The wide variety of vaping cartridges available for purchase has complicated efforts to trace the cause of a mysterious lung disease.Credit: Richard Vogel/AP/Shutterstock

Until a few months ago, pulmonologist Sean Callahan didn’t typically ask his patients if they vaped. He thought that e-cigarettes might help smokers wean themselves off cigarettes, and that the risks of vaping would probably take years to become clear.

The emergence of a mysterious, sometimes lethal, lung injury associated with vaping has changed his mind. Callahan works at the University of Utah Health in Salt Lake City, which has treated about 20 victims of the outbreak. “It was surprising: the overwhelming number of them — and how young they were,” he says.

Researchers and physicians alike were caught unprepared by the illness, which has now sickened about 1,300 US vapers and killed 26. Scientists are scrambling to find out why, and to save other vapers from the same fate. “Everything is rapidly evolving,” says Brandon Larsen, a pulmonary pathologist at the Mayo Clinic in Phoenix, Arizona. “I could tell you something today and next week it could be totally wrong.”

A paper1 published by Larsen and his colleagues in the New England Journal of Medicine on 2 October undercut a popular theory behind the outbreak — and underscored how far researchers still have to go to pinpoint its cause.

Disease detectives

Many of those sickened in the outbreak had vaped cartridges containing tetrahydrocannabinol (THC) — the active ingredient in marijuana — that was diluted with oily chemicals.

Larsen’s study is the largest analysis to date of lung tissue taken from sickened vapers. The scientists searched for evidence of lipoid pneumonia, a condition that arises when oil enters the lungs. It is marked by lipid found in lung tissue and also in cells called macrophages, which normally sweep up debris in the lungs. But Larsen and his colleagues did not find substantial lipid droplets in any of their samples from 17 patients. Instead, their findings point to general lung damage and inflammation caused by exposure to toxic chemicals.

There are reasons to be sceptical of those results, says Kevin Davidson, a pulmonologist at WakeMed, a hospital system based in Raleigh, North Carolina. He says that Larsen looked for signs of disease that would be apparent only if someone had inhaled a large amount of oil all at once, not small amounts over time.

But Larsen’s findings do align with mouse studies2 carried out by Farrah Kheradmand, a pulmonologist at Baylor College of Medicine in Houston, Texas. Her team found lipids accumulating in the lung macrophages of mice exposed to e-cigarettes. The scientists traced the build-up to the breakdown of pulmonary surfactant, a lipid-rich compound produced by the lungs. Kheradmand says this suggests that vaping damages cells that line airways and help to maintain surfactant levels.

She is now hoping to repeat her mouse studies using e-cigarette vapour that contains vitamin E acetate, an oily chemical that has been suggested as a cause of the vaping illness. Other researchers are considering similar experiments. Steven Rowe, a pulmonologist at the University of Alabama, Birmingham, hopes to test suspected culprits using ferrets, to learn how vaping affects ion transport in human lung cells. And Quan Lu, a lung biologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts, is planning an experiment to look at what genes are switched on or off in lung cells taken from vapers. He hopes to get tissue samples from those who have become ill.

But Kheradmand cautions against hoping for quick answers: her initial mouse study took three and a half years to complete.

“Science will win at some point,” says Albert Rizzo, chief medical officer at the American Lung Association in Chicago, Illinois. “But I don’t think it’s going to be as soon as people would like.”

Many suspects

More immediately, researchers are scrambling to categorize the chemicals contained in e-cigarettes. That is no simple task when there are thousands of products available, and a culture of users modifying e-cigarettes and their contents to change characteristics such as flavour or amount of vapour produced. “This is a tough nut to crack, to be honest,” says Larsen. “And that’s where the research really needs to go: figuring out what the contents are in all of these things.”

The range of chemicals that vapers are exposed to is dazzling, says Mignonne Guy, a biobehavioural researcher at Virginia Commonwealth University in Richmond. Her laboratory has studied YouTube videos and other online sources to learn more about how e-cigarette users are modifying their devices. They found that vapers are altering everything from how hot their e-cigarettes get to what chemicals are included in vaping cartridges — including, in at least one instance, liquid Viagra.

Online forums have pointed computational epidemiologist Yulin Hswen towards an early-2019 spike in posts about how to make e-cigarette cartridges. This was soon followed by an increase in posts from users warning about black-market cartridges sold with branding that could mislead the purchaser into thinking they were made by a reputable company. Hswen, who works at the Harvard School of Public Health in Boston, Massachusetts, plans to look more closely to see whether this spike in homebrew cartridges could have contributed to the outbreak.

Ultimately, researchers might never be able to track down a single cause for the outbreak, says David Christiani, a pulmonologist at Harvard's public-health school. But even just narrowing it down to a process — such as using oils to dilute THC — could help to squelch the current epidemic and save lives. “We have a very serious epidemic and we absolutely need to get that under control,” he says. “Then that will allow us to go back to focusing on chronic effects of vaping.”