are a safer alternative 7 . However, e-cigarettes are increasingly initiated by teenagers, some of whom have never previously smoked 8 and who are exposed to unnecessary health risks associated with e-cigarette use, making them a public health issue 9 .

Some of the reported reasons for e-cigarette use in teenagers and young adults include their flavoring 10 , 11 , discreteness 12 , easy accessibility 10 , desire to experiment 10 , perceptions that they are safer 10 , and advertising as well as marketing that directly targets young people 13 . Research on flavoring found that sweet flavors (e.g., fruity or candy flavored) were more often selected by teenagers over tobacco or minty flavored (conventional) e-cigarettes 14 .

Here, we review of the epidemiology of e-cigarette use in teenagers and young adults and associated health risks, theoretical mechanisms, and management, including prevention as well as interventions and policies. The overarching aim is to provide an in-depth overview of e-cigarette usage in teenagers and young adults from a public health perspective and to provide insight into emerging trends as well as opportunities for health promotion.

A review of PubMed (Medline) and Google Scholar was undertaken in September 2021. We broadly included all up-to-date studies that were related to teenage-vaping epidemiology, mechanisms, and global policies published in the English language. Primary studies that were not undertaken in teenager ages 13–18 or young-adult ages 19–24 were excluded. Systematic reviews and meta-analyses were only included if they were related to global policies or epidemiological updated findings related to our study population or highly applicable to it. Studies on youth perceptions of e-cigarettes were only included if the papers addressed policy.

We used broad search terms that included word variations for “e-cigarettes” or “vaping”, “teenagers”, “respiratory health effects”, and “vaping policies”. MESH terminology and free text was used in the search. A medical librarian assisted with the search strategy. Manual hand and primary government-database searches were also undertaken. The details of the Medline search-strategy example are summarized in Table 2 .

After screening 2481 titles against the inclusion and exclusion criteria, followed by abstract screening and full-text retrieval, 113 studies were included in the final review. Figure 1 illustrates the search process (PRISMA flow chart) 15 .

Prisma flow chart.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

The uptake of e-cigarettes has markedly increased in recent years across the globe 16 . A systematic review found that e-cigarette usage in teenagers increased by over 19% between 2011 and 2018 in the United States 12 . Studies have also reported an increase in the prevalence of use in Canada and the United Kingdom 9 . According to the report from the Canadian Student Tobacco, Alcohol, and Drugs Survey, the prevalence of e-cigarette usage in teens (grades 7–12) within the past 30 days was 20 percent in 2018–2019, a doubling of the prevalence in the previous year’s report 17 . A total of 90% had consumed products containing nicotine 17 . Between 2010 and 2014, there was a 24.4% rise in e-cigarette use among teens in Eastern and Central Europe 18 . The study had also found that a large proportion of students (43.7%) had previously tried e-cigarettes 18 , highlighting that many young adults have previously experimented with e-cigarettes.

Prevalence of ever use of e-cigarettes appears to be lower in Asian countries such as Japan, where 3.5% reported past use, and South Korea, where 10.1% reported previous experimentation with e-cigarettes 19 , 20 . One study in China reported a low prevalence of past 30-day use of 1.2%, though the study was undertaken in middle-school students instead of high-school students, which could have underestimated teenage e-cigarette use 21 . However, more studies are needed in this region to better ascertain the prevalence of use and changes over time. Data from South America are further limited, but older studies in Brazil (2015) indicate that 2.1% had ever tried e-cigarettes 22 . Additionally, there was a reported rise in prevalence of teenage e-cigarette usage in Argentina between 2014 and 2015 of 5.2% 23 . There are fewer studies in low-income countries, in particular in Africa and India 24 , where the prevalence of e-cigarette use in teenagers is underreported. There is a gap in the literature in low-income countries, highlighting that the topic of e-cigarette use in teenagers remains relatively unexplored and more research is needed in this area.

Figure 2 compares reported proportions of “ever use” of e-cigarettes in teenagers across high-income countries, including Canada, the United States, Great Britain, and Europe between 2015–2017 and 2018–2019 25 , 26 , 27 , 28 . Figure 3 . compares trends in past 30-day prevalence of e-cigarettes from 2015 to 2020 in North America. Overall, the trends indicate a rise in prevalence and past use of e-cigarettes across countries 9 , 27 , 29 , 30 , 31 , 32 , 33 , though prevalence of use declined in 2020 during the pandemic according to data from Canada and the United States 27 , 31 .

History of “ever use” of e-cigarettes in Canada, the United States, Great Britain, and the rest of Europe between 2015–2017 and 2018–2019 9 , 18 , 25 , 26 , 27 , 30 , 33 . If countries reported history of past use within any of these time periods, they were included. Please note that the 2015–2017 prevalence of ever use is for the following European countries: Belgium, Finland, Germany, Ireland, Italy, the Netherlands, and Portugal 28 . The 2018–2019 report in Europe collected data from Central and Eastern Europe, including the following countries: Poland, Lithuania, Belarus, Slovakia, and Russia 18 . It should be noted that while the report by Hammond et al 9 reported a prevalence of “ever use” in the United Kingdom of 32.7% (2018), the Action and Smoking on Health Report in England 25 produced a significantly lower prevalence of 16.4% for the same period in Great Britain. It could be that Northern Ireland has a higher prevalence of ever use and was omitted from the report.

Past 30-day prevalence of e-cigarette use from 2015 to 2020 in North America (comparisons between Canada and the United States) in teenagers (grades 7 through 12). Reported prevalence declined in 2020 during the COVID-19 pandemic. The Canadian Tobacco and Nicotine Surveys were used for 2015, 2019, and 2020 surveys, respectively 27 , 29 . The 2018–2019 surveys for Canada were obtained from the International Tobacco Control Policy Evaluation Project (ITC) Youth Tobacco and Vaping Survey, in Hammond et al 9 . The NYTS 30 (in the Surgeon’s Report on E-Cigarette Usage), CDC, and FDA data from reports 31 , 32 between 2015 and 2020 were also used. It should be noted that there is a slight discrepancy in reported past 30-day prevalence of use in Canada between a Canadian report in 2017 33 and the ITC survey report 9 (6.6% versus 8.4%) as well as between the FDA USA 32 report and the ITC in 2019 9 (20.8 versus 16.2%).

Health effects and associated risks

Although e-cigarettes appear to be a safer alternative than smoking cigarettes over the short term 7 , they are not without risks, especially when used on a regular basis 34 . The potential benefits and risks of e-cigarettes are summarized in Table 3 . Previous reviews have linked e-cigarettes with asthma and chronic obstructive pulmonary disease 34 . A systematic review found that e-cigarettes were associated with myriad respiratory health effects such as exacerbations of asthma, eosinophilic pneumonia, epiglottitis, bronchitis, and acute respiratory distress 35 . Other notable symptoms in regular teenage vapers have included headaches, generalized coughing, insomnia, weakness, and pain in the chest area 36 .

The FDA had issued a warning in 2019, after a series of cases (N = > 1000 of E-cigarette and vaping use associated lung injury (EVALI)) 37 , which were later confirmed to have been caused by the addition of THC and vitamin-E acetate to vape products 38 , 39 , 40 . The specific effects of e-cigarettes on lung injury in teenagers (seven case series) included tachycardia, shortness of breath, and coughing 41 . Six out of the seven cases required ventilator support and were hospitalized 41 .The odds of getting COVID were also five times greater in teenage vapers relative to their nonvaping counterparts (OR = 5.0; 95% CI = 1.8–14.0) 42 . A total of 25.8% of participants who reported previous vaping had symptoms of COVID when compared with nonvapers (13.5%) 42 . It should be noted, however, that the long-term effects of e-cigarettes on respiratory health cannot yet be ascertained 43 .

There is some emerging research, which suggests that e-cigarettes may have cardiovascular effects in teenagers. A study found a rise in arterial blood pressure and heart rate in young adult vapers using JUUL, but not in e-cigarettes without nicotine 44 . Cardiopulmonary risk is also compounded in dual e-cigarette and cigarette smokers 45 .

In addition to this, nicotine use has been documented to have adverse effects on cognition and the developing adolescent brain 46 , 47 , 48 , as well as fetal brain development 46 . Research in teenagers suggests that it is associated with memory problems and troubles with concentrating and focusing on tasks, with increased impulsive behaviors as adults 48 , 49 . A review also found that nicotine use was associated with imbalances in brain development, whereby teens exposed to nicotine had less-developed regions in the prefrontal cortex responsible for inhibitory control, while the part of the brain responsible for the reward system (dopamine pathway) 50 had been well matured as indicated on functional MRIs, highlighting the imbalance in reward and control regions in the brain 47 . Nicotine use during adolescence has also been linked with an increased risk of mental health problems later in life 47 , 48 .

Furthermore, e-cigarette use is a risk factor for subsequent cigarette smoking. A systematic review and meta-analysis found that e-cigarette users had a 30% chance of initiating cigarette smoking when compared with never-users (7.9%) 51 . The odds of smoking were 3.5-times higher (95% CI = 2.4–5.2) in e-cigarette users when compared with never-users (23.2% of previous e-cigarette users reported smoking versus 7.2% of never-users) 51 . Research in young adults found that 82.6% of e-cigarette consumers concurrently used additional nicotine products such as conventional cigarettes. Prevalence of nicotine dependence in this young population was 68% 52 . Another study found that nearly half of teenage vapers smoked a cigarette two years later when compared with their nonvaping counterparts 53 . A qualitative study in teens found that many identified e-cigarettes as a gateway to cigarette smoking 54 .

E-cigarettes are also associated with downstream substance use. Research has found that teenagers who use e-cigarettes are also more likely to use cannabis when compared with non-e-cigarette users and that it is commonly added to vaping products 52 , 55 . Cannabis vaping has been linked with bronchitis in youth as well 56 .

Finally, there have been incidents of ingestion and intoxication associated with e-cigarettes in preteens 57 . Figure 4 illustrates the health risks associated with vaping.

The following figure illustrates the relationship between e-cigarette exposure and potential health effects in teenagers, which primarily affect the respiratory system, neurodevelopment/cognition, and may increase the risk of dual smoking and addiction to other drugs.

Nicotine is a well-established respiratory irritant 58 , but other chemicals in e-cigarettes (e.g., diacetyl 59 , propylene glycol, carbon monoxide, and formaldehyde 60 ) also have detrimental effects for lung function including respiratory volume 61 . E-cigarettes also contain trace amounts of toxic chemicals such as polycyclic aromatic compounds in tandem with heavy metals, aldehydes, and nicotine derivatives 62 . However, it should be noted that exposure to potentially toxic chemicals is lower in e-cigarettes than in conventional cigarettes 63 . E-cigarettes also irritate mucous membranes and trigger the release of inflammatory markers 64 . Additionally, the sweet-flavoring additives (e.g., candy or fruity flavored) have also been reported to be hazardous to the lung 65 . The cinnamon-flavoring cinnamaldehyde has been identified as being one of the main constituents capable of damaging immune cells in the lungs (macrophage-phagocytosis impairment) even without nicotine as a co-additive 65 . Furthermore, the sweet Crème Brulee flavoring was linked with increased tumor-necrosis factor, interleukin levels, and oxidative stress associated with DNA changes 66 . In terms of e-cigarette or vaping use-associated lung injury (EVALI), vitamin E acetate along with cannabis oil were identified as being the primary causative agents 38 , 39 .

In addition to this, nicotine is a risk factor for cardiovascular disease through its well-known effects on endothelial function and stimulation of inflammatory markers such as C-reactive protein 67 , 68 . Studies in youth have identified a possible mechanism for cardiovascular effects resulting from activation of the splenocardiac axis from inhaled toxins in e-cigarettes 69 .

Nicotine additionally affects the developing brain through its effect on cerebral cortex as well as in the hippocampus 49 . All types of e-cigarettes, including non-nicotine ones, have been reported to induce oxidative stress, thereby increasing the risk of cognitive-related impairment in teenagers 70 . Research also suggests that nicotine can bind to N-acetylcholine receptors, thereby impacting signaling in the prefrontal cortex 47 . Nicotine also has been documented to have an effect on serotonin receptors (5HT1 and 5HT2), which subsequently affects the body’s response to serotonin, supporting the link between exposure to nicotine in adolescence and risk of mood disorders later in life 47 , 48 .

Furthermore, e-cigarettes are thought to increase dual smoking and downstream substance use through the gateway hypothesis, whereby exposure to nicotine products further puts individuals at risk of initiating other substances by stimulating neurotransmitters associated with the reward system 4 , 55 , 71 , 72 , 73 . This feedback loop creates a pathway for substance abuse and dependence 72 .

There is some evidence of second-hand exposure effects, but the exposure dose is much smaller than in conventional cigarettes 74 . However, a study found that teenagers presenting with an asthma attack over a 12-month period were 27% times more likely to be exposed to e-cigarette second-hand smoke relative to their counterparts 75 . Thus, second-hand exposure may be related to respiratory health in youth, including asthma and generalized wheezing 75 , 76 .

Screening, prevention, and management

Research indicates that screening patients for e-cigarette usage in primary practice is not frequently undertaken by medical practitioners 77 . One study found a low prevalence of screening for e-cigarettes in primary-care practice relative to smoking screening (14% versus 86%) in a sample of 776 practitioners across the United States 77 . This low uptake is concerning, given the serious health risks of e-cigarettes. A qualitative study in the United States further confirmed that there is insufficient knowledge of e-cigarettes among physicians, including both the potential benefits and health risks 78 . A study in US college students found that most students did not receive any form of counseling about risks from medical practitioners, including dental hygienists 79 . More research is needed to learn about the global screening prevalence of e-cigarette use in primary care. Studies have also shown that there is a need for stronger education on e-cigarettes in medical curricula, which will allow physicians to begin addressing e-cigarette use in teenagers 80 .

Presently, there is little information on primary-care interventions for e-cigarette use in teenagers and young adults. A case study of a 23-year-old e-cigarette user shows promising results for tapering e-cigarette use with the assistance of a pharmacist 81 , which suggests that different healthcare practitioners may play a role helping patients with gradually tapering off e-cigarettes. A randomized controlled trial of asthmatic teenagers who attended one of four clinics found that physicians discussed smoking during 38.2% of thee visits, but vaping was never brought up as a topic 82 . This emphasizes that physicians should discuss both smoking and vaping during appointments 82 , in particular in youth presenting with asthma 75 .

Medical curricula should stress that concurrent smoking and vaping screening and management interventions should be undertaken in the primary-care setting. This way, many cases will not be missed given the high prevalence of dual use 51 . Family physicians should aim to identify youth at risk of vaping through screening questionnaires and aim to increase awareness of vaping for prevention purposes. This could include handing out brochures to patients and their families about the health risks associated with vaping and therapies that are available, which can assist with gradual tapering of nicotine from e-cigarettes. Family physicians have previously recommended open discussions with youth about risks during appointments 83 , as well as educating families through public health educational campaigns 84 .

It may also be strategic for medical, public health practitioners, and researchers to target particular groups and populations of teenagers that are most vulnerable to using e-cigarettes. A longitudinal study in the United Kingdom found an association between socioeconomic disadvantage and e-cigarette use in teenagers and young adults 85 . A systematic review also found that older teenagers from more affluent homes, of white ethnicity, and with higher levels of education had higher levels of knowledge and awareness of e-cigarette use, highlighting a possible need to educate younger teenagers with less education, ethnic minorities, and from lower-income neighborhoods 86 . It should be noted that one study found conflicting results with regard to the relationship between SES and e-cigarettes, whereby young adults from wealthier families were more likely to use e-cigarette, though the comparison groups were all in the affluent state of Connecticut 87 .

Education was also found to be inversely associated with e-cigarette use in another study, but it had the greatest association in whites when compared with black young adults 88 . Vocational training, without higher education, was found to also be associated with e-cigarette use in youth in Europe 89 . Thus, public health campaigns and medical doctors could potentially target individuals with lower levels of education, lower SES, and racially diverse groups to minimize any potential inequities in health.

Gender differences in e-cigarette use have also been noted in North America as well as Europe, whereby males were more likely to use them 89 , 90 , 91 . Additionally, since research indicates that females use e-cigarettes for mostly weight and stress management 92 , interventions could focus on assisting them with stress along with making healthy lifestyle choices associated with weight.

Other particularly vulnerable groups have also included teenagers with impulsivity as well as those with mental health problems 93 , 94 , 95 . A study that explored EVALI cases found that mental health problems were prevalent in this population 95 . Thus, physicians and public health researchers may also consider screening and targeting individuals with mental health problems.

To date, there have been limited community-based and public health intervention trials to assist with e-cigarette prevention. “Catch my breath” was a prevention intervention in 12 middle schools across the United States. The intervention focused on increasing knowledge on the harms associated with e-cigarette use 96 . The study authors found statistically significant differences in e-cigarette use prevalence in schools that had implemented the program when compared with control schools. They also found increased knowledge of e-cigarettes and the risks associated with their use 96 .

Similarly, public health interventions targeting existing teenage users are in their infancy. There is a current text messaging intervention for e-cigarette cessation in teens in the United States 97 . The intervention provides users with educational content on e-cigarettes, focuses on fostering self-efficacy, assists with resilience building, and provides users with support and encouragement. The study had a very high enrollment after about one month of recruitment, with over 27,000 teenagers and young adults enrolled 97 . This indicates that this form of intervention is feasible, given the willingness for e-cigarette users to enroll 97 . Previous studies have found that text messaging for smoking cessation is effective and acceptable for this population 98 , 99 , 100 , 101 , indicating that it could be used for vaping.

Additionally, there are very few commercially available e-cigarette cessation apps that can help teenagers and young adults quit. A systematic review of apps in the Google Play Store found that most apps encouraged e-cigarette use and that only 2 out of 79 were vaping cessation apps 102 . There is a need to develop an app that can be readily available and accessible to teenagers wanting to quit as well as an educational prevention app.

Strict policies to limit e-cigarette accessibility and exposure play an important role in preventing use. Research indicates that children and teenagers are exposed to e-cigarette marketing 103 . A study in the United Kingdom found that most e-cigarette advertisements were near children’s stores and in areas that were less affluent 103 , indicating that social health inequalities may exist, but more research is needed in this area. A review of 124 e-cigarette marketing publications revealed that companies have increased expenditures on social media campaigns and that they are often marketed as an alternative to cigarette smoking 104 . This is especially concerning given how social media may influence the decisions of teenagers and young adults. A randomized controlled trial found that by exposing youth without prior smoking history ( N  = 417) to e-cigarette advertising (four advertisements), they were more likely to select e-cigarettes and have positive attitudes toward them relative to controls not exposed to this advertising 13 . Research had found that many e-cigarette advertisements on social media had used cartoons on packages to promote vaping in youth along with hashtags for vaping (#ejuice and #eliquid ) 105 . The study authors also found that over 20% of advertisements had used a cartoon (66% of which were promotional posts), indicating that youth are often the targets of these ads across the globally accessible Instagram platform. They recommend similar policies to the ones for smoking including the Historical Master Settlement Agreement that banned advertising to youth 105 . Studies have also found that teenagers require multiple warnings in the forms of messages and ads to reduce their positive interest and susceptibility to e-cigarettes 106 and that perceptions of safety are related to environmental policy restrictions on vaping 107 .

Research also indicates that patterns of e-cigarette use changed markedly in teenagers and young adults during the COVID-19 pandemic 108 . Changes in substance use behavioral patterns included ordering from alternative sellers, buying vaping products online, quitting vaping, and switching to cannabis or other products, resulting from the inherent challenges with making purchases at local vendors 108 . This emphasizes how the availability of vaping products including their placement and immediate accessibility influences e-cigarette behavioral patterns, including quitting 108 .

Besides restricting marketing and advertisements, limiting the availability of e-cigarettes and accessibility to teenagers is greatly needed. A policy review on bans on the sale of e-cigarettes to minors across the United States found that e-cigarette use decreased along with smoking traditional cigarettes 109 . A qualitative study of adult vapers found that many agree with bans on advertising to minors to protect them 110 .

A review of global vaping policies found that 68 countries regulate e-cigarettes and that the most frequent cross-national governmental policies include age limits (over 18 years of age), restricting advertisements, and placing bans on vaping in public places, while e-cigarette taxes are not commonly used 111 . The review found that Australia, the Czech Republic, and Malaysia classified e-cigarettes as toxic and poisonous substances 111 . Countries that have enacted child safety policies to protect children include Canada (banned flavoring and marketing to children) 112 , Australia (available by prescription only with a child safety seal) 113 , New Zealand (banned vaping near schools) 114 , the United Kingdom 111 , the United States (some states have banned JUUL) 115 , Finland, Germany, Ireland, Italy, Lithuania, Malta, Netherlands, and the Philippines 111 . Some countries with vape-free restrictions that were also identified include France, Germany, Greece, Jamaica, Nepal, Portugal, Slovakia, Spain, Turkey, Venezuela, and Vietnam 111 . Countries with taxes on e-cigarettes include Italy, Latvia, Portugal, Republic of Korea, Togo, and the United Kingdom 111 . Asian countries that have banned e-cigarettes include Singapore and Thailand, and Japan has banned the use of nicotine-containing e-cigarettes but not e-cigarettes without nicotine 116 . Vaping products are also prohibited in the United Arab Emirates 116 . Switzerland had banned the sale of vaping products until 2018, but now they are available on the market 117 .

In developing countries, where resources are depleted and there is less regulatory oversight 118 , concerns are raised about efforts to protect minors. Although data in India are limited, protective measures have nonetheless have been put into place in 2019, when e-cigarettes were banned to protect minors 119 . Concern has been raised in Guatemala over the lack of regulatory control over flavored e-cigarettes that are enticing for teenagers 120 . While little is known about Africa, South Africa is planning on placing restrictions on e-cigarettes in 2021 121 , but there has been strong opposition from the Tobacco Industry 122 .

Recommendations

Without stricter interventions and policies, teenagers and young adult vapers will continue to be at risk of multiple health problems associated with e-cigarettes.

The following are a set of recommendations:

Strengthen global policies to restrict marketing, use of enticing flavoring, accessibility, and exposure to e-cigarettes in the environment

Increase physician education on screening and nicotine tapering in the primary-care setting .

Increase public health education campaigns and develop evidence-based interventions .

Develop collaborations between physicians and public health researchers through joint efforts in education, screening, and referral .

Figure 5 illustrates strategies that may be applied from a social-marketing perspective 123 to e-cigarettes by emphasizing that the health risks 41 , 46 , 51 should be reduced by restricting their access to children and teenagers 9 , while the benefits of their use may be maximized when safely used in adult smokers attempting to quit 7 . It illustrates that screening, prevention, and intervention can take place in primary-care settings and through public health interventions. Figure 6 illustrates a three-tiered approach to screening, education, prevention, and interventions for e-cigarettes in youth.

The North Axis represents the benefits of e-cigarettes for smokers and the South axis represents the risks, while the East and West axes represent the strategies that may be adopted at an individual level and community/population level. By maximizing the benefits in select adult smokers through harm reduction and minimizing the risks of exposure in minors, e-cigarettes may be safely used.

The following figure illustrates a three-tiered approach to managing e-cigarette use in minors, which includes policy changes, awareness, and prevention campaigns, and finally public health interventions that target existing teenage users.

In summary, e-cigarettes pose a health threat to teenagers and young adults, given the rise in the prevalence of use. While e-cigarettes are a safer alternative than smoking cigarettes and may be used as a harm-reduction strategy in existing smokers, measures need to be urgently put into place to protect children and teenagers from unnecessary use and potential dual smoking and e-cigarette uptake. The outlook depends on whether sufficient primary care and public health strategies will be implemented to protect minors and young adults. As the long-term effects are unknown 62 , it is especially prudent to limit unnecessary exposure. There is an urgent need to develop evidence-based primary-care intervention and public health interventions that target vulnerable groups. Furthermore, there is need for stronger public health protection policies and bans to protect youth.

Data availability

No datasets were generated nor analyzed from this study. Source data for Figs. 2 – 3 are detailed in the paper (i.e., data on vaping prevalence are available on the CDC and FDA websites).

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Acknowledgements

The corresponding author LNL would like to thank her friend medical librarian, Lars Eriksson at the University of Queensland for his advice with the searches. LNL would also like to thank Distinguished Professor Robert Hogg at SFU for his mentorship during COVID-19.

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Lyzwinski, L.N., Naslund, J.A., Miller, C.J. et al. Global youth vaping and respiratory health: epidemiology, interventions, and policies . npj Prim. Care Respir. Med. 32 , 14 (2022). https://doi.org/10.1038/s41533-022-00277-9

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Vaping Could Raise Your Risk for Heart Failure

By Ernie Mundell HealthDay Reporter

TUESDAY, April 2, 2024 (HealthDay News) -- Think vaping is the "healthy" alternative to smoking?

Think again: A new study finds it raises people's odds for heart failure .

“More and more studies are linking e-cigarettes to harmful effects and finding that it might not be as safe as previously thought,” said study lead author Dr. Yakubu Bene-Alhasan , a resident physician at MedStar Health in Baltimore. “The difference we saw was substantial. It’s worth considering the consequences to your health, especially with regard to heart health.”

According to background information in a news release from the American College of Cardiology (ACC), heart failure currently affects more than 6 million Americans.

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The illness can often set in after a heart attack, and involves a weakening of the heart so it can no longer pump blood effectively. Heart failure can be disabling and lead to hospitalization and death.

The new study is slated to be presented Sunday at the ACC's annual meeting in Atlanta.

It's estimated that between 5% and 10% of teens and adults now vape , with many becoming addicted to the nicotine in e-cigarettes.

In the research, Bene-Alhasan and colleagues scoured a U.S. national health database to compare e-cigarette use and any diagnosis of heart failure in almost 176,000 adults.

People averaged 52 years of age, 60.5% were female and just over 3,240 participants developed heart disease over a follow-up period of just under four years.

People who vaped were 19% more likely to receive a heart failure diagnosis than those who didn't, the Baltimore team reported. That remained true even after they accounted for other heart disease risk factors and the use of other substances, such as tobacco or alcohol.

The effect seemed specific to a particular kind of heart failure, known as heart failure with preserved ejection-fraction (HFpEF). In this condition, heart muscle stiffens so that the heart doesn't fill with blood as it should between contractions. The authors note that rates of HFpEF have risen in recent years.

“I think this research is long overdue, especially considering how much e-cigarettes have gained traction,” Bene-Alhasan said. “We don’t want to wait too long to find out eventually that it might be harmful, and by that time a lot of harm might already have been done. With more research, we will get to uncover a lot more about the potential health consequences and improve the information out to the public.”

The researchers noted that the U.S. Centers for Disease Control and Prevention does not recommend vaping as a means of quitting smoking. Instead, the agency advises a combination of quit-smoking counseling and medications as the best way to kick the habit.

Because these findings were presented at a medical meeting, they should be considered preliminary until published in a peer-reviewed journal.

More information

Find out more about how to quit smoking at the American Lung Association .

SOURCE: American College of Cardiology, news release, April 2, 2024

Copyright © 2024 HealthDay . All rights reserved.

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Research reveals vaping really can help people quit smoking cigarettes

By Isobel Williams via SWNS

Switching from cigarettes to vaping is now more likely than ever to help smokers quit, according to a new study.

Researchers have found that smokers who switch to electronic cigarettes are now more likely to stop smoking regular cigarettes, whereas in the past they mostly continued smoking both.

Since their emergence in 2007 e-cigarettes or vapes have shot up in popularity, causing controversy in recent years for their fun colors and flavors which appeal to kids.

Scientists have been debating for years on whether vaping actually helps people who smoke combustible cigarettes to quit smoking, which was their intended purpose.

Some research suggests improved cigarette quitting-related outcomes with e-cigarette use, while other research suggests the opposite.

The new paper, published in the journal Nicotine & Tobacco Research , has found that in recent years e-cigarettes have become more effective in helping smokers to quit traditional cigarettes.

The team examined differences in real-world trends in population-level cigarette discontinuation rates from 2013 to 2021, comparing US adults who smoked combustible cigarettes and used e-cigarettes with US adults who smoked combustible cigarettes and did not use e-cigarettes.

Using data from a national longitudinal study of tobacco use from people from all over the United States, the researchers found that between 2013 and 2016, rates of discontinuing cigarette smoking among adults were statistically indistinguishable between those who vaped and those who did not.

But the quit rates changed in subsequent years.

The team found that between 2018 and 2021 only 20 percent of smokers who did not use e-cigarettes stopped smoking but some 30.9 percent of smokers who did vape stopped smoking quit.

The team says that their findings suggest vapes do help smokers to quit and this updated research should be considered when making public health decisions such as bans on electronic products.

Assistant Professor Karin Kasza, of Roswell Park Comprehensive Cancer Center in New York, said: “Our findings here suggest that the times have changed when it comes to vaping and smoking cessation for adults in the US.

“While our study doesn’t give the answers as to why vaping is associated with cigarette quitting in the population today when it wasn’t associated with quitting years ago, design changes leading to e-cigarettes that deliver nicotine more effectively should be investigated.

“This work underscores the importance of using the most recent data to inform public health decisions.”

The post Research reveals vaping really can help people quit smoking cigarettes appeared first on Talker .

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• Clin Exp Dent Res
• v.7(3); 2021 Jun

The impact of vaping on periodontitis: A systematic review

Carlos alberto figueredo.

1 Faculty of Medicine and Dentistry, University of Alberta, Edmonton Canada

Nancy Abdelhay

3 Faculty of Dentistry, Alexandria University Egypt

Carlos Marcelo Figueredo

2 School of Dentistry and Oral Health, Griffith University Gold Coast, Australia

Raisa Catunda

Monica prasad gibson, associated data.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Background and objective

While tobacco cigarette smoking has been proven to be a risk factor for periodontitis, limited information is available regarding vaping, a new alternative to smoking that has been branded as less harmful. Several important in vitro studies have shown that vaping has a similarly damaging effect as cigarette smoking on the health of the periodontium. However, a comprehensive review is lacking in this field. Therefore, we aimed to systematically review the literature about the impact of vaping on periodontitis.

The research question was created using the PICOs format. A systematic search of the following electronic databases was performed up to March 2020: Medline, Embase, PubMed, Cochrane, and grey literature. Human studies that assessed periodontal status (plaque index, bleeding on probing, clinical attachment loss, marginal bone loss, and probing depth) in e‐cigarette users compared to non‐smokers (control group) were assessed based on an estimate of fixed effects. The weights of the studies were calculated based on their risks of bias.

After duplicates were removed, 1,659 studies were screened and 8 case–control studies that investigated the relationship between vaping and periodontal parameters in humans were selected after their risk of bias assessment. Estimated effects of vaping after weighting results based on their standard deviation showed increased plaque, marginal bone loss, clinical attachment loss, pocket depth, and reduced bleeding on probing.

This study concluded that there is not enough evidence to fully characterize the impacts of vaping on periodontitis. However, within the limitations of our review and the selected included studies, the available results point to increased destruction of the periodontium leading to the development of the disease.

1. INTRODUCTION

Periodontal diseases are defined as an inflammatory process associated with bacterial activity and mediated by the host's immunologic response (Armitage, 1999 ; Tonetti et al., 2018 ). This aggression may result in the loss of connective tissue attachment and consequently bone loss (Armitage, 1999 ; Tonetti et al., 2018 ). Gingivitis, a reversible form of periodontal disease, is initially characterized by gingival inflammation caused by bacterial colonization forming the biofilm (Armitage, 1999 ; Tonetti et al., 2018 ). In susceptible individuals, gingivitis may progress to an irreversible form of the disease, periodontitis, where there is the loss of periodontal ligament and apical migration of the junctional epithelium (Armitage, 1999 ; Tonetti et al., 2018 ). Risk factors, such as diabetes, genetics, and smoking, have been related to the susceptibility, prevalence, and severity of the disease (Armitage, 1999 ; Tonetti et al., 2018 ).

It is well established that cigarette smoking is considered as a risk factor in the development of periodontitis (Armitage, 1999 ; Leite et al., 2018 ; Tonetti et al., 2018 ). It has been shown that patients who smoke suffer from more severe forms of periodontitis (Javed et al., 2013 ). Disease progression is directly related to the frequency of smoking, where heavy smokers show more severe forms of the disease compared to light smokers (Tonetti et al., 2018 ). Different studies categorize the frequency of smoking differently but according to one review, smoking less than 9 cigarettes per day is considered light, and more than 31 is considered heavy smoking (Johnson & Guthmiller, 2000 ). A recent systematic review with meta‐analysis showed that smoking increases the risk of developing periodontitis by 85% (Leite et al., 2018 ). Smoking also impacts the response to periodontal treatment; smokers show only 50%–75% improvement in their clinical parameters after scaling and root planing compared to non‐smokers (Tonetti et al., 2018 ). Another study analyzed the effects of cigarette smoking on periodontal parameters and found significant increases in plaque index, pocket depth, and clinical attachment loss levels in cigarette smokers compared to non‐smokers (Javed et al., 2017 ). It has been evidenced that tobacco smoking results in a proinflammatory effect by stimulating the secretion of specific cytokines and radical oxygen species (ROS) that play a role in the destruction of periodontal tissues (Katz et al., 2005 ).

Vaping electronic cigarettes (e‐cigarettes) have grown into a popular recreational activity among teenagers and young adults in Canada in the last few years. Since the Tobacco and Vaping Products Act (TVPA) became legal in Canada in May 2018, adults have the right to purchase vaping products with nicotine as an allegedly less harmful option than smoking (Government of Canada: Smoking, Vaping, and Tobacco, 2020 ). Instead of burning tobacco, as traditional cigarettes do, e‐cigarettes heat up and vaporize nicotine or other flavoring products that might be included in it. The Canadian Tobacco, Alcohol and Drugs Survey conducted on students between grades 7 and 12 between 2016 and 2017 concluded that 23% of students in grades 7–12 had tried a vaping product at least once. Ten percent reported using them within the last 30 days and 53% of all students thought it would be” fairly easy” or” very easy” to get a vaping product if they wanted one (Government of Canada: Smoking, Vaping, and Tobacco, 2020 ). Interestingly, while 74% of current smokers recognize a great risk in smoking traditional cigarettes regularly, only 24% of current vape users recognize risk in vaping electronic cigarettes.

The literature on vaping e‐cigarettes has shown that there are systemic impacts of vaping (Gaur & Agnihotri, 2019 ; Government of Canada: Smoking and Oral Cancer, 2011 ). Vaping with nicotine exposes users to nicotine addiction and side effects such as altered teen brain development and cognitive and behavioral problems (Government of Canada: Smoking and Oral Cancer, 2011 ). Vaping without nicotine still proposes risks of exposure to the chemicals that are released in the heating process of the device, such as aluminum, copper, and lead (Gaur & Agnihotri, 2019 ). E‐cigarettes also pose a hazard for traumatic injuries. Blast injuries caused by battery explosion are also an associated risk, mainly in countries where there is no regulation on the manufacture and safety of e‐cigarettes (Kite et al., 2016 ). An in vitro study correlated e‐cigarette aerosol exposure to DNA damage and mitochondrial dysfunction in lung fibroblasts (Lerner et al., 2016 ). Another study compared the effects of cigarette smoke and e‐cigarette aerosol in bone marrow‐derived mesenchymal stem cells and found that e‐cigarette aerosol exposure causes overproduction of ROS (Shaito et al., 2017 ). Focusing on a correlation between oral health and vaping, a recent study showed that e‐cigarette exposure‐mediated carbonyl stress leads to increased levels of prostaglandin‐E2 and cyclooxygenase‐2 in human gingival epithelium compared to control (Lerner et al., 2015 ). Several studies, such as the ones included in this review, analyzed the impact of vaping on periodontal parameters and found increased levels of plaque index, pocket depth, clinical attachment loss, and marginal bone loss in vaping groups compared to non‐smokers (Al‐Aali et al., 2018 ; AlQahtani et al., 2018 , 2019 ; ArRejaie et al., 2019 ; BinShabaiba et al., 2019 ; Javed et al., 2017 ; Mokeem et al., 2018 ; Vohra et al., 2020 ). Despite all the evidence that smoking can negatively affect the periodontal tissues, there is still little evidence about the impact of vaping. Based on the available literature, we hypothesize that we may find similar clinical periodontal manifestations in vapers as seen in cigarette smokers. Therefore, we aimed to systematically review available evidence about the impact of vaping e‐cigarettes on periodontal statuses.

2. MATERIALS AND METHODS

2.1. protocol, registration, conduct, and reporting.

This systematic review was conducted according to the Cochrane Handbook (Cochrane handbook for systematic reviews of interventions, 2020 ), and adhered to the Preferred Reporting Items for Systematic Review and Meta‐Analyses (PRISMA) to ensure the higher methodological quality of the study. The protocol for this systematic review was registered in Prospero – International prospective register of systematic reviews (Centre for reviews and dissemination, University of York, York, United Kingdom) under ID CRD42018114837 (International Prospective Register of Systematic Reviews, PROSPERO, 2011 ). The authors have stated explicitly that there are no conflicts of interest in connection with this article.

2.2. Eligibility criteria

This systematic review only included human studies that investigated an association between vaping and periodontal status in a clinical context. Studies that included parameters such as plaque index (PI), bleeding on probing (BOP), clinical attachment loss (CAL), probing depth (PD), and marginal bone loss (MBL) were included. Also, these studies included patients who did not receive periodontal treatment 6 months before the study. No age or sex restrictions were applied.

2.3. Exclusion criteria

Descriptive studies, case reports, case series, abstracts, systematic/scope reviews, and expert opinions were not included. Exclusion criteria for patients: pregnancy, current cigarette smokers, waterpipe smokers, or smokeless tobacco users, immunocompromised patients, diabetic patients, patients who went through periodontal therapy during the last 6 months, patients taking anti‐inflammatory or antibiotic medication, and edentulous patients.

The researchable question was created using the PICOs (Population, Intervention, Comparison, Outcome) format. Population: Group A inclusion criteria: Participants who are not using any form of tobacco; ages 13 and up. Group B inclusion criteria: Participants who reported vaping e‐cigarettes for at least 1 year before the study. Intervention: History of vaping of e‐cigarettes. Comparison: Non‐smokers. Outcomes: Presence of periodontal disease as indicated by increased probing depth, attachment loss, gingival recession, and bone resorption.

2.5. Search strategy

A systematic search of the following electronic databases was performed up to March 2020: Medline, Embase, PubMed, and Cochrane. Additional information about vaping laws and prevalence statistics were obtained from the Canadian government website. The search was restricted to the English language and no year restriction was applied. The search strategy used tried to include all terminology that refers to electronic cigarettes and periodontal parameters.

2.6. Study selection

A two‐phase process to select the final articles was followed. In the first phase, two reviewers (CF and RC) independently screened titles and abstracts from all gathered references. In the second phase, full‐text articles were assessed by reviewers to confirm their final selection. In the case of disagreements, the consensus was reached after discussion, a third person (NA) was involved when necessary.

2.7. Risk of bias in individual studies

The studies were evaluated by 2 reviewers following The Joanna Briggs Institute (JBI) critical appraisal checklist tool (Joanna Briggs Institute critical appraisal tools, 2017 ). The critical appraisal checklist tool for analytical cross‐sectional studies was used to assess the risk of bias. This tool of assessment describes the following main components: true random sequence generation, allocation concealment, blinded outcome assessment, selective outcome assessment, and appropriate statistical analysis. Studies would be assigned to the highest risk of bias if the sequence generation and allocation concealment were unclear.

2.8. Data synthesis

SPSS was used to make a linear mixed model of the extracted results. In this model, the dependent variables are the mean values being affected by the factor of vaping or not. Mean values are weighted by their standard deviations (weight = 1/SD). The linear mixed model provides an estimate of fixed effects that vaping is causing on each clinical measurement. Each parameter has a value representing the difference between vaping and control groups.

3.1. Studies selection

The search found 1766 studies across 4 databases as demonstrated in the PRISMA flowchart (Figure ​ (Figure1). 1 ). Duplicates were removed and 1659 studies were screened. After title and abstract reading, 66 studies were selected for full‐text reading. From these, 8 studies fit in our inclusion criteria and were suitable for fulfilling our research question. The studies that were not included due to full‐text assessment were excluded due to irrelevant study design, comparison, intervention, or population.

Flow diagram of literature search divided into the identification, screening, eligibility, and phases. Reasons for study exclusions are included in the eligibility phase

3.2. Study characteristics

Study characteristics are reported in Table ​ Table1. 1 . All eight studies (Al‐Aali et al., 2018 ; AlQahtani et al., 2018 , 2019 ; ArRejaie et al., 2019 ; BinShabaiba et al., 2019 ; Javed et al., 2017 ; Mokeem et al., 2018 ; Vohra et al., 2020 ) had a cross‐sectional design and they were all carried out in Saudi Arabia. They had a combined sample size of 582 (574 males and 8 females) ranging from 24 to 45 years of age. All studies were published between 2017 and 2019. History of vaping habits ranged from 0.9 to 8.7 years.

Study characteristics are divided into the year, country and journal of publication, study design, inclusion criteria for included groups, sample, and vaping habit characteristics

Note : All studies were carried out in Saudi Arabia and had a case–control design.

3.3. Risk of bias within studies

The Joanna Briggs Institute assessment tool for risk of bias of cross‐sectional studies was used, results are reported in Table ​ Table2 2 (Joanna Briggs Institute critical appraisal tools, 2017 ). The risk of bias was categorized as high if the percentage of yes is equal or lower than 49, moderate if the percentage of yes was between 50% and 69%, and low if the percentage of yes was equal or higher than 70%. Following these criteria, four of the included studies were at low risk of bias and the other four at moderate risk of bias.

Joanna Briggs Institute risk of bias tool for cross‐sectional studies

Q1. Were the criteria for inclusion in the sample clearly defined?

Q2. Were the study subjects and the setting described in detail?

Q3. Was the exposure measured in a valid and reliable way?

Q4. Were objective, standard criteria used for measurement of the condition?

Q5. Were confounding factors identified?

Q6. Were strategies to deal with confounding factors stated?

Q7. Were the outcomes measured in a valid and reliable way?

Q8. Was appropriate statistical analysis used?

Q: Question.

Y: Yes. N: No.

3.4. Results of individual studies

All extracted results from included studies that compared the periodontal status of vape users and non‐smokers can be found in Table ​ Table3. 3 . These studies looked at differences between PI, BOP, CAL, PD, MBL mesial, and MBL distal. The linear comparison of these results is shown in Figures ​ Figures2, 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7. 7 . The results in Table ​ Table3 3 are divided into mean values and standard deviation of the means. From all the periodontal parameters, only BOP and PI were reported by all eight shortlisted studies. Mean values for BOP were consistently higher in control compared to vaping groups. Meanwhile, PI values were consistently higher in vaping groups compared to control.

Extracted study results with means and standard deviations

Note : Percentage of plaque index (%). Percentage of bleeding on probing (%). Clinical attachment loss in millimeters (mm). Probing depth in millimeters (mm). Marginal bone loss in millimeters (mm).

Abbreviations: BOP, bleeding on probing; CAL, clinical attachment loss; MBL: marginal bone loss; PD: pocket depth; PI: plaque index; SD, standard deviations.

Linear plaque index (PI) comparison across studies (%). Where 0 is the control and 1 is the vaping group. PI results are consistently increased across studies with the use of e‐cigarettes

Linear bleeding on probing (BOP) comparison across studies (%). (%). 0 indicates the control group and 1 the vaping group. BOP results are consistently and dramatically lowered with e‐cigarette intervention

Linear clinical attachment loss (CAL) comparison across studies (mm) (%). 0 indicates the control group and 1 the vaping group. CAL results are increased with e‐cigarette intervention in all studies with exception to Vohra et al

Linear probing depth (PD) comparison across studies (mm) (%). 0 indicates the control group and 1 the vaping group. PD results are increased with e‐cigarette intervention in all studies with exception to Vohra et al

Linear mesial marginal bone loss comparison across studies (mm). (%). 0 indicates the control group and 1 the vaping group. Mesial MBL results showed a trend to increasing with e‐cigarette intervention, however, some studies reported lower levels in vaping groups

Linear distal marginal bone loss comparison across studies (mm) (%). 0 indicates the control group and 1 the vaping group. Distal MBL results showed a trend to increasing with e‐cigarette intervention, however, some studies reported lower levels in vaping groups. Figures ( ​ (2, 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7): 7 ): Effect of vaping in mean values of periodontal parameters from each study, where control groups are represented by 0 and vaping groups are represented by 1. (2–3) Measures in percentage, and (4–7) measures in millimeters

CAL results were reported in four of the included studies (BinShabaiba et al., 2019 ; Javed et al., 2017 ; Mokeem et al., 2018 ; Vohra et al., 2020 ). With exemption to one study which showed no difference between the two groups, all other results for CAL were increased in vaping groups (Vohra et al., 2020 ). This indicated that subjects who vaped consistently showed more loss of clinical attachment compared to non‐smokers. Differences in probing depth (PD) results were reported in three of the included studies (BinShabaiba et al., 2019 ; Mokeem et al., 2018 ; Vohra et al., 2020 ). Two of these studies showed increased PD in vaping groups while one study showed no difference (BinShabaiba et al., 2019 ; Mokeem et al., 2018 ; Vohra et al., 2020 ). MBL results are divided into mesial and distal measurements, they were reported in all studies with one exception (Alqahtani et al., 2019 ).

Overall results except for two studies showed increased values in the vaping groups (Javed et al., 2017 ; Vohra et al., 2020 ). Interestingly, one study reported mild changes in all periodontal parameters related to vaping (Vohra et al., 2020 ). This was the only study that was found to show this phenomenon. Most of the studies, as it can be seen from Figures ​ Figures2, 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7, 7 , reflected a different trend that alluded to the negative effect of vaping on periodontal tissues.

Statistical analysis was made with a linear mixed model, and the estimate of fixed effects is shown in Figure ​ Figure8. 8 . The values reported in Figure ​ Figure8 8 reflect the combination of all results from individual studies reported in Figures ​ Figures2, 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7, 7 , generating one value to represent the effect vaping is causing in each periodontal parameter. Estimate of fixed effect of vapers compared to controls for BOP was 13.73% ( p < .0001) less, for PI was 13.32% ( p < .015) more, for CAL was 0.2 mm more ( p < .5), for PD in % greater than 4 mm was 3.26% more ( p < .2), PD in mm was 1.18 mm more ( p < .03) for MBL mesial was 0.19 mm more ( p < .4) and MBL distal was 0.12 mm more ( p < .7).

Fixed effect regression model weighted by standard deviations calculated with IBM SPSS. Summary of effects of vaping in each periodontal parameter, where 0 and the bars are a representation of the combined values from Figures ​ Figures2, 2 , ​ ,3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7 7 after weighting. In this figure, 0 is the control group and the bars are the differences between control groups and vaping groups

4. DISCUSSION

This was the first review conducted to assess the impact of vaping on periodontitis by investigating the changes in periodontal parameters in vape users compared to control groups. Several recent studies have illustrated the effects of vaping on periodontal parameters and we found it relevant to the dental community to have their results combined and analyzed to better understand what impacts to expect from this trend.

Previous studies have compared the effects of vaping to smoking on periodontal parameters, using three group models with cigarette smokers, vape users, and non‐smokers, and found that vape users have results closer to non‐smokers than smokers do (Javed et al., 2017 ; Subhi et al., 2019 ). This goes following the results we are seeing in this review, wherewith combined results, vape users did not have exacerbated differences from non‐smokers.

However, there are potentially harmful effects of vaping in general health that should be considered. Besides the previously mentioned metals present in the aerosol, blast injuries, DNA damage, and overproduction of ROS (Kite et al., 2016 ; Lerner et al., 2016 ; Shaito et al., 2017 ), vaping have been linked to cases of severe pulmonary disease in the US (Hammond, 2019 ).

For the statistical analysis of the extracted results, we assigned weights to each study inversely proportional to their standard deviation. Two of the included studies were assigned the highest weights (Javed et al., 2017 ; Mokeem et al., 2018 ). These studies assess CAL, which would be the measurements of choice to detect periodontitis as suggested by the latest classification (Tonetti et al., 2018 ). The results from these two studies show the most reliable data representing the effects of vaping on periodontal disease in a generalizable context.

The comparison of CAL between the two groups did not show a significant p value in the estimate of fixed effects due to the limitation in the number of available results. Whereas, PD, PI, and BOP had significant p values. Changes in the PD and PI point to the deleterious effect of vaping on periodontal tissues. Vaping groups present lower BOP when compared to controls. Differences in BOP may be attributed to the presence of nicotine in e‐cigarettes. Nicotine is known to be a vasoconstrictor, which would lead to reduced natural blood flow to the gums and could result in tissue ischemia and impaired healing properties (Silverstein, 1992 ). A reduction is BOP is a rather negative effect than positive, as gingival bleeding is a symptom that could alarm patients about the need for professional treatment. Without bleeding, the first clinical symptom the patient can perceive is tooth mobility, in a more advanced stage of periodontal disease.

PD results showed deeper pocket depths in vape users compared to control. A deeper pocket site raises a flag for a possible region of inflammation with further tissue destruction. The results from the statistical analysis of this review suggest that vaping might mediate the host's immune response leading to further tissue destruction. Given the popularity vaping has been gaining over recent years, it is important to bring attention to different side effects associated with its use. The papers included in this review were the first ones to analyze the effects of vaping on periodontitis and yield clinical measurement results. However, a few considerations should be taken when interpreting these results.

Firstly, vaping is a relatively new activity, and the duration of the activity until the investigation point may be too short to express all its effects. Also, the selected studies for data extraction were all case–control studies with no follow‐up (Al‐Aali et al., 2018 ; AlQahtani et al., 2018 , 2019 ; ArRejaie et al., 2019 ; BinShabaiba et al., 2019 ; Javed et al., 2017 ; Mokeem et al., 2018 ; Vohra et al., 2020 ). It would be more applicable to have a longitudinal approach to investigate how vaping influences the periodontal status of the users over the years.

Lastly, there was a limited number of available studies, only eight clinical studies investigating vaping effects on periodontal status were eligible. From these, four were at moderate risk of bias (Al‐Aali et al., 2018 ; AlQahtani et al., 2018 ; ArRejaie et al., 2019 ; Vohra et al., 2020 ). Furthermore, all eight extracted results from a homogeneous population, all groups consist exclusively of males from Saudi Arabia. It must also be noted that in this region, shisha smoking is a very popular activity, and could have influenced these studies results. More studies from different regions are needed to better understand the impacts of vaping on periodontitis.

5. CONCLUSION

The effects reported in this review are relatively non‐significant in a clinical context, however, as mentioned earlier, these results should be interpreted with caution, as four of the eight included studies fell into the moderate risk of bias. Although there is not enough evidence to fully characterize the impacts of vaping on periodontitis, the available results point to an unhealthy impact of vaping in the disease, which calls for further clinical studies to assess the effects of vaping on periodontitis longitudinally.

Figueredo CA, Abdelhay N, Figueredo CM, Catunda R, Gibson MP. The impact of vaping on periodontitis: A systematic review . Clin Exp Dent Res . 2021; 7 :376–384. 10.1002/cre2.360 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

[Correction added on 30 December 2020, after Online publication: First and third author affiliations have been corrected in this current version.]

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