Introduction
According to the World Health Organization (WHO) forecast, the number of smokers in the German population over 15 years old could reach around 16.2 million by 2025. In the USA, on average, about 1500 youth aged 12–17 smoke their first cigarette daily, and more than 200 adolescents aged 12–17 become daily smokers. This would continue the downward trend, and the number would be more than a quarter lower than in 2000 (22.22 million). Regular smoking can cause various pathologies such as cardiovascular disease [
1], respiratory disorders [
2], and periodontitis [
3‐
6] and is the single most preventable cause of death worldwide. Triggers for many pathologies include over 90 proven carcinogenic and toxic cigarette substances, some resulting from the burn process. These include polycyclic hydrocarbons, nitrosamines, and aldehydes [
7,
8]. Electronic nicotine delivery systems (ENDS) (e.g., electronic cigarettes, vaporizers, vape pens, shisha pens, and e-pipes) are said to prevent the formation of unwanted products by bypassing the combustion process.
The tobacco industry and related industries market and promote ENDS as “safer” alternatives to traditional cigarettes, and many users consider them to be significantly “less harmful” than tobacco products, particularly cigarettes [
9]. Consequently, the rising frequency of use of electronic cigarettes, particularly in the USA and Europe, with prevalence rates of regular and/or current use among adults ranging between 0.9 and 1.8%, respectively, is unsurprising [
10‐
12]. By 2018, more than 3.6 million adolescents had tried ENDS, including 4.9% of middle school students and 20.8% of high school students [
13]. Initial scientific studies reporting lower physical harm caused by ENDS and emphasizing their benefits in smoking cessation further promoted their popularity and international sales.
While Public Health England and the Royal College of Physicians argued for a 95% reduction in health risks from electronic cigarettes based on evidence from short-term studies [
14,
15], another set of experimental studies, such as those from the University of Rochester’s School of Medicine and Dentistry, refuted the harmlessness of vaporizers [
16]. To date, evidence on using ENDS as a cessation aid is inconclusive. Since the oral cavity, the first upper respiratory tract station, is the primary exposed region when smoke is introduced, the influence on oral health and here specially on periodontal health is significant. Current studies proved that smoking and vaping are risk factors (ENDS: odds ratio = 2.3, 95% confidence interval (CI) = 1.52 to 3.59; conventional cigarettes: odds ratio = 2.2, 95% CI = 1.76 to 2.68) for periodontal disease [
17] with about eight million of periodontal disease cases in Germany and about forty million worldwide linked to smoking [
18]. One of the main reasons is smoke-related functional and morphological impairment of gingival fibroblasts [
19]. Besides, smokers have been reported to have a poorer oral hygiene when compared to non-smokers [
20]; tar in tobacco products might conduct pigmentation and accumulation of bacteria on tooth surfaces [
21]. Nicotine-dependent oral effects are local vasoconstriction and a reduced blood flow that will reduce gingival oxygen and blood supply. Tobacco and ENDS might also decrease oral immunoglobulin levels [
22] and alter the oral microbiome [
23], leading to several pathogenic microbes [
21,
24]. Smoking results in discoloration of the tooth structure; changes in taste and olfactory perception are also reported [
5]. In addition to periodontal disease, cigarette smoke is considered a significant cause in the development of oral squamous cell carcinoma [
25‐
27]. This systematic review and meta-analysis aimed to determine whether and to what extent the consumption of ENDS bears advantages and disadvantages on periodontal health (bleeding on probing (BoP), plaque index (PI), probing depth (PD), attachment loss (AL), marginal bone loss (MBL), tooth loss, molecular inflammation markers, salivary flow rate) compared to conventional cigarette smoke and non-smokers.
Discussion
Available data on the oral harms of e-cigarettes remain limited and show little evidence, not least because of the need for high-quality randomized controlled trials. Another problem is the need for comparability of most studies due to individually different, non-standardized compositions of the e-liquids and the vast difference in ENDS systems. While the effects of nicotine on oral mucosal tissue types are known in many aspects, the influence of the regularly added flavor components [
70], as well as the carrier substances propylene glycol (PG) and glycerol, especially after vaporization, is mainly unknown [
71]. For instance, it has been shown that increased concentrations of menthol are more likely to cause oral mucosal irritation than increased concentrations of nicotine [
70]. Commonly reported oral symptoms of e-cigarette use or direct e-liquid exposure included dryness, burning, irritation, bad taste, bad breath, pain, and discomfort [
72]. Most of the symptoms were short-term effects that were less frequent or less severe in e-cigarette users than in cigarette smokers.
This systematic review and meta-analysis examined how e-cigarettes and cigarettes affect periodontal health when compared to non-smokers. To objectify the periodontal health status, the parameters: bleeding on probing (BoP), plaque index (PI), periodontal probing depth (PD), attachment loss (AL), marginal bone loss (MBL), and molecular inflammation markers as signs of periodontal inflammation, were systematically summarized. These parameters were regularly analyzed in the literature [
20,
72,
73]. Other surrogate parameters were tooth loss rate and unstimulated salivary flow rate.
BoP was the primary test parameter in this study. In clinical practice, BoP is an early marker for gingivitis and periodontal disease [
74]. BoP was examined in seven of the included studies, whereby analysis revealed that BoP was significantly increased in non-smokers compared with smokers [
20,
56,
57,
61,
63]. Reasons given for the lower bleeding in smokers relate to the vasoconstrictive effects of nicotine [
75,
76]. Nonetheless, there is controversy among authors regarding the vasoconstrictive effects, as experimental studies indicated a short-lasting increase in blood flow on nicotine [
77‐
81]. The long-term negative impact of nicotine consumption on gingival blood flow was demonstrated in a study by significantly lower gingival oxygen saturation in smokers compared to non-smokers [
82]. Smoking does not seem to influence the microcirculatory vessel quantity, so instead of reducing the number of vessels, a restructuring could be detected [
83], which could ultimately promote functional vascular changes causing endothelial dysfunction [
84,
85].
Regarding BoP in periodontal screening, it should continually be assessed considering the reduced gingival blood flow in long-term smokers and e-cigarette users [
66,
86]. When comparing cigarette smokers and e-cigarette users, there was a 0.33-fold reduced chance of positive BoP in e-cigarette users (
p = 0.03) [
20,
56,
57,
63,
66,
67,
68]. Critically, none of the included studies gave information on the nicotine concentration or the vaporizer models used, which complicates the comparability of the studies. The main problems are associated with different parameters such as coil voltage [
88], puff topography [
89], and nicotine delivery rates [
90]; also, one needs to consider that a majority of e-cigarette users might have smoked conventional cigarettes before and this effect might be an additional bias. Meta-regression analyses examining the influence of various covariates revealed that age did not positively influence the odds of a positive BoP test in cigarette smokers or e-cigarette users. This contradicts the literature and the postulation of decreasing gingival perfusion with increased age [
91‐
94]. Likewise, neither the duration nor the daily use of cigarettes or e-cigarettes significantly impacted a positive BoP event. When comparing non-smokers and e-cigarette users, it was found that the risk of a positive BoP test result was significantly (
p < 0.01) increased (OR = 0.01) in non-smokers than in e-cigarette users. In addition to the long-term nicotine-induced reduction in gingival perfusion, patient-related (better oral hygiene in e-cigarette users than in non-smokers [
20]) or examiner-dependent aspects (varying sounding pressure can lead to false-positive or false-negative results [
95] or undetected minor bleeding) may also be influencing factors. Regression analyses in this meta-analysis revealed no significant effect of the covariates age, duration, and frequency of exposure on the risk of bleeding when comparing e-cigarette users and non-smokers.
Regarding the PI, the analyzed studies showed that cigarette smokers presented an increased tendency to form adherent biofilms compared to e-cigarette users and non-smokers [
20,
56,
57,
61,
63,
65,
66]. This follows previous findings by Rad et al. and others who demonstrated a significantly (
p = 0.002) increased PI in cigarette smokers compared with non-smokers [
96‐
99]. Changes in the mineral content due to smoking, namely, a higher calcium concentration in the saliva that could promote plaque accumulation, were initially speculated to be the reason for this observation [
100]. However, emission spectrometric analysis refuted this, showing no difference in potassium, sodium, calcium, phosphate, and magnesium in the saliva due to smoking [
101]. Instead, smokers showed increased salivary mucosity, which is assumed to result from a smoking-associated alteration of the parotid gland [
102].
Similarly, the sublingual and submandibular salivary glands may be affected by smoke in a way to produce predominantly mucosal saliva. Alteration of salivary composition, including enzymes and immunoglobulins, leads to loss of defense functions and may promote plaque formation [
102‐
104]. The influence of the salivary flow rate in this context has been rebutted in the study by Mokeem et al. [
57], whereas others demonstrated a significant reduction of salivary flow rate in smokers compared to non-smokers [
96,
105]. Possible reasons suggest a chemical-thermal degradation of nitric oxide [
106], an autoregulator of salivary secretion, and a reduction of salivary secretion due to nicotine-mediated vasoconstriction [
107,
108]. Inadequate oral hygiene [
109], which manifests itself in shorter brushing times [
110‐
112], is another aspect that should also be considered for increased plaque formation. Motivation and oral hygiene among e-cigarette users [
20] and non-smokers [
106,
113,
114] are mostly higher than in smokers.
PD is an important indicator of periodontal health. As the distance between the enamel-cement interface and the sulcus floor increases, the damage to the periodontal attachment area increases as well. Across the reviewed studies in this work, significantly increased probing depth was seen in cigarette smokers compared to e-cigarette users and non-smokers [
20,
56,
57,
61,
63]. The suspected cause is nicotine, which induces cell membrane damage, tissue degeneration, endothelial cell damage, and vascular muscle changes in a concentration-dependent manner [
3]. The more significant damage in terms of increased probing depths in cigarette smokers compared with e-cigarette users is most likely due to the prolonged exposure to noxious substances in usually older cigarette smokers (mean = 42 years) compared with e-cigarette users (mean = 28 years) [
56,
57,
61,
63,
66]. Only one study concluded that PD in e-cigarette users did not significantly differ from smokers. This could be explained using prolonged abuse, i.e., the period during which the user smokes or vapes, and a long smoking history among e-cigarette users [
20].
In contrast, other researchers found that e-cigarette users were almost three times more likely to report gingival disease than non-smokers/non-users [
115]. This is consistent with the results of the included studies [
57,
61,
63]. Pathogenetically, it is assumed that epithelialization, collagen synthesis, and angiogenesis are postponed while immune cell function is reduced at an increased age [
91‐
94,
116]. Clinical attachment loss, defined as the distance between the enamel-cement interface and the gingival margin, was addressed in four included studies [
56,
57,
61,
63]. Significantly increased attachment loss was observed in cigarette smokers compared to e-cigarette users and non-smokers [
57,
61]. However, all included studies found no difference between e-cigarette users and non-smokers. In brief, one possible explanation could be the younger average age of e-cigarette users with shorter exposition history and superior regeneration potential.
MBL in millimeters, defined as the distance 2 mm below the enamel-cement interface or implant platform to the crestal alveolar bone [
20], was analyzed radiographically in all included studies [
56,
57,
61]. The
κ-values for determining the interrater reliability ranged between 0.8 and 0.9. Bone loss was significantly higher in cigarette smokers than in non-smokers in the included studies. In addition to nicotine [
117], other noxious substances such as benzenes and cadmium are considered responsible for inhibiting osteoblast proliferation and a chemokine-mediated reduction in bone-forming processes [
118‐
122]. Other impairments from cigarette smoking were also shown concerning vitamin metabolism, as smokers were 50% more likely to have vitamin D deficiency than non-smokers [
123]. In combination with a dysregulated calcium metabolism, this could be a possible explanation for an increased MBL in smokers. Compared with e-cigarette users, MBL was also significantly increased in cigarette smokers within the included studies of this meta-analysis [
20,
57,
61]. Comparing non-smokers and e-cigarette users, the included literature was inconsistent, ranging from no difference [
57,
61] to significantly increased rates of marginal bone loss in e-cigarette users [
20].
Concerning the number of lost teeth, the included studies revealed no significant differences between smokers, e-cigarette users, and non-smokers [
56,
61,
63]. Potential reasons could involve selecting participants in different age groups and, thus, divergent exposition profiles.
Bioanalytical methods were used to determine molecular markers. For this purpose, either sulcus fluids [
20,
61] or saliva samples [
57] were taken from the patients. Immunoassays then reveal concentrations of interleukins (IL), interferons (IFN), matrix metalloproteinases (MMP), and tumor necrosis factors (TNF). The included publications indicated significantly increased levels of IL-1β, IL-6, IFN-γ, TNF-α, MMP-8, and MMP-9 in smokers compared with non-smokers [
20,
57,
61]. A specific metabolite of nicotine, the alkaloid nornicotine, is assumed to trigger a higher concentration of cytokines. Pathogenetically, nornicotine-triggered overexpression is thought to involve gingival localized receptors for advanced glycation end product (RAGE) expression. RAGE binds proteins and/or lipids, which are glycolyzed into advanced glycation end products (AGEs) after exposure to sugar, causing the release of oxygen radicals and cytokines [
124‐
127]. This results in an excessive immune response, which leads to periodontal degeneration in terms of connective tissue degeneration and osteoclast-mediated bone resorption [
126]. As smokers in the included studies had significantly increased cytokine levels, it is questioned whether the formation of the alkaloid nornicotine is reduced or completely absent in e-cigarette users. This was disproved by Bustamante et al. when a transformation product of nornicotine, N′nitrosonornicotine (NNN), was also detected in the urine of e-cigarette users. However, the concentration was significantly reduced in e-cigarette users, which could explain the lower cytokine levels compared to cigarette smokers [
128]. While two of the included studies did not find significant mediator differences between e-cigarette users and non-smokers [
57,
61], ArRejaie et al. showed significantly increased IL-1β and TNF-α levels in e-cigarette users [
20]. Likewise, it is essential to highlight the correlation between elevated mediator levels and increased marginal bone atrophy in cigarette smokers (MMP-9 and IL-1β) and e-cigarette users (IL-1β) [
20]. However, both mediators play a crucial role in bone degradation, which nicotine enhances. Accordingly, the observations in the literature are consistent with the findings in the publications included. Smokers demonstrated the highest bone atrophy and levels of MMP-9 and IL-1β compared to e-cigarette users and non-smokers. E-cigarette users also had significantly increased IL-1β and MMP-9 in peri-implant sulcus fluid compared with non-smokers [
20]. However, MBL was not increased. This could be explained by the reduced formation of oxygen radicals in e-cigarette users, which has already been demonstrated in vitro [
128].