To date, the exact pathophysiology of EVALI is still unknown. While VEA was identified in most BALF of EVALI patients, other constituents within the vaping device could play a role. There may be a hyperactive immune response inciting sterile exogenous pneumonitis,[15] as all EVALI patients did not have a superimposed bacterial infection through testing and antibiotics did not help this disease.[16] One paper proposed two theories: the direct chemical theory and the two-hit phenomenon. The first theory states that an e-liquid constituent when inhaled within the aerosol product by vaping is cytotoxic to certain lung cells ultimately leading to cellular necrosis, neutrophilic inflammation, and an overall pro-inflammatory state.[17] The latter theory states that inhalation of the base liquid in e-cigarettes (such as vegetable glycerin/propylene glycol [VG/PG], medium-chain triglycerides oil, and VEA) can alter the homeostatic state of lung immune cells that results in extensive inflammation.[17] Pulmonary surfactant composed of phospholipids (90% being dipalmitoylphosphatidylcholine [DPPC]) is the foundation of preventing alveolar collapse by reducing surface tension during inspiration and expiration. Using neutron spin-echo and artificial DPPC with VEA in a model system suggested that it is capable of minimizing the elastic properties of surfactant and thereby could be playing a role in EVALI by modulating the critical function of surfactant.[18]

As per the CDC prevention report, chest imaging and radiographic findings are a criterion for diagnosing EVALI.[13] The most common imaging findings observed in studies done on patients who fulfilled the CDC criteria for EVALI include: (a) GGO[192021] with or without centrilobular nodules, consolidation, septal thickening,[192021] subpleural sparing,[192021] and peribronchovascular (PBV) sparing;[21] (b) diffuse alveolar damage/acute lung injury;[21] (c) acute eosinophilic-like pneumonia;[2122] and (d) diffuse alveolar hemorrhage (DAH).[2123] Subpleural sparing was observed in most patients with radiographic findings.[192021]

The most common pattern of injury associated with EVALI is organizing pneumonia,[202124] which is a pattern of lung injury that commonly manifests as diffuse or lower lobe predominant, bilateral, and mostly symmetrical GGO commonly seen with areas of subpleural and lobular sparing.[24] In patients with EVALI, organizing pneumonia can manifest in an airway-centered pattern with diffuse centrilobular nodules and little-to-no GGO on a CT scan.[2125] A retrospective study of 14 pediatric patients who presented to a tertiary care hospital with EVALI had similar results to the adult population. Chest radiographic findings showed GGO in 14 of 14 (100%) and consolidation in 9 of 14 (64%). Findings in both chest radiographs were bilateral in 14 of 14 (100%) and symmetric in 13 of 14 (93%).[20]

A large multicenter study consisting of 160 patients comparing various imaging patterns of EVALI revealed that patients with mild disease severity on CT scan had less PBV sparing than those with moderate disease severity, but this difference was not determined to be significant (P = 0.11).[21] PBV sparing was also observed in younger patients (mean age, 25.1 ± 9.2 vs. 29.9 ± 12.4 years; P = 0.016).[21] Lymphadenopathy was less common in patients with milder disease albeit not statistically significant (P = 0.13). They also noted a negative correlation between vaping >6 months and diffuse alveolar damage patterns but noted no significant association between CT findings and vaping-related variables (THC, nicotine, and THC plus nicotine) nor with demographics.[21]

Diffuse alveolar damage is the histological finding of acute lung injury. It is observed during the 1^st week of alveolar injury and manifests as GGO with or without consolidation on imaging.[2526] It can progress to organizing pneumonia as a result of fibroblast proliferation in response to injury.[2526] Hypersensitivity pneumonitis (HP) is another pattern commonly observed in patients with EVALI.[212527] HP is a challenging diagnosis to make as it can be difficult to differentiate from interstitial lung disease.[27] There are many proposals in literature aiming to simplify this diagnosis by taking into consideration histological, clinical, and radiological findings. Radiological findings include diffuse GGO seen on imaging. Fibrosis, seen in chronic HP. has not been linked to vaping with statistical significance in the current literature.[2127]

Lipoid pneumonia is a pattern also associated with vaping.[28] It presents as GGO on imaging and can be observed as early as 30 min after inhalation.[29] Acute eosinophilic pneumonia, characterized by diffuse GGO on imaging,[30] is rarely reported as an adverse effect from using e-cigarettes.[223132] Pleural effusions and septal thickening are often present and could be mistaken for pulmonary edema.[30] DAH, a rare pattern seen on CT,[2123] is characterized by centrilobular GGO seen on CT.[2123] Unlike the previously described patterns where GGO is symmetrical, DAH can be asymmetric.[21]

The pathology of EVALI based on imaging and clinical findings is poorly understood.[33] Nonspecific histological patterns consistent with acute to subacute lung injury were noted throughout the literature.[223435] Studies exploring histopathological patterns seen in patients with EVALI or probable diagnosis of EVALI demonstrated patterns of acute lung injury, including acute fibrinous pneumonitis, interstitial edema, diffuse alveolar damage, or organizing pneumonia among patients.[223436] Airway-centered accumulation of foamy macrophages and pneumocyte vacuolization was commonly observed.[34] However, there is no evidence of lipoid pneumonia associated with EVALI.[343637] There are a few reported cases of lipoid pneumonia associated with vaping, with BALF cells staining positive for oil red O.[283839] The significance of this finding remains unclear, and it is suggested to interpret this finding with caution, as it may simply be a marker of exposure[34] or a finding associated with aspiration, obstruction, or infection[34374041] and not necessarily associated with toxicity.[34]

Vitamin E is a linactant and a potent modulator of lateral phase separation that reduces the line tension at the two-dimensional phase boundaries, leading to increased surface viscosity of pulmonary surfactant. Unlike Vitamin E, inhaled VEA does not readily undergo esterase-mediated hydrolysis[5455] but remains unhydrolyzed in the lung of vaping users. In theory, VEA may induce liquid crystalline phase in pulmonary surfactants, and influence respiratory compression-expansion cycling.[56]

VEA is also known to get incorporated into lipid drops and intra-alveolar lipid-laden macrophages (LLMs) are observed in EVALI patients with diagnosed acute lipoid pneumonia.[38] A similar macrophage phenotype was observed in a mouse model of VEA inhalation, where animals were exposed to 77.3–167.5 μg/g VEA daily for 2 weeks.[57] A recent study looking at LLM in tobacco smokers, e-cigarette users, and nonsmokers/vapers, found LLM in half of the healthy e-cigarette users and almost all healthy smokers.[58] Another animal study found that one inhalation dose of VEA to lipopolysaccharide-treated rats greatly attenuated the inflammation.[55] Since VEA has multiple functions, VEA is suggested to influence similar signaling such as the diacylglycerol kinase and protein kinase C signaling pathway,[59] xenobiotic-sensing pregnane X receptor signaling,[60] and modulate lateral phase separation.[61] A recent study did observe sex as a confounding factor in e-cigarette users, with females having lower levels of plasmalogens that are glycerophospholipids secreted by alveoli cells and required for normal surfactant formation and function.[62]

Exogenous lipoid pneumonia is an uncommon condition which is known to affect patients who ingest mineral oils largely present in laxatives or various aerosolized industrial products. It usually presents with nonspecific respiratory tract symptoms. When ingested, these oils cause a foreign body reaction which can ultimately cause fibrosis of the lung.[63] This diagnosis is usually one of the exclusions and can be confirmed by presenting with LLMs when stained in oil red O in various respiratory samples but not limited to sputum or BALF.[64] Radiographic analysis observes airspace consolidations, ground-glass attenuation, airspace nodules, and a “crazy-paving“ pattern.[64] This is unfortunately nonspecific and can include differential diagnosis such as carcinoma.

The lungs struggle to extract long-chain hydrocarbons from the airspaces. Most commonly, exogenous lipid pneumonia is a product of the aspiration of oils described by phagocytosis of oils by macrophages and subacute inflammation, ultimately leading to fibrotic lung lesions and gas exchange abnormalities as stated above.[6465] In one study, paraffin oil was shown to cause alveolar type II (ATII) cell injury consisting of destruction of microvilli and cytoplasmic vacuolization.[66] The type of damage induced by oils is largely based on its chemical component and droplet size.[646566] In typical exogenous lipoid pneumonia, aspiration is commonly by large oil globules into a focal lung region, while aerosolized VEA and other oils produce small droplets allowing them to reach distal airways into alveoli evenly throughout the lung. This unique exposure differs significantly from previous reports of lipoid pneumonia and would expect different patterns of toxicity.[26]

A retrospective study of 17 cases of EVALI showed the presence of LLMs in peribronchiolar airspace along with vacuolization of the cytoplasm of hyperplastic type 2 pneumocytes in every sample.[34] Although some did show cholesterol clefts, no sample showed the accumulation of large fat droplets seen in exogenous lipoid pneumonia. In true lipoid pneumonia, this would be predominant as water-insoluble oil droplets have exorbitant interfacial tension that can make fat droplets coalescence and form larger oil droplets.[67] At the same time, CT findings did show bilateral GGO in which six showed a distinct bronchocentric distribution.[34] In a retrospective study of 3 EVALI cases, a radiologic characteristic of both lipid pneumonia and EVALI appears to have areas of low attenuation (−30 to − 50 Hounsfield units) on computed tomography, proposing fatty infiltration within the airways and parenchyma.[68] Currently, the role of lipids in the pathogenesis of EVALI is unclear and this may represent a form of airway-centered chemical pneumonitis due to multiple inhaled toxic substances rather than exogenous lipoid pneumonia.[34]

In one animal study, twice-daily exposure to 1 h of aerosolized VEA for 6 or 15 days resulted in increased extravascular lung water (EVLW), protein in BALF (a marker of lung injury), and increased plasma surfactant protein (SP)-D when inhaling aerosolized VEA compared to aerosolized JUUL product (Juul Labs, Inc., an American electronic cigarette company) or control.[69] SP-D is an indicator for alveolar epithelial injury and prognostic marker in ARDS.[7071] An increase in EVLW is a readout of hydrostatic pulmonary edema and acute respiratory distress syndrome, which was seen in many EVALI patients.[72] A concentration-dependent surface pressure was also observed in serum albumin, which can surpass the respreading pressures of collapsed monolayer in vitro and ultimately play into the pathophysiology of EVALI.[73] The increase in protein can lead to inactivation of lung surfactant and cause alveolar collapse from overwhelming surface tension.

When comparing aerosolized VEA to VG/PG in mice, increased levels of airspace neutrophils, large vacuolated macrophages, and neutrophil chemoattractants MCP-3 and interleukin 8 (IL-8) were observed.[69] Histologically these animals exposed to aerosolized VEA versus JUUL showed monocytic and neutrophilic alveolar and interstitial inflammation in a bronchiolocentric pattern with increased LLMs in the airspaces.[69] Another mouse study observed an overall increase in BALF albumin, increased number of leukocytes, and LLMs in aerosolized VEA compared to PG/VG.[57] Tissue pathology demonstrated LLMs in the cytoplasm of the cells lining the alveoli. Aerosolized VEA induced cellular toxicity to human ATII cells but not in ATII cells exposed to JUUL aerosol.[69] A recent publication analyzed the byproducts of aerosolized VEA condensate by mass spectrometry and observed that VEA did not pyrolyze to Vitamin E plus ketene during vaping and that intact VEA vapor is toxic.[74] They did observe that airspace cells actively hydrolyzed the VEA to release α-tocopherol, increased plasma malonaldehyde, and detected the oxidized form of Vitamin E in lung cells. This study also observed not only lung inflammation in mice exposed to prolonged VEA but also systemic inflammation and greater lung injury upon influenza infection.[74]

Patients with vaping-associated lung diseases can present with acute eosinophilic pneumonia,[31] DAH,[75] lipoid pneumonia,[2876] and respiratory-bronchiolitis interstitial lung disease. Several respiratory and systemic symptoms are observed with EVALI that could be linked to VEA, including shortness of breath (85%), cough (85%), chest pain (52%), pleuritic chest pain (36%), hemoptysis (8%), fever (84%), and chills (60%).[77] All EVALI case patients had bilateral infiltrates on chest imaging, and 77% had gastrointestinal symptoms.[77] The majority of EVALI patients (83%) have a chest radiograph with diffuse hazy or consolidative opacities.[217778] Bilateral opacities are observed frequently in EVALI patients with one study observing them in 100% of 98 patients, either on the chest radiograph or chest CT.[77] Immune cell profiling in EVALI patients gives variable findings, with increased neutrophil numbers frequently observed (58%, ranging from 10% to 91%), eosinophils are observed in isolated cases, and LLMs are a common feature.[3177]

The question of whether VEA and other byproducts of it could cause epigenetic changes within ATII cells is of interest. There were noted to be 752 differential genes at a false discovery rate <0.1 between VEA exposed and control ATII cells. Pathway analysis divulged a significant increase in IL-17, MAPK, and tumor necrosis factor signaling pathways, as well at genes associated to osteoclast differentiation.[69] Figure 1 shows an overview of the major confounding factors for EVALI.

This work was supported by grants made available to P.G. (the Alpha-1 Foundation, 493373 and 614218).

There are no conflicts of interest.