[♪ INTRO] Imagine an episode of your favorite medical drama.

In it, a young patient presents with coughing, shortness of breath, nausea, lost sense of smell, pneumonia, and low blood-oxygen levels. The doctors begin treatment for COVID-19 while waiting for accurate test results.

But those test results… come back negative. Now what? This isn’t TV after all, but a real condition that’s been making it harder to get patients needed care, especially at the height of the pandemic.

The culprit is E-cigarette or Vaping product use-Associated Lung Injury, or EVALI for short, and it can cause an uncannily similar host of symptoms to COVID-19. And they also overlapped with each other in time. This is complicating our understanding of two different public health threats.

See, when diagnosing patients, doctors are told that if they hear hoofbeats, to assume that it is a horse, not a zebra. It’s a common saying in med school, at least in the English-speaking world, and it means that unlike in said medical dramas, patients are way more likely to have a common condition than a rare one. But EVALI… is a zebra.

So let’s take a closer look at the research on vaping and lung injury, the ways that EVALI is different from COVID-19, and what treatments are available so far. In October 2019, the US Food and Drug Administration raised the alarm about a spate of severe cases of respiratory problems. These symptoms were bringing otherwise healthy teenagers to the emergency room.

Specifically, doctors and healthcare providers found that patients who used specific kinds of e-cigarettes or vaping products were showing up with damaged, inflamed lungs, leading them to coin the name EVALI. By the end of December 2019, thousands of people in the U. S. alone had been diagnosed with EVALI, and 55 had died from it.

The first fatal case of EVALI in Europe was recorded in Belgium in January 2020. However, most EVALI cases have been identified in the U. S.

And you know what happens next. COVID-19 was first detected in the US in late January 2020, though later research suggested that it had probably already been here in mid- to late December. The pandemic has dominated the public health conversation ever since, out of necessity.

But it came at just the right time to step on EVALI’s toes, and muddy the waters when it comes to diagnosing and treating respiratory diseases. Because the truth is, EVALI looks a whole lot like COVID in young people. It can take anywhere from days to weeks to become symptomatic.

It shows up as fever, coughing, shortness of breath, stomach pain, vomiting, diarrhea, and nausea. So when someone has these symptoms and seeks out medical care, doctors will likely begin treatment for COVID straight away, without waiting for test results. To be clear, that’s a reasonable strategy.

By starting treatment for the most likely diagnosis right away, while running tests to identify the specific problem, doctors have a better chance at stopping the disease before it gets really bad. Horse. Not zebra.

The good news is, the same frontline treatment you’d give a COVID patient in the hospital will probably help someone with EVALI. They’re pretty similar kinds of lung damage, after all. That includes oxygen, as well as corticosteroids.

Those reduce harmful inflammation in the lungs, which causes severe symptoms in both COVID and EVALI. And in the most severe cases, patients might need to be put on a ventilator either way. However, the thing is, you sort of have to assume a patient has COVID until you rule it out – and a negative COVID test needs to be double checked a few times.

In fact, there are no formal diagnostic criteria for EVALI. In all likelihood, doctors will figure out what’s wrong by first ruling out COVID, plus looking at a patient history that includes vaping. It may not make much difference, though, for the person sitting in that hospital bed.

They’re getting something that will make them better. The bad news is, if EVALI patients are given drugs specifically meant for COVID, those will not help. Let’s take a closer look at why.

COVID-19 is caused by the SARS-CoV-2 virus. The virus is a little sphere covered in spike proteins, which it uses to break into animal cells with another protein, called ACE2. ACE2 is practically everywhere in the human body, so it’s no surprise that people with COVID can have a whole wide range of symptoms.

Scientists are actively working to understand the ways the virus causes all of these symptoms, and why new variants change things up so much. But we know that coughing and lung problems are some of the most common and dangerous symptoms of COVID-19. If we zoom in to a cellular level, researchers have found that the virus interferes with the way that blood vessels carry oxygen into tissues.

Endothelial cells are cells that form a layer around blood vessels, like veins, and regulate how stuff from the bloodstream gets into the tissue and vice versa. Severe COVID-19 seems to damage the endothelial cells indirectly. When nearby cells are infected, the lungs become inflamed in self-defense, which can lead to blood clots, swelling, and fluid building up in the lungs.

And all of this makes it harder for oxygen to get from the lungs into the blood. Treatments for COVID are designed to stop the infection, and thus disease, from getting more severe. Monoclonal antibodies are one option.

They attach themselves to the spike protein of the virus so that it can’t infect new cells. And antiviral medications like paxlovid attach to uninfected cells, blocking the path that the virus would take in an infection. Once someone is sick enough to need oxygen, it’s more likely they’ll get remdesivir, which stops the virus from replicating.

If you give those to someone with EVALI, it probably wouldn’t do too much harm before doctors reach the correct diagnosis. But that’s now, years into the pandemic. Early on, when doctors were throwing everything against the wall to get something to stick?

You generally don’t want to put people at risk of side effects you don’t have to and, like, who knows. Finally, in some cases, COVID infections can progress to a life-threatening stage. If so much fluid fills the lungs that they can no longer do their job, and the patient struggles to breathe, it’s called acute respiratory distress syndrome, or ARDS, a form of lung failure.

Patients with ARDS usually need a ventilator in order to breathe at all, and people who recover from both COVID and ARDS can be left with permanent scarring in their lungs. And that brings us back to EVALI. One study in 2020 found that young people who vape, but are otherwise healthy, can develop ARDS.

If someone has respiratory symptoms that aren’t explained by another disease or condition, plus chest imaging that shows lung damage, resting blood oxygen saturation under 95%, and a history of vaping, then they may be diagnosed with a more severe form of EVALI. In one study of data submitted to the US Centers for Disease Control and Prevention, about half of people in the hospital for EVALI needed intensive care for respiratory failure. Almost a quarter needed to be intubated and put on a ventilator in order to breathe.

When it comes to treatments for EVALI, that’s kind of the whole story. Oxygen, steroids, and ventilators – basically supportive care. So it’s, like, okay if doctors first assume COVID and start those treatments.

The issue is more that EVALI throws a real curve at the doctors listening to the hoofbeats and figuring out how to help patients. Like, what if you think it’s a horse and pursue more aggressive COVID-specific treatments, and the patient continues to not improve? But there is not a cure for EVALI that they can try, in part because we’re still working out a cause.

Researchers haven’t yet agreed on what specifically about e-cigarettes or vaping causes lung injury. That’s why it’s called associated injury. But they do have hypotheses, and early data to back them up.

Most people hospitalized with EVALI reported vaping THC products, but some used a mixture of THC and nicotine, and some 14 percent vaped only nicotine-containing products. That’s why some researchers suspect EVALI comes from adulterants added to illicit vape cartridges. So, not the THC itself.

Especially because not all of the patients had used THC. One study showed vitamin E acetate, a chemical form of the vitamin that makes it more stable, present in the lung fluid of 48 out of 51 EVALI patients, but not the lung fluid of non-vapers. And 94% of EVALI patients in the same study also either had THC in their lung fluid, or reported using a THC product in the previous 90 days.

Vitamin E acetate is just one of many additives that get mixed into vape pens and e-cigarettes to adulterate them. This means that it makes a cheap, counterfeit cartridge look like it has high purity oil inside when in reality, it’s been diluted. And the timing was suspicious as well.

As these additives were being added to more THC products, EVALI cases were on the rise. But like, how bad can a vitamin be? Vitamins are an essential part of our diet, but note the diet part.

Like most things that you eat, they’re not so good for you when inhaled. Your gut can process these molecules in ways your lungs, of course, can’t. It’s thought that vitamin E acetate can create liquid crystals in the mucus that lines your lungs.

This could reduce surface tension, making them worse at picking up oxygen. And it’s not just vitamin E acetate that researchers are worried about, either. Vape pens create fumes by heating up the vape juice, and heating vitamin E acetate can cause the molecule to break down into smaller pieces.

So some of it might be inhaled whole, while some of it might break down into other harmful molecules at the same time. Some of the products of that reaction are known to irritate and injure lungs. And there are other additives to think about.

The same study of 51 EVALI patients found that one person with EVALI who didn’t have vitamin E acetate in their lung fluid had a different additive: limonene, which adds a citrus fragrance to products like vape juice. It’s also used in cleaning products and industrial cleaning of metals and electronics, and has caused lung irritation in people who are exposed to those cleaning products for too long. Lung fluid is part of an inflammation in the lungs, and inflammation is part of the immune system’s strategy to isolate potential threats like these additives from reaching the rest of the body.

And that’s probably why corticosteroids work to treat EVALI as well as COVID. They can reduce inflammation in a bunch of different ways. They turn down the dial on immune system responses, and turn up the dial on the body’s anti-inflammatory factors.

Doctors use corticosteroids to reduce the amount of organ damage that inflammation could otherwise cause, whether it’s responding to SARS-CoV-2 infection or vape cartridge adulterants. So, ok. We have met the horse, and we have met the zebra, and we’ve seen why the same front line treatment is ok to give to either one.

But that means that they are draining resources from the same pool. Two public health threats happening at the same time are more likely to make the whole situation worse, even though different groups are at different levels of risk for COVID compared to EVALI. Part of that is the age factor: Over the last few years, almost three quarters of the people who have died of COVID-19 have been older than 65.

While 78% of EVALI patients are under 35 years old. In part, that’s because young people have the largest proportion of e-cigarette and vape use. According to the CDC, around 25 percent of people in the US aged 18 to 24 have used e-cigarettes or vape, compared to less than 5 percent of people over 65.

But that does not mean the risks of COVID and EVALI are totally separate. For one thing, the pandemic may have caused more people, especially young people, to try vaping. Pandemic closures affected many brick and mortar vape shops, sending people online.

But online marketplaces are harder to regulate, and their products may be more dangerous as a result. Plus, regulations might restrict sales of vape products or THC to minors, but that’s harder to accomplish when it’s not happening in person. All those factors could lead to more harmful, illicit vape cartridges finding their way into the hands of young people.

And as COVID may have led to more risky vaping, increasing the risk of EVALI, vaping may also increase the risk of severe COVID-19. Research has shown that someone who vapes and gets COVID is more likely to have worse symptoms than a comparably healthy person who catches COVID and doesn’t vape. But while we’ve all heard about COVID over the last few years, in one survey, only about half of smokers had heard of EVALI.

And no amount of social distancing will stop a counterfeit vape cartridge from harming your lungs. Unless you… socially distance from bad vapes. This metaphor is getting away from me.

We can only speculate that the overwhelming nature of the pandemic has drowned out any messaging that might otherwise have taken place. It’s almost certainly made it harder to keep track of who develops EVALI. And it’s meant more people have needed care, such as ventilators, when such things were in short supply.

Which is not to say that EVALI patients don’t deserve treatment, it’s to say that unscrupulous, illicit manufacturers are the ones who opened the stable door and let this zebra loose when there were about to be a whole lot of horses running around. It is a reminder that zebras do turn up sometimes, and nothing happens in a vacuum. COVID may be a whole lot bigger than EVALI, but that makes EVALI way more complicated.

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