Since July, scientists have scrambled to uncover what exactly has been happening inside the lungs of 805 patients with a severe “vaping related illness” around the country. At first, both the vape products responsible and the illness itself were complete mysteries. Now, researchers are inching towards identifying the catalyst, and a study released Wednesday points to a likely culprit.

The symptoms of vaping related illnesses are easy to identify. The most common ones are respiratory and include shortness of breath, coughing, and chest pain. But patients have also reported stomach discomfort: nausea, vomiting, diarrhea, and abdominal pain, going by an analysis of cases published in the New England Journal of Medicine. The effects can be severe: As of September 27 12 deaths have been attributed to the condition.

We still don’t know what this illness is but a new analysis, also published in the New England Journal of Medicine, conducted by a team at the Mayo Clinic provides a clue. They’re proposing that the illness is “airway-centered chemical pneumonitis.” In other words, a severe inflammation of airways that makes it incredibly hard to breathe. That inflammation, they propose, is caused by inhaling “one or more toxic substances” that are hidden inside the vape cartridges these patients used.

Brandon Larsen, Ph.D., the senior author of this study and a surgical pathologist at the Mayo Clinic describes the illness as “severe” damage to the airways in line with what you might see in a person exposed to a toxic chemical spill:

“The lungs bear a very close resemblance to what we see in workers where an industrial accident has occurred, with a toxic chemical spill or toxic fume exposure, or perhaps a poisonous gas exposure,” Laden tells Inverse.

Sean Callahan, M.D., an assistant professor at the University of Utah who has treated some patients with “vaping related illness” himself, adds that these findings regarding the origin of the vaping related illness fit well with what he’s seen in his experience. Callahan was not a part of this new research.

“This study is really helpful is leading physicians towards the right way of taking care of these patients,” he tells Inverse

What is the vaping related illness?

The Mayo Clinic report cites analysis of lung tissue samples from 17 patients in Arizona, Minnesota, and Florida, two of whom died from vaping related illness. Seventy-one percent of those patients used THC vaping products. The Mayo Clinic team doesn’t know what “toxic substances” caused the damage, but this finding does change the way that scientists have been looking at the problem.

Dank Vapes, bootleg black market cartridges, have tested positive for high levels of vitamin E acetate. NYDOH

One circulating idea was that vaping related illness was a type of exogenous lipoid pneumonia. That’s basically an accumulation of fat in the lungs that’s deposited there from an outside source, like a chemical additive in a vape cartridge.

Early in September, state investigations were narrowing in on Vitamin E acetate or Vitamin E oil — a thickener that was added to THC vapes sold on the black market to make products appear legitimate. On September 5 New York State detected Vitamin E in all the vape products linked to illness in the state, though no direct connections between Vitamin E acetate and lipoid pneumonia were drawn by investigators. But the reason it seemed like a plausible explanation was that lipoid pneumonia in some cases, is caused by inhaling oils.

However, there good were reasons not draw that connection too hastily.

In a letter published in the New England Journal of Medicine on September 6, Callahan and a team from Utah presented their analysis of six patients in Utah. They found that they all did have lipids in their lungs but Callahan noted that their symptoms were very different from lipoid pneumonia patients he had treated before.

“People typically aren’t behaving like [they have] a lipoid pneumonia,” Callahan told Inverse in early September. “They’re dealing with shortness of breath but people don’t usually end up intubated and needing a ton of oxygen and stuff.”

Taken with these recent findings Callahan suggests that lipids in the lungs might be a marker of the disease, but not the true “smoking gun” that might be behind it. A letter accompanying the Mayo Clinic report, echoes that statement:

While it is difficult to discount the potential role of lipid, to us, the histologic changes instead suggest that vaping-associated lung injury represents a form of airway-centered chemical pneumonitis from one or more inhaled toxic substances rather than exogenous lipoid pneumonia per se, but the agents responsible remain unknown.

In other words, we don’t want to discount lipids entirely but inhaling unknown toxic substances in those cartridges (that then cause severe inflammation) could be the real culprit.

Inhaling “toxic substances”

Figuring out what those toxic substances are will be a big part of the FDA and CDC’s ongoing investigation. That starts with nailing down what kind of vape products these patients are actually using.

Right now, no single product can claim responsibility for all the damage done. But a CDC report released last Friday took aim at THC vaping products, which were used by 76.9 percent of the 514 patients interviewed in that analysis.

An additional analysis of cases from Wisconsin and Illinois called out a brand called Dank Vapes, an illegal black market enterprise with no central distributor. Dank Vapes are just packages that can be filled with anything by anyone who buys them.

On the black market there is no quality control, which means that pesticides and cutting agents could be present in any given Dank Vape cartridge or any other black market cartridge, for that matter. And even for legal vape products, there’s still a huge lack of information on what types of flavoring agents are safe to add to vape cartridges.

Some e-juice flavoring agents can cause throat irritation. Pexels

These agents could be anything from flavoring agents used in vape products (even legal ones) to pesticides that are commonly found in black market carts on the street. As Inverse previously reported, and a September 27 CNBC report also notes, some of these black market cartridges contain Mycolbuntanil, a common fungicide. When that substance is heated, it becomes hydrogen cyanide, a deadly gas.

Still, this report doesn’t name the actual agents that could be responsible for this condition. And figuring out what they are will be a big task for the ongoing effort to track these cases, and the substances that cause them, to their sources.

Author’s accompanying letter:

Despite accumulating data on the clinical and imaging features of vaping-associated lung injury, its pathology is poorly understood. We reviewed lung biopsies from 17 patients (13 men, median age 35 years, range 19-67), all of whom vaped (71% with marijuana or cannabis oils) and were clinically suspected to have vaping-associated lung injury. All presented acutely or subacutely with bilateral pulmonary opacities. Eleven met criteria for a “confirmed” diagnosis of vaping-related lung injury, with the remaining six meeting criteria for a “probable” designation. Histopathologically, all cases showed patterns of acute lung injury, including acute fibrinous pneumonitis, diffuse alveolar damage, and/or organizing pneumonia, usually bronchiolocentric and accompanied by bronchiolitis. No histologic findings were specific, but foamy macrophages and pneumocyte vacuolization were universal findings and could be useful diagnostic clues in an appropriate clinical context. Pigmented macrophages were sometimes present, but were never a dominant feature. Neutrophils were often prominent, but eosinophils were rare and granulomas were absent. Bronchioloalveolar lavage fluid was available in two cases, both of which contained abundant foamy macrophages. Despite steroids and maximum supportive care, two patients with diffuse alveolar damage died.

To date, only a few reports of vaping-associated lung injury have included histopathologic findings, and even fewer included illustrations thereof. Our cases corroborate many of these descriptions and provide some preliminary insight into the pathogenesis of this problem. Much attention has been given recently to the possibility that this may represent exogenous lipoid pneumonia. None of our cases showed histologic evidence of exogenous lipoid pneumonia and no radiologic evidence thereof has been found, calling into question the diagnostic utility of identifying lipid-laden macrophages or performing oil red O staining on bronchioloalveolar lavage fluid as a marker of vaping-associated lung injury, as has been proposed. The significance of this observation remains unclear, particularly in patients with a known vaping history, and until more data accumulates, our data suggests that this finding should be interpreted with caution, as it may simply represent a marker of exposure and not necessarily a marker of toxicity. While it is difficult to discount the potential role of lipid, to us, the histologic changes instead suggest that vaping-associated lung injury represents a form of airway-centered chemical pneumonitis from one or more inhaled toxic substances rather than exogenous lipoid pneumonia per se, but the agents responsible remain unknown.

Editor’s note: This story has been updated to include comment from the Brandon Larsen, the study’s senior author.