It was the arrival of the second man in his early 20s gasping for air that alarmed Dr. Dixie Harris. Young patients rarely get so sick, so fast, with a severe lung illness, and this was her second case in a matter of days.

Then she saw three more patients at her Utah telehealth clinic with similar symptoms. They did not have infections, but all had been vaping. When Harris heard several teenagers in Wisconsin had been hospitalized in similar cases, she quickly alerted her state health department.

As patients in hospitals across the country combat a mysterious illness linked to e-cigarettes, federal and state investigators are frantically trying to trace the outbreaks to specific vaping products that, until recently, were virtually unregulated.

As of Aug. 22, 193 potential vaping-related illnesses in 22 states had been reported to the Centers for Disease Control and Prevention. Wisconsin, which first put out an alert in July, has at least 16 confirmed and 15 suspected cases. Illinois has reported 34 patients, one of whom has died. Indiana is investigating 24 cases.

Lung doctors said they had seen warning signs for years that vaping could be hazardous, as they treated patients. Medically it seemed problematic, since it often involved inhaling chemicals not normally inhaled into the lungs. Despite that, assessing the safety of a new product storming the market fell between regulatory cracks, leaving doctors unsure where to register concerns before the outbreak. The Food and Drug Administration took years to regulate e-cigarettes once a court determined it had the authority to do so.

“You don’t know what you’re putting into your lungs when you vape,” said Harris, a critical care pulmonologist. “It’s purported to be safe, but how do you know if it’s safe? To me, it’s a very dangerous thing.”

Off the radar

When electronic cigarettes came to market about a decade ago, they fell into a regulatory no man’s land. They are not a food, not a drug and not a medical device, any of which would have put them immediately in the FDA’s purview. And, until a few years ago, they weren’t even lumped in with tobacco products.

As a result, billions of dollars of vaping products have been sold online, at big-box retailers and in corner stores without going through the FDA’s rigorous review process to assess their safety. Companies like Juul, Blu and NJoy quickly established their brands of devices and cartridges, or pods. And thousands of related products are sold, sometimes on the black market over the internet or beyond.

“It makes it really tough because we don’t know what we’re looking for,” said Dr. Ruth Lynfield, the state epidemiologist for Minnesota, where several patients were admitted to the intensive care unit as a result of the illness. She added that if it turns out that the products in question were sold by unregistered retailers and manufacturers “on the street,” outbreak sleuths will have a harder time figuring out exactly what is in them.

With e-cigarettes, people can vape — or smoke — nicotine products, selecting flavorings like mint, mango, blueberry crème brûlée or cookies and milk. They can also inhale cannabis products. Many are hopeful that e-cigarettes might be useful smoking cessation tools, but some research has called that into question.

The mysterious pulmonary disease cases have been linked to vaping, but it’s unclear whether there is a common device or chemical. In some states, including California and Utah, all of the patients had vaped cannabis products. One or more substances could be involved, health officials have said. The products used by several victims are being tested to see what they contained.

Because e-cigarettes aren’t classified as drugs or medical devices, which have well-established FDA databases to track adverse events, doctors say there has been no clear way to report and track health problems related to vaping products.

And this has apparently been the case for years.

Multiple doctors described seeing earlier cases of severe lung problems linked to vaping that were not officially reported or included in the current CDC count.

Dr. Laura Crotty Alexander, a pulmonologist and researcher with the University of California-San Diego, said she saw her first case about two years ago. A young man had been vaping for months with the same device but developed acute lung injury when he switched flavors. She strongly suspected a link, but did not report the illness anywhere.

“It wasn’t that I didn’t want to report it, it’s that there’s no pathway” to do so, Alexander said.

She said she’s concerned that many physicians haven’t been asking patients about e-cigarette use and that there’s no way to document a case like this in the medical coding system.

Dr. John E. Parker of West Virginia University said he saw his first patient with pneumonia tied to vaping in 2015. Doctors there were intrigued enough to report on the case at the annual meeting of the American College of Chest Physicians. Parker and his team didn’t contact a federal agency, and Parker said it was unclear whom to call.

Numerous other cases have been reported in medical journals and at professional conferences in the years since. The FDA’s voluntary system for reporting tobacco-related health problems included 96 seizures and only one lung ailment tied to e-cigarettes from April through June of this year. The system appears to be utilized most by concerned citizens, rather than manufacturers or health care professionals.

But several lung specialists said that due to the patchwork nature of regulatory oversight over the years, the true scope of the problem is yet to be identified.

“We do know that e-cigarettes do not emit a harmless aerosol,” said Brian King, a deputy director in the Office on Smoking and Health at the CDC in a call with media on Aug. 23 about the outbreak. “It is possible that some of these cases were already occurring but we were not picking them up.”

Regulatory limits

The FDA has had limited authority to regulate e-cigarettes over the years.

In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act, empowering the FDA to oversee the safety and sale of tobacco products. But e-cigarettes, still new, were not top of mind.

Later that year, the FDA tried to block imports of e-cigarettes, saying the combination drug-device products were unapproved and therefore illegal for sale in the United States. Two vaping companies, Smoking Everywhere and NJoy, sued, and a federal judge ruled in 2010 that the FDA should regulate e-cigarettes as tobacco products.

It took the agency six years to finalize what’s become known as the “deeming rule,” in which it formally began regulating e-cigarettes and e-liquids.

By then, it was May 2016. The e-cigarette market had swelled to an estimated $4.1 billion, Wells Fargo Securities analyst Bonnie Herzog said at the time.Market researchers now project that the global industry could reach $48 billion by 2023.

Critics say the FDA took too long to act.

“I think the fact that FDA has been dillydallying [has made] figuring out what’s going on [with this outbreak] much harder,” said Stanton Glantz, a University of California-San Francisco professor in its Center for Tobacco Control Research and Education. “No question.”

The agency began by banning e-cigarette sales to minors and requiring all new vaping products to submit applications for authorization before they could come to market. Companies and retailers with thousands of products already on the market were granted two years to submit applications, and the FDA would get an additional year to evaluate the applications. Meanwhile, existing products could still be sold.

But when Dr. Scott Gottlieb arrived as the new FDA commissioner in 2017, the rule hadn’t been implemented and there was no formal guidance for companies to file applications, he said. As a result, he pushed the deadline back to 2022, drawing ire from public health advocates, who called foul over his previous ties to an e-cigarette retailer called Kure.

“I thought e-cigarettes at the time — and I still believe — that they represent an opportunity for currently addicted adult smokers to transition off of combustible tobacco,” he said in an interview, adding that other parts of the deeming rule went into effect as planned. “All I did was delay the application deadline.”

Gottlieb’s thinking changed the following year, when a national survey showed a sharp rise in teen vaping, which he called an “epidemic.” He announced that the agency would rethink the extended deadline and weigh whether to take flavors that appeal to kids off the market.

A judge ruled last month that e-cigarette makers would have only 10 more months to submit applications to the FDA. They’re now due in May 2020.

Asked about the lung injuries appearing now, Gottlieb, who left the FDA in April, said he suspected counterfeit pods are to blame, given the geographic clustering of cases and the fact that, overall, the FDA is inspecting registered e-cigarette makers and retailers to make sure they’re complying with existing regulations.

“I think the manufacturers are culpable if their products are being used, whether the liquids are counterfeit or real,” he said. “Ultimately, they’re responsible for keeping their products out of the hands of kids.”

Juul, the leading e-cigarette maker, agreed that children shouldn’t be able to vape its products, and said curtailing access should be done “through significant regulation” and “enforcement.”

“When people say ‘Why aren’t these being regulated?’ They actually are all being regulated,” Gottlieb said.

For example, companies are required to label their products as potentially addictive, sell only to adults and comply with manufacturing standards. The agency has conducted thousands of inspections of e-cigarette manufacturers and retailers and taken enforcement actions against companies selling e-cigarettes that look like juice boxes, and a company that was putting the ingredients found in erectile dysfunction drugs into its vape liquid.

Health departments investigating the outbreak told Kaiser Health News that e-cigarettes’ niche as a tobacco product instead of a drug has presented challenges. Most weren’t aware that adverse events could be reported to a database that tracks problems with tobacco products. And, because e-cigarettes never went through the FDA’s “gold standard” approval process for drugs, doctors can’t readily look up a detailed list of known side effects.

But like other arms of the FDA, the tobacco office has tools and a team to investigate a public health threat just as the teams for drugs and devices do, Gottlieb said. It may even be better equipped because of its funding.

“I don’t think FDA is operating in any way with hands tied behind its back because of the way that the statute is set up,” he said.

Teen vaping has exploded during this regulatory tussle. In 2011, 1.5 percent of high school students reported vaping. By 2018, it was 20.8 percent, according to a CDC report.

Unknown components

Still, doctors and researchers are concerned about the ingredients in e-cigarettes, and how little the public knows about the risks of vaping.

In Juul’s terms and conditions, posted on its website, it says, “We encourage consumers to do their own research regarding vapor products and what is right for them.” Many ingredients in e-cigarette products, however, are protected as trade secrets.

Since at least 2013, the flavor industry has expressed concern about the use of flavoring chemicals in vaping products.

The vast majority of the chemicals have been tested only by ingesting them in small quantities, as they’re encountered in foods. For most of these chemicals, there have been no tests to determine whether it is safe to inhale them, as happens daily by millions when they use e-cigarettes.

“Many of the ingredients of vaping products, including flavoring substances, have not been tested for … the exposure one would get from using a vaping device,” said John Hallagan, a senior adviser to the Flavor and Extract Manufacturers Association. The group has sent cease-and-desist letters to e-cigarette companies in previous years for using the food safety certification of the flavor industry to imply that the chemicals are also safe in e-cigarettes.

Some flavor chemicals are thought to be harmful when inhaled in high doses. Research suggests that cinnamaldehyde, the main component of many cinnamon flavors, may impair lung function when inhaled. Sven-Eric Jordt, a professor at Duke University, says he presented evidence of its dangers at an FDA meeting in 2015 — and its relative abundance in many e-cigarette vaping liquids. In response, one major e-cigarette liquid seller, Tasty Vapor, voluntarily took its cinnamon-flavored liquid off the shelves.

In 2017, when Gottlieb delayed the FDA application deadline, the product was back. A company email to its customers put it this way:

“Two years ago, Tasty Vapor allowed itself to be intimidated by scaremongering tactics. … We lost a lot of sales as well as a good number of long time customers. We no long see reason to disappoint our customers hostage for these shady tactics.”

At the time of publication, Tasty Vapor’s owner did not reply to a request for comment.

Jordt said he is frustrated by the delays in the regulatory approval process.

“As a parent, I would say that the government has not acted on this,” he said. “You’re basically left to act alone with your addicted kid. It’s kind of terrifying that this was allowed to happen. The industry needs to be held to account.”

KHN correspondents Cara Anthony, Markian Hawryluk and Lauren Weber and reporter Victoria Knight contributed to this report.

This KHN story first published on California Healthline, a service of the California Health Care Foundation.

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