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Review Article

Radiologic Review With Pathology Correlation of E-Cigarette or Vaping Product Use-associated Lung Injury

Bin Saeedan, Mnahi MD, MPH*; MacMurdo, Maeve G. MBChB; Mukhopadhyay, Sanjay MD; Choi, Humberto MD; Parkar, Nadeem MD*; Ghosh, Subha MD, MBA*

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doi: 10.1097/RTI.0000000000000526
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Abstract

KEY POINTS

  • E-cigarette, or Vaping Product Use-associated Lung Injury (EVALI) should be considered in any patient with bilateral lung opacities and a history of vaping within 90 days of the onset of symptoms.
  • This entity remains a diagnosis of exclusion in which presenting symptoms, imaging, and pathologic findings are all nonspecific.
  • Organizing pneumonia and diffuse alveolar damage (DAD) are the most commonly described patterns on both imaging and pathology examinations.

INTRODUCTION

E-cigarettes are battery-powered devices that vaporize nicotine concentrates or tetrahydrocannabinol (THC)-containing oils, creating an aerosol (vapor) that users inhale (vape).1,2 E-cigarettes first entered the US market in 2007, advertised as a “safer” alternative to traditional tobacco use and a potential tool to facilitate smoking cessation. Since then, use of e-cigarettes has rapidly increased throughout the United States. Utilized initially by adult cigarette smokers as a nicotine-replacement device, usage among adolescents is now common.

EVALI first gained significant public attention after a report of clusters of young patients presenting with severe hypoxia, dyspnea, and abnormal lung imaging in Illinois and Wisconsin in 2019.2 Since that time, >2000 cases of EVALI have been identified, with 42 deaths to date.3 Before this outbreak, sporadic cases of lung injury associated with vaping had been reported in the literature.4–8

The majority of the cases in the recent outbreak of EVALI appear to be related to vaping of THC-containing oil, although 11% of patients with EVALI report vaping nicotine alone.2,9 Increasing evidence suggests that vitamin E acetate (a diluent used for “cutting” THC oils) may play a causal role in the development of EVALI. Vitamin E acetate has been detected in vape cartridges seized after the EVALI outbreak, and was found in the bronchoalveolar lavage (BAL) fluid of a series of patients with known EVALI.3

Patients with vaping-associated lung injury have abnormal findings on chest imaging; although some imaging patterns predominate, a fairly wide variety of patterns have been reported.2,9–12 This article aims to review the spectrum of vaping-associated lung injury, with a focus on imaging findings.

CLINICAL FEATURES

Patients with vaping-associated lung injury present with nonspecific respiratory symptoms of variable onset and severity. Cough, dyspnea, and chest pain are common, as are nonrespiratory symptoms, particularly fever and gastrointestinal complaints. Severity at presentation varies, ranging from mild influenza-like symptoms, to fulminant respiratory failure requiring mechanical ventilation and advanced life support. Specific inquiry about recent vaping is key to confirming the diagnosis. EVALI should be considered in all patients presenting with acute or subacute respiratory symptoms who report e-cigarette use within 90 days of symptom onset and who lack an alternative cause for their symptoms. Treatment with corticosteroids typically leads to rapid clinical improvement.2

ROLE OF IMAGING

Abnormal lung findings on chest imaging have been described in all reported cases of vaping-associated lung injury with evidence of bilateral involvement. Basilar-predominant consolidation and/or ground-glass opacities, often with subpleural sparing, are a commonly described imaging pattern (Figs. 1–3).2,9,10,12 Various other imaging abnormalities have been described, depending on the mechanism of lung injury and tissue response on pathology examination.2,9–11 DAD and organizing pneumonia are commonly observed patterns.2,9 Pleural effusions, pneumomediastinum, and pneumothorax have been reported in some patients.2

FIGURE 1
FIGURE 1:
Coronal (A) and axial (B) CT images in a 21-year-old man show diffuse ground-glass opacities with dense consolidations in the posterior lower lobes, suggestive of DAD. Trace pleural effusions (asterisks) are noted.
FIGURE 2
FIGURE 2:
Axial CT images in a 19-year-old woman (A, B) show diffuse central ground-glass opacities with peripheral sparing. The patient was managed with supportive treatment and steroids. Axial CT image (C) from a follow-up scan obtained after 1 month shows near-complete resolution of ground-glass opacities.
FIGURE 3
FIGURE 3:
Axial CT images in a 38-year-old woman (A, B) at presentation show diffuse ground-glass opacities with areas of subpleural and lobular sparing. Axial CT images (C, D) obtained after 2 weeks show heterogenous consolidative opacities with coarse interstitial markings. Trace pleural effusions (asterisks) and pneumomediastinum (arrows) have developed. The patient required intubation and extracorporeal membrane oxygenation for acute respiratory distress syndrome. Axial CT images (E, F) obtained 2 months after the second CT show interval resolution of consolidation with residual heterogenous ground-glass opacities and peripheral reticulations, architecture distortion, and bronchiolar dilation (dashed circles highlight some areas of probable early traction bronchiolectasis) in both the lower lobes.

ROLE OF BRONCHOSCOPY AND LUNG BIOPSY

Neither bronchoscopy nor lung biopsies are mandatory for the diagnosis of vaping-associated lung injury. However, because “absence of pulmonary infection on initial workup” and exclusion of “alternative plausible diagnoses” are part of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis, bronchoscopy and/or lung biopsies are often performed to exclude these possibilities, the most important of which is infection.

Lung Injury Patterns

The most common histologic abnormalities in lung biopsies from patients with vaping-associated lung injury are organizing pneumonia and DAD (Fig. 4).9,13 Additional nonspecific findings include varying degrees of interstitial chronic inflammation, variable numbers of airspace macrophages (sometimes foamy), fibrinous exudates within the airspaces (acute fibrinous and organizing pneumonia), and reactive type 2 pneumocytes. These pathologic findings confirm the presence of significant lung damage, but are nonspecific with respect to etiology. Organizing pneumonia, DAD, and airspace macrophages can be seen in a wide variety of conditions other than EVALI.9

FIGURE 4
FIGURE 4:
Pathology findings of organizing pneumonia (A) and DAD (B) in transbronchial biopsies from 2 patients with EVALI. A, Fibroblast plug (Masson body) in lung biopsy (arrow), diagnostic of organizing pneumonia (hematoxylin-eosin, ×200). B, Interstitial fibroblast proliferation (arrow), typical of DAD, organizing stage (hematoxylin-eosin, ×200).

ORGANIZING PNEUMONIA

Organizing pneumonia pattern is a commonly observed pattern in patients with vaping-associated lung injury.2,7,9 Organizing pneumonia is characterized by the presence of polypoid and serpiginous collections of fibroblasts (“fibroblast plugs” or “Masson bodies”) within the airspaces.14 Imaging features of organizing pneumonia on computed tomography (CT) are several and variable include peripheral or peribronchial ground-glass opacities, often associated with consolidation (Fig. 5), and focal nodular or diffuse ground-glass opacities.15 Perilobular opacities outlining the periphery of the secondary pulmonary lobule can also be observed in organizing pneumonia (Fig. 6).16 The “reversed halo sign” (Fig. 5)—characterized by ground-glass opacities with surrounding consolidation—is a classic but nonspecific sign that can be seen in organizing pneumonia and not frequently reported with vaping.17,18 The pattern of organizing pneumonia in EVALI patients appears to be less heterogenous, with diffuse ground-glass opacities being a common pattern, often bilateral and relatively symmetric, frequently with subpleural sparing with areas of lobular sparing. If present, consolidation is usually mild. Interlobular septal thickening is frequently observed.18

FIGURE 5
FIGURE 5:
Axial CT images in a 30-year-old woman (A–D) show bilateral peripheral and peribronchial, nodular, and arc-like ground-glass opacities with areas of subpleural sparing and reversed halo sign (arrows). Imaging findings are suggestive of organizing pneumonia.
FIGURE 6
FIGURE 6:
Axial CT images in a 28-year-old man (A, B) show scattered upper lobe centrilobular ground-glass nodules and patchy perilobular ground-glass and consolidative opacities in the bilateral lower lobes. The coronal CT image (C) image highlights the perilobular opacities (arrows), which is suggestive of organizing pneumonia. Transbronchial biopsy images (D, E) show organizing pneumonia, defined by the presence of a fibroblast plug (arrow) within an airspace (D, hematoxylin-eosin, ×200). Numerous macrophages are present within airspaces (E, CD68 immunostain, ×200). CD68 is an immunohistochemical marker of macrophages. The intracytoplasmic brown staining in the cells on the CD68-stained slide (arrows) supports the contention that the cells within the airspaces are macrophages.

DAD

DAD is an acute lung injury pattern described in vaping-associated lung disease.2,9,19 Ground-glass opacities, heterogenous consolidations, crazy-paving (ground-glass opacities with septal thickening), or combinations of some of these findings with predominant involvement of dorsal dependent parts of both lungs are suggestive CT findings of the acute (exudative) phase of DAD (Figs. 1, 3). Reticulation, architectural distortion, and traction bronchiectasis may develop and suggest evolution into the organizing phase (Fig. 3). Although some patients may show improvement in symptoms and imaging findings, others may require mechanical ventilation and extracorporeal oxygenation, depending on severity (Fig. 3).20

Although DAD and organizing pneumonia are unique entities at the end of a spectrum, it is important to realize that cases with overlapping features of these 2 patterns are common. Because both DAD and organizing pneumonia are manifestations of acute lung injury and commonly coexist in lung biopsies from the same patient, it is not surprising that some degree of overlap in their imaging findings can occur.

OTHER PATTERNS

Additional sporadic cases with variable imaging and pathology patterns have been reported with vaping. These include hypersensitivity pneumonitis,8,10,11 acute eosinophilic pneumonia,6,10,11,21 and diffuse alveolar hemorrhage.11,22 Assuming that the reported imaging patterns accurately reflect the underlying pathology, the presence of these diverse imaging patterns may reflect different mechanisms of lung injury associated with vaping of different toxic substances.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis is an immune response to an environmental antigen (usually organic). No known antigens related to vaping have been identified.10 The described cases of hypersensitivity pneumonitis in association with vaping were diagnosed on the basis of temporal correlation of symptoms and observed imaging findings to exposure, without pathologic confirmation.10,11 Upper and mid lung predominant ground-glass opacities and ill-defined centrilobular ground-glass nodules with or without mosaic attenuation on chest CT are suggestive imaging features of hypersensitivity pneumonitis.23 Interestingly, these imaging features can also be caused by respiratory bronchiolitis, which is associated with tobacco smoking or other inhalational injuries.24 It is therefore possible that imaging finding caused by smoking may have been mistakenly attributed to hypersensitivity pneumonitis. We have encountered a patient who presented with diffuse ill-defined centrilobular ground-glass nodules, which were seen predominantly in mid and upper lungs, suggesting hypersensitivity pneumonitis; however, the lung biopsy did not show definitive features of this entity (Fig. 7).

FIGURE 7
FIGURE 7:
Axial CT image (A) in a 60-year-old woman shows diffuse ill-defined centrolobular ground-glass nodules, which were seen predominantly in mid and upper lungs. The differential diagnosis of imaging findings includes respiratory bronchiolitis and hypersensitivity pneumonitis. Transbronchial biopsy (B) shows nonspecific interstitial inflammatory infiltrate rich in lymphocytes (hematoxylin-eosin, ×200). There were also foci of organizing acute lung injury (not shown).

Acute Eosinophilic Pneumonia

Acute eosinophilic pneumonia is a rapidly developing form of acute lung injury that has been reported with vaping,6,10,11,21 taking into consideration that it is can be associated with starting smoking or changing smoking habits.25 Both the pathologic and imaging findings of this entity overlap considerably with DAD. The presence of interstitial and alveolar eosinophils combined with DAD features can suggest this diagnosis. This can be a challenging diagnosis to make because imaging findings are nonspecific and indistinguishable from other etiologies of DAD, and peripheral eosinophilia can be absent at the time of presentation. Pleural effusions and prominent septal thickening in the absence of left heart dysfunction can be seen with acute eosinophilic pneumonia due to an increase in vascular permeability. The clinical features that are needed to be present to diagnose this entity include evidence of acute febrile illness of <5 days, progression to hypoxemic respiratory failure, lung abnormities on chest imaging, >25% eosinophils in BAL, prompt response to steroid therapy, and absence of underlying infection.26 We have not encountered a histologically confirmed case of acute eosinophilic pneumonia in EVALI, or a case that fulfilled the above-mentioned clinical criteria.

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage has been reported with vaping.11,18,22 Hemoptysis is commonly reported, although not always present. On imaging, it can present with focal or diffuse airspace opacities that can be unilateral or bilateral. Bilateral opacities are often more asymmetric compared with cases with organizing pneumonia and DAD patterns. Consolidation and ground-glass opacity seen with pulmonary hemorrhage can spare the lung periphery. Aspirated or retained blood products in distal bronchioles can manifest as centrilobular or tree-in-bud nodular opacities. Evidence of persistent or increasing blood on sequential BAL confirms the diagnosis.18

LIPOID PNEUMONIA: TRUTH OR MYTH?

The moniker “acute lipoid pneumonia” was coined by some authors in early reports of vaping-associated lung injury and attributed to vegetable glycerin used in nicotine solutions. However, this diagnosis was based solely on the presence of oil red O-positive macrophages in BAL fluid.5,11,27 Two independent lung biopsy series reviewed by expert lung pathologists failed to confirm these observations. It is possible that the lipid detected by the oil red O stain in macrophages in BAL fluid is derived from the cell membranes of endogenous cells damaged by vaping and subsequently phagocytosed by macrophages during clearance of cell debris. This phenomenon (endogenous lipoid pneumonia) is well known to occur in a wide variety of airway and parenchymal lung diseases and can explain the presence of these lipid-filled cells. It is important to emphasize that lipid-laden macrophages are not specific for lung injury caused by exogenous lipids, that is, exogenous lipoid pneumonia. The nonspecific nature of oil red O positivity has been recently reviewed in detail.28 Exogenous lipoid pneumonia is characterized by airspace macrophages with large, coarse intracytoplasmic vacuoles, and frequent involvement of the interstitium by lipid vacuoles surrounded by foreign-body-type giant cells. None of these findings were seen in even a single case of EVALI in 2 separate lung biopsy series.9,13 Exogenous lipoid pneumonia manifests on CT with middle and lower lobe-predominant ground-glass opacities or consolidations in a segmental or lobar distribution, occasionally with a “crazy-paving” appearance. Classic cases of exogenous lipoid pneumonia show low CT attenuation values within the opacities (fat attenuation).29 It is noteworthy that none of the reported lipoid pneumonia cases that were linked to vaping had shown this classic feature on CT.

AN OUTLIER

The authors encountered 1 unusual case with a subacute presentation and atypical imaging pattern (Fig. 8). CT examination revealed bilateral clusters of innumerable micronodules with ground-glass opacities. These fairly demarcated “geographic” clusters of micronodules were associated with areas of septal and peribronchovascular nodular thickening that suggested a perilymphatic distribution. Mild enlargement of mediastinal and hilar lymph nodes was also noted. Endobronchial ultrasound-guided fine-needle aspiration of the mildly enlarged lymph nodes showed rare granulomas in the form of epithelioid histiocytes and an occasional multinucleated giant cell. A rare granuloma was also present in transbronchial lung biopsy. Follow-up CT after the patient stopped vaping showed near-complete resolution of imaging findings. This case is an outlier, and whether it truly represents a granulomatous reaction to vaping or whether the rare granulomas are unrelated to vaping remains unclear.

FIGURE 8
FIGURE 8:
Axial (A–C) and coronal (D) CT images in a 34-year-old woman show multifocal, bilateral clusters of micronodules with ground-glass opacification, associated with smooth interlobular septal and peribronchovascular nodular thickening (arrows) suggestive of perilymphatic distribution. These “geographic” clusters with fairly demarcated margins were new compared with previous CT performed few months before presentation for oncology surveillance and before the reported onset of vaping use. Borderline enlarged mediastinal and hilar lymph nodes (10 mm in short axis and less) were present (not shown) and increased in size compared with the previous study. Endobronchial ultrasound-guided fine-needle aspiration of the lymph nodes (E, F) showed several non-necrotizing granulomas in multiple lymph node stations (Diff-Quik, ×400). A rare granuloma was also present in the lung biopsy (not shown). CT scan after the patient stopped vaping (not shown) revealed near-complete resolution of the lung findings and interval reduction in the size of the lymph nodes.

CONCLUSIONS

Vaping-associated lung injury is characterized by abnormal findings on chest imaging. Although several imaging patterns can be observed, none of these are specific for vaping. Basilar-predominant ground-glass opacities with consolidation and areas of subpleural or lobular sparing are the most common imaging pattern. Radiologists are encouraged to familiarize themselves with the common imaging patterns of vaping-associated lung injury. This entity remains a diagnosis of exclusion in which presenting symptoms, imaging, and pathologic findings are all nonspecific. The diagnosis should be considered in any patient with bilateral lung opacities and a history of vaping within 90 days of the onset of symptoms.

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Keywords:

electronic cigarettes; vaping; acute lung injury; imaging; computed tomography; diffuse alveolar damage; organizing pneumonia

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