ICUs across the country were reeling last year, when the electronic cigarette or vaping product use-associated lung injury (EVALI) outbreak sent thousands of people to the hospital.
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.
On Aug. 1, 2019, the first cases of 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 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.
The outbreak has slowed but is still ongoing, said ACP Member Dixie L. Harris, MD, another pulmonary and critical care medicine physician at Intermountain Healthcare. “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.
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 accurately diagnosed 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.
Because there aren't many flu cases in August, some clinicians were inclined to think the illness could be viral bronchitis, Dr. Blagev said. “When it was happening, everyone was wondering, ‘Why are all these young people coming in?’ Some of them had flu testing, but none of it was positive. . . . I think if it were during flu season, we might have thought, ‘This is a really bad flu season,’” she said.
Dr. Harris was the first physician at the health system to recognize and start reporting these cases. During a shift in early August 2019, she was asked to do an emergency bronchoscopy in a patient who had been vaping, had been in the hospital for several days, and was not getting better despite being treated for pneumonia. “I found on the bronchoscopy no infection, but inflammation,” Dr. Harris said.
When she told a colleague about the case, she learned that similar cases had been reported in the previous month to the Wisconsin Department of Health Services. By a couple of days later, Intermountain clinicians had diagnosed five cases at five different hospitals, and the number of cases quickly grew from there, she said.
The health system is currently in the process of analyzing its second batch of cases and is planning to do long-term follow-up studies, Dr. Harris said. “We are still just at the beginning of understanding all the different complications and medical problems that occur with vaping,” she said.
In addition, about 20% to 25% of the EVALI patients had asthma, Dr. Blagev said, so the team also wants to look into potential correlations. Perhaps vaping makes folks susceptible to developing asthma, or maybe having asthma predisposes vape users to EVALI or other lung complications, she said. “We don't know any of those associations, so we're going to try and look at it and find out.”
Role of 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.
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. “Because the presentation of EVALI overlaps so much with the presentation of community-acquired pneumonia, and the risk of withholding antibiotics for patients who are that sick is too high, most clinicians treated with antibiotics while awaiting test results to confirm or exclude infection,” 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.
Dr. Harris said she has aggressively followed up on patients, several of whom have had to be on long-term steroids and on oxygen at discharge. “All the cases I've been involved in have been able to be weaned off steroids and off oxygen, so that's good,” she said.
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.”