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Subspecialties Clinical care, Histology

Smoke and Mirrors

Vaping, the use of e-cigarettes, is becoming increasingly popular. Many choose it over traditional smoking because they believe it is safer – but research reveals that vaping can cause acute lung injuries not seen in smoking. More data is needed to determine its long-term effects, but the practice (especially if it involves illicit tetrahydrocannabinol) carries clear risks even in the short term

A new craze is sweeping the smoking world: “vaping,” or the use of electronic products designed to act like cigarettes. These e-cigarettes are popularly believed to be safer than traditional tobacco products and can be used to deliver not only nicotine, but also flavored products, marijuana, and other drugs. Because they are relatively new to the market, not much is known about the health risks of using e-cigarettes – but most contain nicotine and all contain other substances that are potentially harmful when aerosolized.

Recent research has raised the concerning issue of e-cigarette or vaping product use-associated lung injury (EVALI) – damage caused to the lungs by vaping. At the moment, little is known about this phenomenon or its development, so we spoke to Sanjay Mukhopadhyay – Director of Pulmonary Pathology at the Cleveland Clinic and lead author of a recent study into the pathology of the disease – to find out more.

What inspired you to investigate the potential dangers of vaping?

In September 2019, as the first large reports on the outbreak of EVALI were coming out in the medical literature, we began to receive lung biopsies from patients who had fallen ill after vaping. We quickly realized that there was no systematic study in the literature on the pathology of this condition. Also, the few descriptions out there were based on bronchoalveolar lavage (BAL) cytology, not lung biopsies, and were leading to an incorrect label (“lipoid pneumonia”) for this entity. And that’s why we decided to describe the pathology of this disease in lung biopsies.

When we did, we found acute lung injury patterns known as “organizing pneumonia” and “diffuse alveolar damage” (see Figure 1). Lung pathology experts see these patterns frequently in daily practice, because they are common ways in which the lung reacts to injury, regardless of the exact cause.

Figure 1. A CT scan showing the lungs of an individual who had vaped THC.

How does vaping damage the lungs?

Most cases of EVALI are caused by vaping illicit tetrahydrocannabinol (THC)-containing oils. The CDC has reported that vitamin E acetate, which is used to “cut” THC-containing oils and mislead customers, is the prime suspect (1). It has been found in counterfeit THC cartridges used by patients with EVALI, as well as in BAL fluid from the lungs of these patients. This chemical probably injures the lung when inhaled (see Figure 2), and it may be especially toxic when heated to high temperatures.

Figure 2. Histology of acute lung injury caused by vaping THC (20X).

The appearance of these injuries under the microscope is very different to those caused by traditional smoking (see Figure 3). Smoking causes accumulation of a fine, brown pigment within macrophages in the lung, whereas vaping does not. Smoking also causes chronic lung damage in the form of emphysema and fibrosis (“smoking-related interstitial fibrosis”) or Langerhans cell histiocytosis, none of which are caused by vaping. In emphysema, the substance of the lung is gradually destroyed over several years and loses elastic recoil, like an inflated balloon that has turned into an empty brown paper bag. In smoking-related interstitial fibrosis, the walls of the lung sacs are thickened by collagen. Pulmonary Langerhans cell histiocytosis results in the formation of numerous tiny collections of abnormal cells within the lungs and can cause scarring and cyst formation in the long term. In contrast, the lung injuries seen in vaping resemble injuries that result from inhaling toxic chemicals like bleach or mustard gas, or from taking drugs like amiodarone or bleomycin.

Figure 3. A comparison of smoking-related interstitial fibrosis (left) with acute lung injury in EVALI (right).

Overall, the changes caused by vaping develop rapidly (and we consider them acute), whereas those caused by smoking generally develop over several years (and are considered chronic). Unfortunately, we don’t yet have any good data on the lung pathology of long-term vaping. This will require examination of lung biopsies or other lung specimens from patients who have vaped for several years. Nevertheless, I would strongly advise anyone who is a non-smoker to stay away from vaping.

Is vaping actually safer than smoking?

It’s hard to say at this point because, other than nicotine addiction, the health effects of vaping store-bought, nicotine-containing e-cigarettes are not well understood. In contrast, we know that smoking is extremely dangerous – probably the worst thing you can do to your lungs. However, vaping illicit THC is very dangerous, can lead to EVALI, and should be strongly discouraged.

We know that children, teenagers, young adults, pregnant women, and individuals who do not currently use tobacco products should never vape. Whether smokers should vape to quit cigarettes is a more difficult question – more research is needed to determine if vaping is “safer” than smoking.

What should other pathologists know about this new type of respiratory injury?

The oil red O stain is not required for the diagnosis of EVALI, and a positive oil red O does not prove “lipoid pneumonia.” Lung biopsies have not confirmed a single case of exogenous lipoid pneumonia in EVALI. We are currently conducting a study involving the oil red O stain, with a focus on specificity. From all accounts, pathologists are extremely skeptical of the utility of this stain for the diagnosis of EVALI.

The biggest limitation of pathology is that it does not involve testing for chemicals. Biopsies are helpful only in that they show the type and severity of damage the chemical is causing in the lung. Chemical testing is the way forward; some of this work has already been done by the CDC (2). Specifically, the CDC conducted chemical testing by isotope dilution mass spectometry on BAL fluid samples from the lungs of 29 patients with EVALI in 10 different states. All 29 of the samples tested contained vitamin E acetate; THC was found in 23 of 28 samples tested; and nicotine was found in 16 of 26 samples tested. None of the samples contained plant oil, mineral oil, medium-chain triglyceride oils, or terpenes. No other potential toxins were found (3).

Vitamin E acetate was already a prime suspect in the causation of EVALI based on testing of product samples (vape cartridges) used by EVALI patients. Finding it in biologic samples such as BAL fluid has added another piece of evidence to build the case that this chemical might be causing lung damage in EVALI.

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  1. Centers for Disease Control and Prevention, “Outbreak of lung injury associated with the use of e-cigarette, or vaping, products” (2019). Available at:
  2. Centers for Disease Control and Prevention, “For Healthcare Providers” (2019). Available at:
  3. BC Blount et al., “Evaluation of bronchoalveolar lavage fluid from patients in an outbreak of e-cigarette, or vaping, product use-associated lung injury – 10 states, August-October 2019”, MMWR Morb Mortal Wkly Rep, 68, 1040 (2019). PMID: 31725707.
About the Author
Sanjay Mukhopadhyay

Sanjay Mukhopadhyay is Director of Pulmonary Pathology at the Cleveland Clinic and Associate Editor (Pulmonary) for the American Journal of Clinical Pathology, Cleveland, Ohio, USA.

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