Lung Biopsy Findings in Severe Pulmonary Illness Associated With E-Cigarette Use (Vaping)

A Report of Eight Cases

Sanjay Mukhopadhyay, MD; Mitra Mehrad, MD; Pedro Dammert, MD; Andrea V. Arrossi, MD; Rakesh Sarda, MD; David S. Brenner, MD; Fabien Maldonado, MD; Humberto Choi, MD; Michael Ghobrial, MD


Am J Clin Pathol. 2019;153(1):30-39. 

In This Article


The main finding of this case series—one of the first to report lung biopsy findings in vaping-associated pulmonary illness—is that acute lung injury patterns are the most consistent histologic findings in this entity. Other findings include variable numbers of airspace macrophages and varying degrees of interstitial chronic inflammation. Fibrinous exudates within the alveoli, termed acute fibrinous and organizing pneumonia by some authors, are also seen focally in most cases. These findings are nonspecific with regard to etiology but help to confirm the presence of significant lung damage. Lung biopsies are not currently required for the diagnosis of vaping-associated pulmonary illness, but they provide another modality to exclude the possibility of infection.

From a histologic standpoint, the two major acute lung injury patterns are DAD and organizing pneumonia.[8] It is well known that a wide variety of toxic inhalants can cause acute lung injury, including amitrole-containing herbicides,[9] mixtures of household ammonia and bleach,[10] chlorine gas, crack cocaine, hydrogen sulfide, mercury vapor,[11] nitric acid fumes, nitrogen dioxide, high concentrations of inspired oxygen, paint remover, smoke,[12] smoke bombs (ZnCl2), sulfur dioxide, and war gases (phosgene and nitrogen mustard).[8] It is plausible, therefore, that inhalation of a potentially toxic mix of chemicals into the lungs (vaping and dabbing) could cause these injury patterns. Such chemicals include flavoring compounds such as diacetyl, 2,3-pentanedione, volatile organic compounds, ultra-fine particles, and heavy metals such as nickel, tin, and lead. Since e-cigarette aerosols can reach high temperatures, it is also conceivable that thermal injury may play a role in some patients. Finally, the fact that all patients in our series—and many in the reported literature—report vaping THC-containing products, rather than nicotine-containing products alone, raises the possibility that THC or a component in THC-containing vape fluid may be implicated in vaping-associated pulmonary illness. The lung biopsy findings described in our cases are not specific for vaping. Both DAD and organizing pneumonia have a long list of potential etiologies, which are only rarely diagnosable on the basis of histologic findings.[13,14] Examples of histologically identifiable etiologies of acute lung injury include viral cytopathic changes, fungal organisms, parasites, and aspirated food particles. In contrast, most other etiologies, including toxic inhalants, toxic drugs, aspirated gastric acid, connective tissue diseases, and most viruses, lack pathognomonic pathologic findings.[13–16] A pathologic diagnosis of acute lung injury is therefore a mixed blessing. On one hand, it provides strong and helpful evidence of moderate to severe acute injury to the lung and affords a histologic correlate for abnormal imaging findings. On the other hand, it seldom implicates a specific etiologic agent. These principles also apply to vaping-related lung injury.

The results of this series strongly suggest that vaping does not cause true exogenous lipoid pneumonia. The label "lipoid pneumonia" has been associated with vaping in several reports based mainly on the presence of oil red O–positive lipid-laden macrophages in BAL fluid.[1,5,7] One of the first cases in which oil red O–positive lipid laden macrophages were found was reported by McCauley et al[7] in 2012. On this basis, the findings were labeled "exogenous lipoid pneumonia" and attributed to vegetable glycerin used in nicotine solutions, although morphologic features of the macrophages were not illustrated and no lung biopsy was performed. A case study from 2018 reported biopsy findings in a surgical lung biopsy specimen from a patient with suspected vaping-associated pulmonary illness; the biopsy specimen was reported as "suggestive of lipoid pneumonia," although review of the illustrations does not show classic features of exogenous lipoid pneumonia.[6] A more recent series of six cases of vaping-related lung disease from Utah reported oil red O–positive lipid-laden macrophages in BAL fluid. The authors felt that since imaging in these individuals did not show the low attenuation typical of exogenous lipoid pneumonia, these macrophages could not be explained by aspiration of exogenous lipoid material. They hypothesized that these cells might be a useful marker of the disease.[5] Similarly, Davidson et al[1] labeled their cases of vaping-related lung disease as "acute lipoid pneumonia" based on the presence of oil red O–positive macrophages on BAL in three of five patients. We would like to emphasize that foamy (lipid-laden) macrophages are a common finding in BAL specimens and lung biopsy specimens and are not specific for aspirated or inhaled lipid. There are many potential explanations for their presence, the most common being airway narrowing or obstruction. "Exogenous" causes are less common, the most frequent being inadvertent aspiration of oily substances such as mineral oil–containing laxatives into the lower respiratory tract. The macrophages seen in biopsy specimens from vaping-related lung injury are most similar in morphology to those commonly seen in so-called endogenous lipoid pneumonia, which is not a true entity but merely a nonspecific histologic lesion characterized by the accumulation of foamy (lipid-laden) macrophages with fine intracytoplasmic vacuoles within alveolar spaces.[17] The lipid in these cells is derived from cholesterol in the cell membranes of endogenous cells and is presumably phagocytosed by macrophages during clearance of cell debris from the lung. In contrast, exogenous lipoid pneumonia is a well-defined entity characterized by areas of low-attenuation (similar to fat) consolidation on chest CT and macrophages with coarse intracytoplasmic vacuoles on histology, along with frequent involvement of the interstitium by lipid vacuoles surrounded by foreign body–type giant cells.[17–19] The difference between macrophage morphology in endogenous lipoid pneumonia and exogenous lipid pneumonia is illustrated in Image 5. With the caveat that our experience is limited, we believe that oil red O staining lacks specificity and is potentially misleading in this setting. However, since this impression is based on only a small number of cases, we do not believe that we are in a position to issue a strong recommendation regarding discontinuation of this stain at this point. A potential area for future studies is to systematically examine the specificity of this stain.

Image 5.

Exogenous vs endogenous lipoid pneumonia. A, Exogenous lipoid pneumonia (for comparison only; not from the current series). Note large coarse vacuoles within macrophage cytoplasm (H&E, ×400). B, Endogenous lipoid pneumonia, case 3. Macrophages are "foamy," with small fine vacuoles (H&E, ×400).

The limitations of this report include the small number of cases and the predominance of transbronchial biopsy specimens. It is conceivable that as more cases are reported, additional pathologic findings will emerge and the histologic spectrum of vaping-related lung injury will widen. It is also possible that examination of surgical lung biopsy specimens or autopsy samples will yield additional histologic information.

In summary, lung biopsy specimens from this small series of patients with severe pulmonary disease associated with electronic cigarette product use (vaping) show histologic features of acute lung injury, supporting the contention that inhalation of the aerosol generated by electronic cigarettes (vaping) can cause lung damage.