Thomas A. Wills and colleagues just published “E-cigarette Use and Respiratory Disorder: An Integrative Review of Converging Evidence from Epidemiological and Laboratory Studies” in European Respiratory Journal that, as the title indicates, sums up the evidence linking e-cigarette use with respiratory disease epidemiological studies of the population as a whole as well as briefly summarizing the biological studies on how e-cigarettes adversely affect the lung. The bottom line: For 15 studies of asthma (11 of youth, mostly high school students, and 4 of adults), the pooled adjusted odds ratio (AOR) was 1.39 (CI 1.28-1.51) and for 9 studies of chronic obstructive pulmonary disease (COPD) the AOR was 1.49 (CI 1.36-1.65).
One issue that e-cigarette enthusiasts like to highlight is that most e-cigarette users are former smokers or dual users of cigarettes and e-cigarettes, so that the associations the epidemiology detects is an artifact of smoking rather than effects of e-cigarettes. Wills et al paid particular attention to this issue:
Four general issues are important for interpretation of this literature. First, because combustible cigarette smoking is correlated with e-cigarette use and is a risk factor for respiratory disease, it is crucial to control for this correlation in multivariable analyses. As noted in the tables, most of the studies did control for cigarette smoking, indicating that observed effects for e-cigarettes are not attributable to confounding with smoking. Second, when e-cigarette use and cigarette smoking are entered together in a multivariable analysis, if they both show significant contributions to respiratory disease (i.e., additive effects) then the implication is that persons who both use e-cigarettes and smoke cigarettes will be worse off than exclusive e-cigarette users or exclusive smokers. … Third, it is possible that the association between smoking and respiratory disease is different for persons who use e-cigarettes (i.e., interaction effect). … Fourth, with cross-sectional data the finding of a positive association for e-cigarettes and respiratory disease could be interpreted as meaning that persons who develop disease quit smoking cigarettes and take up e-cigarettes (i.e., reverse causation). This possibility may be addressed in cross-sectional data through internal analyses that logically would work against an interpretation of reverse causation. Alternatively, longitudinal data showing that e-cigarette use precedes disease development in time would work against a reverse-causation interpretation. [cites and statistical details deleted]
Wills et al convincing eliminated these issues and, most important, found that the effects of e-cigarettes add to the effects of cigarettes. In other words, e-cigarettes are an independent risk factor for lung disease and that dual use, the most common use pattern, is more dangerous than smoking alone. In addition to the pooled (meta-analysis) results, Wills et al noted that,
A significant association of e-cigarette use with respiratory disorder was found across 23 of the 24 studies reviewed, and e-cigarette use typically added independently to risk derived from cigarette smoking. The studies had large representative samples drawn from multiple states and countries, and the analyses included a number of covariates so as to rule out several possible types of confounding.
Building on earlier reviews of the biological effects of e-cigarettes (references 27, 28, and 62 in their paper and, more recently and comprehensively, Gotts et al), Wills et al also summarize and update biological studies that predict the population epidemiological studies:
Laboratory studies have shown e-cigarettes to have effects on four biological processes that are relevant for respiratory disease. Evidence is found for exposure to e-cigarette liquid or aerosol producing cytotoxic effects and oxidative stress. Results for inflammation are less consistent but effects on cytokines and other indices of inflammation have been found in several studies. Both cell studies and animal models indicate that bacterial virulence and indices of susceptibility to infection are increased by e-cigarette exposure and that bacteria- and virus-infected animals show higher morbidity and mortality when they are exposed to e-cigarette aerosol. Finally, studies of genetic variables have found e-cigarettes to cause DNA damage and e-cigarette use to suppress genes involved in immune function, with pathways that can be distinct from those found for cigarettes. While comments have been made about specific aspects for some of the studies (107-110), the finding of biological effects for e-cigarettes across four outcome domains in both cell cultures, animal models, and human studies shows a replicable body of findings linking e-cigarettes to several biological processes involved in the pathogenesis of respiratory disease in humans.
Summing things up, they conclude:
Epidemiological studies have consistently noted that dual users have significantly more respiratory symptomatology compared with exclusive e-cigarette users or exclusive smokers. While e-cigarette use tends to be correlated with smoking, they are not interchangeable and they produce additive effects. Laboratory studies of genetic expression also show that effects of e-cigarettes occur in part through different biological pathways than cigarettes. E-cigarette use does not merely parallel effects of smoking, but contributes independently to risk. Thus there is every reason to work actively to deter e-cigarette use among smokers as well as nonsmokers.
The bottom line, this paper substantially strengthens the case that e-cigarettes cause lung disease and that dual use is more dangerous than just smoking. Policymakers, including regulators at the FDA and other similar agencies around the world, have to accept the fact that e-cigarettes generate substantial and reasonably rapid increases in risk of lung disease in both youth and adults and remove these dangerous products from the market. Countries that have not allowed these products to be sold should maintain those policies. In the meantime in the USA, state and local authorities should continue to end the sale of these products to fill the vacuum that the FDA has left.
Here is the abstract:
Background. Use of electronic cigarettes (e-cigarettes) is prevalent among adolescents and young adults but there has been limited knowledge about health consequences in human populations. We conduct a systematic review and meta-analysis of results on respiratory disorder from studies of general-population samples and consider the mapping of these results to findings about biological processes linked to e-cigarettes in controlled laboratory studies.
Method. We conduct a literature search and meta-analysis of epidemiological studies on the association of e-cigarette use with asthma and with chronic obstructive pulmonary disease (COPD). We then discuss findings from laboratory studies about effects of e-cigarettes on four biological processes: cytotoxicity, oxidative stress/inflammation, susceptibility to infection, and genetic expression.
Results. Epidemiological studies, both cross-sectional and longitudinal, show a significant association of e-cigarette use with asthma and COPD, controlling for cigarette smoking and other covariates. For asthma (n = 15 studies), the pooled adjusted odds ratio (AOR) was 1.39 (CI 1.28-1.51); for COPD (n = 9 studies) the AOR was 1.49 (CI 1.36-1.65). Laboratory studies consistently show an effect of e-cigarettes on biological processes related to respiratory harm and susceptibility to illness, with e-cigarette conditions differing significantly from clean-air controls though sometimes less than for cigarettes.
Conclusions. The evidence from epidemiological studies meets established criteria for consistency, strength of effect, temporality, and in some cases a dose-response gradient. Biological plausibility is indicated by evidence from multiple laboratory studies. We conclude that e-cigarette use has consequences for asthma and COPD, which is of significant concern for respirology and public health.
The full citation is: Wills TA, Soneji SS, Choi K, et al. E-cigarette Use and Respiratory Disorder: An Integrative Review of Converging Evidence from Epidemiological and Laboratory Studies. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.01815-2019). It is available here.
Credit for illustration: https://coloradoallergy.com/asthma-101/