Evidence from laboratory studies has linked the outbreak to THC vape products contaminated by vitamin E acetate which is delivered to respiratory epithelial-lining fluid the presumed site of injury
Evidence from laboratory studies has linked the outbreak to THC vape products contaminated by vitamin E acetate, which is delivered to respiratory epithelial-lining fluid, the presumed site of injury in the lung. Illustration by David Cutler

5 key takeaways from vaping crisis

The electronic cigarette or vaping product use-associated lung injury (EVALI) crisis has reached critical mass, sending thousands to the hospital and sometimes proving fatal.

It was the summer of thousands of sick young people, and perhaps even more confused clinicians.

On Aug. 1, 2019, the first cases of electronic cigarette or vaping product use-associated lung injury (EVALI) were reported to the CDC. Visits to the ED that were related to EVALI began to spike in June 2019, peaked in September 2019, and have decreased ever since, according to a study published in December 2019 by the New England Journal of Medicine.

Most patients with EVALI have been men and adolescent boys (67%) and have been younger than age 35 years (78%), the study found. Of patients with EVALI who had data on substance use, 82% reported using vaping products containing tetrahydrocannabinol (THC), the main psychoactive component of cannabis, according to a CDC study published on Jan. 14 by Morbidity and Mortality Weekly Report.

Before the outbreak, a young person would occasionally end up in the ICU with acute lung injury or acute respiratory distress syndrome, said Denitza P. Blagev, MD, a pulmonary and critical care medicine physician at Intermountain Healthcare in Utah. But during last summer's spike, “Half the ICU was full of young people, and that really stood out,” she said.

The outbreak has slowed but is still ongoing, added ACP Member Dixie L. Harris, MD, a pulmonary and critical care medicine physician at the health system. “We still have a couple of cases trickling in. I reported four more on [Dec. 31], and we're probably well over 110 right now,” she said, adding that those totals include only confirmed, not probable, cases.

Some cases of EVALI have proven deadly. As of Feb. 4, more than 2,700 hospitalized cases of EVALI or deaths had been reported to the CDC from all 50 states, Washington, D.C., Puerto Rico, and the U.S. Virgin Islands. At least 64 patients have died, according to the CDC.

“The good news is that cases are going down, and the CDC is transitioning from a centralized emergency response to individual CDC offices, particularly the Office of Smoking and Health,” said Cynthia D. Smith, MD, FACP, ACP's Vice President of Clinical Education and representative to the CDC on the issue.

Although the EVALI outbreak is subsiding, internists need to stay vigilant and separate facts from media hype, experts said. They offered five takeaways to help clear the air.

1. EVALI has three main symptoms.

When clinicians first recognized the outbreak at Intermountain, the health system set up its telecritical care system to keep a database of validated EVALI cases. Of 60 patients (median age, 27 years; 80% male) who presented with EVALI at 13 hospitals or outpatient clinics between June 27 and Oct. 4, 2019, more than half were admitted to an ICU, according to a study published online in November 2019 by The Lancet.

Patients presented with three main types of symptoms: respiratory (98%), constitutional (88%), and gastrointestinal (GI) (90%). Respiratory symptoms mainly included shortness of breath, cough, and chest pain, and a minority of patients were coughing up small amounts of blood, said Dr. Blagev, who was co-lead author of the study with Dr. Harris. Constitutional symptoms included fevers, night sweats, and influenza-like body aches, she said, and GI symptoms included nausea, vomiting, and abdominal pain.

Some patients presented early on in the disease course, weren't recognized at first, and continued to vape while becoming worse, Dr. Blagev said. “They might go to urgent care and be sent home thinking it's a viral illness, and then continue to get sicker and then eventually come in and have low oxygen and have that [EVALI] diagnosis,” she said.

2. Steroids seem to work.

Within three weeks of Intermountain's first EVALI cases, its task force of five pulmonary and critical care physicians developed a guideline for diagnosis and treatment that was shared with clinicians through email. Patients who presented with EVALI had radiographic abnormalities of the lungs, Dr. Blagev said. “Commonly, it would be what we call ‘ground glass' on a chest CT or on an X-ray—not necessarily dense pneumonia infiltrates, but the ground glass—and that overlaps with atypical pneumonia like Mycoplasma,” she said.

That's why 90% of the 60 EVALI cases in the report in The Lancet received antibiotics. Clinicians often treated EVALI patients for community-acquired pneumonia, typically prescribing a few days of antibiotics, Dr. Blagev said. “It is often impossible to distinguish between EVALI and pneumonia when patients first present, and the risk of withholding antibiotics in someone who is that sick is high enough that most physicians treat for pneumonia empirically while awaiting test results,” she said.

Of the 60 cases, 95% received steroids, but many did not receive them early on because they had an unclear diagnosis, Dr. Blagev said. Patients would be in the hospital on antibiotics for a day or two but would still require a lot of oxygen, she said. “Then, you'd get some of the testing back ruling out infection and feel comfortable giving them steroids. The next day, it would be like a brand-new person. It was really remarkable,” she said.

Steroid dose and duration depended on illness severity. For patients in the ICU, a higher dose might be 125 mg of IV methylprednisolone, whereas patients on the wards might get 40 to 60 mg of prednisone, said Dr. Blagev, adding that most courses lasted five to 10 days. As the clinicians got better at recognizing and diagnosing EVALI, they could send patients who weren't sick enough to be hospitalized home on short courses of oral steroids, she added.

Interim CDC guidelines, published in October 2019, recommended that EVALI patients discharged from the hospital have a follow-up visit within one to two weeks. Then, later in 2019, the CDC bumped up its outpatient follow-up recommendation to within 48 hours of discharge, ideally with a primary care clinician or pulmonologist.

Unfortunately, some younger patients don't understand that they still have to go see the doctor even after they feel better, Dr. Harris said. “I will say that the sicker they are, they tend to be better at following up, at least for one or two follow-ups,” she said, adding that nearly all of them have quit vaping.

“If they've been in the ICU, they almost all quit. It scares them,” Dr. Harris said. “[But] what they tell me is almost all of them cannot get their friends to stop.”

3. Evidence points to THC vapes contaminated by vitamin E acetate.

While the exact cause of EVALI is still unknown, evidence from laboratory studies has linked the outbreak to THC vape products contaminated by vitamin E acetate.

Vaping products can deliver vitamin E acetate to respiratory epithelial-lining fluid, the presumed site of injury in the lung, one study found. Forty-eight (94%) of 51 EVALI patients in 16 states had vitamin E acetate detected in their bronchoalveolar lavage fluid, according to results published in December 2019 by the New England Journal of Medicine. The three patients with no vitamin E acetate detected were probable, not confirmed, EVALI cases.

Drug dealers have realized that they can increase their profits by using vitamin E acetate as a filler in illegal THC vapes, said Jonathan Foulds, PhD, a smoking-cessation researcher and professor of public health sciences and psychiatry at Penn State University College of Medicine in Hershey, Pa. “It's used because it has the same density and color as real THC,” he said.

Vitamin E acetate is also used in cannabis vapes because it is good at solubilizing THC and cannabidiol, which are not soluble in water, said cardiologist Neal L. Benowitz, MD, a smoking-cessation researcher and emeritus professor of medicine at the University of California, San Francisco. On the other hand, the solvents in nicotine e-cigarettes are typically propylene glycol and glycerin, he said.

“I don't rule out the fact that someone could have made an illicit nicotine vape with vitamin E acetate as well,” he said, but there would be no good reason to do so because propylene glycol and glycerin work well and are much cheaper than vitamin E acetate.

Initially, the two epidemics of EVALI and youth vaping led to some conflated messages from public health authorities and the media, according to an editorial published in January 2020 by Drug and Alcohol Review. “However, over the past 6 months, the evidence has strengthened considerably that nicotine vaping products are not the cause of EVALI,” the editorialists wrote.

In turn, the CDC and FDA have strengthened their recommendations that people not use THC-containing vaping products, particularly from informal sources like friends, family, or in-person or online sellers, instead of regulated channels in states with legal marijuana. In the Jan. 14 Morbidity and Mortality Weekly Report study, 78% of EVALI patients with data on their product source said they acquired vaping products from informal sources only.

THC vapes that are legal and regulated in several states around the country are probably less harmful than those acquired informally, Dr. Foulds said. “If you get it from a licensed THC dispensary in a legal state, we believe it's less likely to have harmful chemicals like vitamin E acetate in it,” he said.

Not all patients with EVALI have reported THC use. In the article in The Lancet, 10 of 60 (17%) EVALI patients reported only nicotine e-cigarette use. However, in the December 2019 New England Journal of Medicine study, nine of 11 patients who reported no THC use had detectable THC or its metabolites in their bronchoalveolar lavage fluid.

Dr. Foulds' explanation was simple: “Most people generally don't like to fess up to their doctor that they got sick by using an illegal drug, particularly if their family members are in the room when they are being interviewed.”

Twenty of 20 THC-containing products seized by law enforcement during the outbreak tested positive for vitamin E acetate, according to a study published in November 2019 by Morbidity and Mortality Weekly Report. In contrast, the FDA has detected no vitamin E acetate in nearly 200 case-associated nicotine products analyzed to date, according to the December 2019 New England Journal of Medicine study.

Nonetheless, the CDC and state health departments continue to investigate the potential role of many other different substances and product sources. There may be more than one cause of the EVALI outbreak, the CDC said.

4. E-cigarettes may not be associated with EVALI, but they still pose risks.

EVALI is a separate issue from the larger question of the role nicotine e-cigarettes and vaping products play in society, said Michael Steinberg, MD, MPH, FACP, professor and chief of the division of general internal medicine at Rutgers Robert Wood Johnson Medical School in New Jersey.

“The hope for these products was that they could present a less harmful alternative for current adult cigarette smokers,” Dr. Steinberg said. “As it turned out, the overwhelming majority of people who are using these products today are young people who aren't current cigarette smokers.”

One study published in November 2019 by JAMA found that the prevalence of current e-cigarette use was 27.5% among high school students and 10.5% among middle school students in the 2019 National Youth Tobacco Survey. In contrast, an estimated 5.8% of high schoolers and 2.3% of middle schoolers reported current cigarette smoking.

If e-cigarettes are going to be a viable alternative for adult cigarette smokers, the youth vaping epidemic must be addressed, said Dr. Benowitz. “I'm personally supportive of e-cigarettes for smokers who can't quit any other way, but I think we have to solve the youth use issue, otherwise it's not going to survive,” he said.

Dr. Benowitz hopes new age and flavor restrictions will make a difference. After the American Medical Association called for a total ban on all e-cigarette and vaping products, the FDA in late 2019 changed the federal minimum age to purchase tobacco products, including e-cigarettes and vaping cartridges, from 18 to 21 years. Then, in early 2020, the agency announced that it will ban fruit and mint (but not menthol) flavors of e-cigarette and vaping products to make them less appealing to young people.

Some vaping retailers have responded by selling “fill-your-own pod” kits for certain vapes, said Randol W. Hooper II, MD, an ACP Resident/Fellow Member and a pulmonary and critical care medicine fellow at Temple University Hospital in Philadelphia. “I don't know how much of an impact the flavor ban is going to have,” he said. “It's going to make it marginally less convenient for people, which is a good thing, but we'll see how things look in a year.”

Despite the fact that the nicotine e-cigarette industry has been the “Wild West” in the U.S. and many other countries, these products have demonstrated relative safety in millions of regular users, said Dr. Foulds. Plus, e-cigarettes have about a dozen chemicals, compared to 7,000 chemicals in cigarette smoke, he said. This point is in line with the most recent Surgeon General's report, published in January 2020, which said that “E-cigarette aerosol has been shown to contain markedly lower levels of harmful constituents than conventional cigarette smoke.”

However, use of e-cigarettes is not without potential risks, including long-term health effects that remain unknown, the report said. Plus, nicotine is as addictive as ever. It also activates the sympathetic nervous system, increases heart rate, and increases catecholamines, prompting some health concerns, especially in patients with heart disease, said Dr. Benowitz. Dr. Hooper added that nicotine itself is a potentially toxic chemical, and cases of poisoning from vape liquid have been reported in toddlers and pets.

“I think that cigarettes are so bad for heart health that switching is a good thing, if they can't quit any other way,” Dr. Benowitz said. “But I do encourage my patients who have switched to think eventually about getting off the e-cigarettes also.” Dr. Foulds added that nonsmokers should not start vaping, which the CDC also recommends.

5. Smoking history should include use of e-cigarettes and vaping products.

Whether it's THC or nicotine, physicians must consider vaping behavior in everyday patient care, according to a perspective piece published in January 2020 by Annals of Internal Medicine. Getting a thorough vaping history is a good place to start, said Dr. Hooper, coauthor of the piece, “And it should not add more than five or 10 seconds to taking your history.”

When asking the question, it's important to be specific, Dr. Foulds said. “Unfortunately, if you just say, ‘Do you smoke?,’ and the person says no, you don't really know anything. That person could have just walked into your office having smoked a joint or a THC vape,” he said.

As director of the Rutgers Tobacco Dependence Program, Dr. Steinberg said the typical tobacco screening question has changed. In addition to “How would you describe your smoking status: never smoker, former smoker, or current smoker?” the program now asks patients if they have ever used any e-cigarettes or vaping products, he said.

“If you wanted to just ask one question, it should be a comprehensive one, such as, ‘Do you use any tobacco products, including cigarettes, cigars, and electronic or vaping devices?’” said Dr. Steinberg.

From e-hookah to pod mods to dabs, the terminology around smoking and vaping is always changing. To help familiarize clinicians, the CDC recently published a visual dictionary of vaping products. “Don't be afraid to use the sort of terminology that your patients use,” said Dr. Hooper.

In October 2019, the Royal College of Physicians restated its advice on e-cigarettes, which says that vaping is not risk-free but is far less harmful than smoking tobacco. The U.K. group advises those who have switched to e-cigarettes to “carry on” and to not return to smoking.

However, there are significant regulatory differences between vaping in the U.S. versus the U.K., Dr. Hooper noted. For example, the nicotine content in some U.S. brands is about three times the U.K. limit, he said. “I think that e-cigarettes had the potential for being used in smoking cessation, but the way these devices have been marketed in the U.S. has been as a recreational drug and a tobacco alternative,” Dr. Hooper said.

In contrast, nicotine replacement therapies (e.g., gum, aerosol inhalers, patches, lozenges) were introduced from the very beginning as tobacco cessation tools and are also medical devices or drugs that are subject to strict regulatory standards that e-cigarettes are not, he said. “I am regularly asked by patients about using e-cigarettes to help quit tobacco cigarettes, and I always recommend FDA-approved nicotine replacement therapy,” said Dr. Hooper.

The CDC recommends that adults using e-cigarettes or vaping products as an alternative to cigarettes should not go back to smoking and should consider trying FDA-approved cessation medications. While e-cigarettes are “clearly less harmful” than combusted tobacco, they don't always work for smoking cessation, Dr. Steinberg said.

“Almost everybody who comes to our program for help quitting smoking has tried e-cigarettes” and was unsuccessful, he said. “For us, the most effective interventions have been the FDA-approved medications, combined with behavioral counseling, group therapy, and good, close follow-up.”

When talking to patients, Dr. Harris said she sends a clear message about vaping. “As a lung doctor, I tell patients, ‘Breathe in nothing but clean air unless it is a prescribed medication (not THC),’” she said.