E-cigarettes and respiratory disease: from "no available evidence" to "significant concern".

Do e-cigarettes cause respiratory diseases (other than EVALI)?

Almost three years have passed since the National Academies on Sciences Engineering and Medicine (NASEM) answered that question with a "we don't know" in their landmark review of the "Public Health Consequences of E-Cigarettes".

The panel of scientists charged with this review looked only at published research that was available before the end of August, 2017. At that time, there were few researchers engaged: of the 17 studies on e-cigarette users the NASEM panel looked at, six were conducted by the same (now somewhat controversial) research team.

With little to go on, the panel found "limited evidence" that on the one hand, e-cigarettes reduced some lung diseases for smokers that switched and, on the other, that it increased lung diseases for non-smokers that vaped. Generally, they concluded that not much was known: "Conclusion 11-1: There is no available evidence whether or not e-cigarettes cause respiratory diseases in humans."

Among their recommendations were a call for the U.S. Food and Drug Administration and others to give priority to funding research into respiratory effects of e-cigarettes. With additional research funding and interest, much more evidence of the impact of e-cigarettes on lung health is available. This post reports on the troubling results of two recently published studies.

Longitudinal study of smokers found e-cigarette users are 30% to 70% more likely to develop respiratory disease

Wubin Xie of Boston University followed 21,000 adults who were participating in the American longitudinal Population Assessment of Tobacco and Health (PATH) study. None of the individuals included in their review reported any respiratory disease at the outset of their participation.

Only a few years later, however, a large percentage of those using e-cigarettes reported respiratory conditions, including COPD, emphysema, chronic bronchitis, and asthma. After adjusting for all possible other factors, the research team found that e-cigarette use was associated with a 30% increase in the risks of chronic bronchitis and asthma, a 60% increase in the risk of chronic obstructive pulmonary disease (COPD), and a 70% increase in the risk of emphysema. They tested for reverse causation and found it not to be an explanatory factor. They repeated the analysis, restricting the analysis to those who had never smoked cigarettes. The results did not change substantially. While cigarette smoking is a known risk factor for respiratory diseases, this study shows that e-cigarette use is an additional independent risk factor for respiratory diseases.

Study: Wubin Xie and colleagues. Association of electronic cigarette use with incident respiratory conditions among US adults from 2013 to 2018.

A review and meta-analyses of the relationship of e-cigarette use and respiratory diseases finds e-cigarette users have a 40% increase in the risk of asthma and 50% increase in the risk of COPD

While Wubin Xie and colleagues were conducting their research in Boston, another group of researchers, Thomas Wills and colleagues were independently researching the same subject from their base in Hawaii, using very different methods. They reviewed past epidemiological studies and conducted meta-analyses of the association of e-cigarette use with asthma and COPD, controlling for cigarette use and other covariates. There were 15 studies in the asthma meta-analysis and 9 studies in the COPD meta-analysis. (Four of the papers they looked at were included in the NASEM review, the others did not meet their selection criteria).

The results of this systematic review were remarkably similar to those posted by Wubin Xie and colleagues: there was a 40% increase in the risk of asthma and a 50% increase in the risk of COPD. The researchers tested competing explanations including possible self-report bias, the possible "ill-worker-effect" and possible reverse causality. None of these alternative explanations stood up to their scrutiny, giving them confidence that the meta-analyses results reflect real relationships.

Dr. Wills and colleagues also provided an updated review of laboratory studies and found that e-cigarette vapours cause biological changes that can lead to respiratory diseases. These adverse biological changes were observed in cell cultures, animal studies and human studies.

The team also assessed their findings against the established criteria for inferring causal relationships, and found that they met the criteria of consistency, strength of effect, temporality, biological plausibility and, in some cases, dose-response gradient. They conclude that "E-cigarette use has consequences for asthma and COPD, which is of significant concern for respirology and public health." 

Study: Thomas Wills and colleagues. E-cigarette use and respiratory disorder: An integrative review and converging evidence from epidemiological and laboratory studies. 

Growing global concerns

Three years after the NASEM report a much larger body of evidence from independent researchers is available for review, and additional scientific panels have been commissioned by international organizations and national governments to consider the evidence. These reviews have been broader in scope, covering other health effects, not just respiratory diseases, and generally conclude that e-cigarettes are not safe.

These reviews include reports by or for the World Health Organization, the European Union, the Irish Government, the Government of the Netherlands, the Australian Government, and the Spanish Government.

In February 2020, the World Health Organization concluded "ENDS [electronic nicotine delivery systems] on their own are associated with increased risk of cardiovascular diseases and lung disorders and adverse effects on the development of the fetus during pregnancy. ENDS are undoubtedly harmful, should be strictly regulated, and, most importantly, must be kept away from children."

In September 2020, based on evidence available up to April 2019, European Union's Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) concluded that:

• for users of electronic cigarettes the overall weight of evidence for risks of local irritative damage to the respiratory tract is:
• moderate for heavy users of electronic cigarette due to the cumulative exposure to polyols, aldehydes and nicotine, and
• not to be excluded for average and light users. However, the overall reported incidence is low.

In June 2020, after reviewing 67 recent pertinent studies, the Irish Health Research Board concluded that e-cigarette use was responsible for "probable harms" due to respiratory diseases.

In April 2020, the Trimbos Institute reported to the Dutch government that "Newer studies provide more and more indications that the use of an e-cigarette could lead to damage to the respiratory tract and the cardiovascular system."

The Australian government website states categorically that e-cigarettes are not safe. The web-site goes on to state "many scientists are concerned that using e-cigarettes could increase risk of lung disease, heart disease and cancer."

A 2020 Spanish Health Department report states that the adverse short-term effects on the respiratory system are similar to those of cigarette smoking.

There is a growing global scientific consensus that e-cigarette use leads to increased risk of respiratory diseases.