Experts Review History of E-Cigarettes and Mechanisms of Vaping-Associated Lung Illness


During the session The Past, Present, and Future of E-Cigarette or Vaping Associated Lung Illness (EVALI) on May 16 at ATS 2022, an international panel of experts reviewed what is known about EVALI, mechanisms of injury, and the needed clinical, public health, and regulatory efforts to curb EVALI and prevent future e-cigarette induced lung injury.

Elif Dagli, MD
Elif Dagli, MD

Elif Dagli, MD, Marmara University, Istanbul, Turkey, opened the session with a discussion of the history and public health consequences of EVALI.

The advent of e-cigarettes can be traced, she said, to water pipes in the Middle East, which were used mostly by older men because they were flavorless and very harsh. During the late 1990s, there was a sudden increase of water pipes containing flavors, starting in the Middle East, and moving to Asia, North Africa, Europe, and then the United States.

“Suddenly, even women who had been coming from very restricted backgrounds, religious backgrounds, started using water pipes in the cafes in the open air,” she said.

Few users really knew they contained tobacco and other chemicals. They thought it was just water sweetened with fruit, she said.

From the water pipes came e-cigarettes. Legislation and regulatory mechanisms struggled to keep pace with the changing product characteristics and even the scientific community, Dr. Dagli noted, initially thought they might be less harmful than regular cigarettes. Advertising that encourages smokers to quit smoking and start vaping began popping up.

Matthew D. McGraw, MD
Matthew D. McGraw, MD

Today, Dr. Dagli said, the United States, Canada, and Europe are consuming more e-cigarettes than the rest of the world. Meanwhile, 41 countries have banned selling them; more than 60 countries restrict sales of them; 32 countries regulate nicotine; and Australia only sells nicotine by prescription.

Matthew D. McGraw, MD, pediatric pulmonologist, University of Rochester, spoke next about the spectrum of illnesses from e-cigarettes. He highlighted a 2019 federal report showing that most states were affected by acute EVALI, and that it appears to have peaked in September 2019. After that, the CDC was strapped for time and money because of COVID-19 so tracking EVALI was not prioritized.

Dr. McGraw explained the precise impact EVALI has on the bronchial tubes and lungs and noted that one of the key biomarkers that has been reported by the CDC is the presence of vitamin E acetate in bronchoalveolar lavage fluid.

At the peak of the epidemic in 2019, most EVALI patients were male, but there has been a shift towards the female population, he added.

Brandon T. Larsen, MD, PhD
Brandon T. Larsen, MD, PhD

“We still are in dire need of additional help,” Dr. McGraw said. “Specifically in the outpatient setting where those [with EVALI] that are reported are slim to none. And that’s because, at a national level, we don’t have any way of tracking.”

Brandon T. Larsen, MD, PhD, pulmonology pathologist, Mayo Clinic, Scottsdale, spoke about what pathology has uncovered about EVALI from looking at lung tissue.

The pathology of EVALI shows the entire spectrum of acute lung injury that’s possible with any kind of injury that occurs in the lungs, according to Dr. Larsen. Pathologists have also spotted foamy macrophages and pneumocytes in lung tissue of EVALI patients. According to Larsen, the effects of EVALI resemble those from drug reactions or toxic chemical fume exposures.

The CDC may have stopped tracking it, he said, but “EVALI is still here. It hasn’t disappeared.”

Laura E. Crotty Alexander, MD, ATSF, associate professor, UC San Diego School of Medicine, and section chief of pulmonary critical care at the VA San Diego, spoke about the intersection of e-cigarette use, EVALI, and pathogen infections.

Laura E. Crotty Alexander, MD, ATSF
Laura E. Crotty Alexander, MD, ATSF

The medical community, Dr. Crotty Alexander noted, has long believed that inhaling e-cigarette chemicals on a daily basis alters the immunophenotype of the lung and the body.

She pointed to a 2019 study in mice which showed that those exposed to e-cigarette aerosols, both with and without nicotine, suffered worsening acute lung injury when a viral infection occurred. Subsequent clinical studies have also shown that e-cigarette vapors, particularly in teenagers and adolescents, cause more symptoms when they get COVID-19. The patients have more inflammation, more coughing and more shortness of breath.

“So, this comes back to the messy business that is e-cigarette research and the fact that each of the chemicals in the aerosol need to be understood and looked at in isolation and in combination, which is a bit daunting,” Dr. Crotty Alexander said.

Alexandra Noel, PhD, MSc, BSc, assistant professor of comparative biomedical sciences, Louisiana State University, discussed the mechanisms of e-cigarette components that contribute to injury.

Alexandra Noel, PhD, MSc, BSc
Alexandra Noel, PhD, MSc, BSc

Dr. Noel noted that the 2019 EVALI outbreak resulted in more than 2,800 reported cases and more than 65 deaths. It was mostly linked to vitamin E acetate and THC-containing products. But EVALI has been seen in patients reporting exclusive use of nicotine-containing vaping products since 2012. So, this clearly indicates that EVALI may not be solely caused by vitamin E acetate in the liquid, Dr. Noel said.

Vaping liquids are mainly composed of humectant, flavoring, chemicals and nicotine and the main humectant includes propylene glycol and vegetable glycerin, she said. There are more than 200 unique flavoring chemicals that lead to the creation of more than 16,000 distinct flavored e-liquids. Nicotine can be present in various chemical forms and concentrations. There are also a lot of unlabeled chemicals in the liquids. Juul, for instance, has high concentrations of caffeine, menthol and tobacco, Dr. Noel said.

Many of these ingredients are safe when used as food additives but when they are heated to over 200 degrees Celsius in an e-cigarette, she said, it can lead to the formation of carbonyls, including acetaldehyde, formaldehyde, and acetone, which are known chemical irritants to the respiratory tract. Other studies have shown that the addition of vanillin or cinnamaldehyde flavoring adds to the toxicity of the humectant.

“There’s a pressing need in e-cigarette research to include standardization across different labs and different continents,” said Dr. Noel. “There is also a need to develop comparative toxicity data in terms of biological outcomes based on oxidative stress, DNA damage, and inflammation for all e-cig components and their mixtures.”

Enid R. Neptune, MD, ATSF
Enid R. Neptune, MD, ATSF

Enid R. Neptune, MD, ATSF, Johns Hopkins School of Medicine, closed the session by discussing how a second EVALI epidemic can be prevented by looking at outcomes from the The Environmental, Occupational and Population Health EVALI Workshop.

EVALI reflected a perfect storm of factors, she said, adding that one of the most critical factors is mixology which is dependent on the vape store where cocktails can be generated by recipes available online and often used with refillable cartridges. Many prefilled cartridges were used by persons who had EVALI, Dr. Neptune said, noting that they were illicitly refilled cartridges.

Another factor, she said, was the public perception that e-cigarettes may be safer than combustible cigarettes and cigars.

In addition to those factors, she said the FDA was virtually paralyzed because they were flooded with a marketed product that had not been pre-reviewed, and it was concerned about a lawsuit because of a “pro-business posture” by our legislature and judicial system.

To prevent a second EVALI epidemic, Dr. Neptune said, all components of e-cigarettes and vaping solutions must be identified and submitted for review.

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