Biology-VI
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Case Report
Review of Cases of E-Cigarette or Vaping Product Use-Associated
Lung Injury (EVALI) and Brief Review of the Literature
Amr Essa ,1 Jeffrey Macaraeg,2 Nikhil Jagan,2 Daniel Kwon,3 Saboor Randhawa,1
Matthew Kruse,4 Stanley Thomas,2 Manasa Velagapudi,5 John Horne,5
Shraddha Narechania,2 Michael Kaster,2 Carrie Valenta,1 Venketraman Sahasranaman,2
and Douglas Moore2
1Creighton University School of Medicine, Department of Internal Medicine, Omaha, USA
2Creighton University School of Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Omaha, USA
3Creighton University School of Medicine, Department of Pathology, Omaha, USA
4Creighton University School of Medicine, Department of Radiology, Omaha, USA
5Creighton University School of Medicine, Department of Infectious Diseases, Omaha, USA
Correspondence should be addressed to Amr Essa; [emailprotected]
Received 4 December 2019; Accepted 28 April 2020; Published 15 June 2020
Academic Editor: Takeshi Terashima
Copyright 2020 Amr Essa et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Since the appearance of the E-Cigarette in the early 2000s, its industry, popularity, and prevalence have risen dramatically. In the
past, E-Cigarette use with the vaping of nicotine or cannabis products had been associated with a few reported cases of lung injury.
However, in 2019, thousands of cases of E-Cigarette or vaping product use-associated lung injury (EVALI) were reported in the
United States. Evidence linked this outbreak with vaping of tetrahydrocannabinol (THC). We report two confirmed cases of
EVALI and their associated clinical, radiologic, and pathologic features. This report supports the growing body of information
regarding EVALI. It also discusses various substances, particularly vitamin E acetate, which has been suggested as a causative agent.
1. Introduction
The E-Cigarette is a battery-operated device used to produce
an aerosol that is inhaled into the lungs, the composition of
which is determined by the content of the E-Liquid. It usually
delivers nicotine; however, it can be used to deliver other sub-
stances such as tetrahydrocannabinol (THC), cannabidiol
(CBD), and butane hash oils [1]. Since the introduction of
E-Cigarette into the US market in 2007, there have been a
few published and documented cases which describe lung
disease in relation to vaping of nicotine or extracts of canna-
bis, with the earliest documented in 2012 [25]. The summer
of 2019 witnessed an alarming upsurge in the number of
vaping-induced lung injury cases. The increasing mortality
and associated morbidity catapulted it to national attention
and led to the coining of the term E-Cigarette or vaping
product use-associated lung injury (EVALI) [6]. Despite the
prevalence of vaping in the US and other developed coun-
tries, such as the United Kingdom, wherein 3.2 million peo-
ple vape, an outbreak of this magnitude had never occurred
previously [7]. Collaboration between the Centers for Disease
Control and Prevention (CDC), state health departments, the
medical communities, and the public is ongoing to further
delineate the nature of this outbreak and the causative agents.
An association between EVALI and non-nicotine-containing
liquids has been suggested. Although it remains unclear
which group of chemicals are involved, vitamin E acetate
recently has been implicated. In this report, we highlight
two cases of EVALI which were diagnosed and treated at
our institution. We further discuss the clinical, radiologic,
and pathologic features, with a brief review of the current
body of published literature.
Hindawi
Case Reports in Pulmonology
Volume 2020, Article ID 1090629, 7 pages
https://doi.org/10.1155/2020/1090629
https://orcid.org/0000-0003-1310-643X
https://creativecommons.org/licenses/by/4.0/
https://creativecommons.org/licenses/by/4.0/
https://creativecommons.org/licenses/by/4.0/
https://doi.org/10.1155/2020/1090629
2. Case Presentation
2.1. Case 1. A 42-year-old man with no underlying medical
problems presented with a two-week history of worsening
nonproductive cough, subjective fever, chills, and diaphore-
sis. The history was significant for vaping THC once or twice
weekly for the last one year. He reported no use of tobacco,
alcohol, or illicit drugs. He denied any recent travel, and he
had a desk job with no reported occupational exposures.
On presentation, he was hypoxic with an oxygen saturation
of 85% on room air that improved with one liter of oxygen
via nasal cannula. He was afebrile and hemodynamically sta-
ble. Physical exam was significant for diffuse bilateral rales.
Chest radiograph (CXR) revealed diffuse interstitial pro-
minence (Figure 1). A subsequent computed tomography
(CT) scan of the chest revealed extensive symmetric
ground-glass opacities in all lobes with interlobular septal
thickening and subpleural sparing (Figures 2 and 3). He
was started on broad-spectrum antimicrobial therapy with
azithromycin, ceftriaxone, and levofloxacin to treat poten-
tially bacterial pneumonia, all of which was discontinued
after cultures were sterile (Table 1). Bronchoalveolar lavage
(BAL) of the right middle lobe was performed. A transbron-
chial tissue biopsy of the left upper lobe (upper division and
lingula) (Figures 4 and 5) revealed benign bronchial mucosa
without significant pathologic abnormality. Since an infec-
tious etiology was ruled out, he was discharged on predni-
sone 40mg daily with tapering over four weeks. He
reported improvement of symptoms within one week after
discharge.
2.2. Case 2. A 21-year-old man with a history of exercise-
induced asthma presented with a one-week history of
worsening productive cough, dyspnea, nausea, vomiting,
and malaise. He stated that he vaped THC once every
hour while awake for the last three months and once daily
for the previous year. He reported no use of tobacco prod-
ucts, alcohol, or other illicit drugs. He reported recent
travel to the Southwestern United States and Minnesota
the month prior to hospitalization. He denied any occupa-
tional exposure. On presentation, he was hypoxic with an
oxygen saturation of 88%, which improved with two liters
of oxygen via nasal cannula. He was afebrile and hemody-
namically stable. Physical exam was significant for bibasilar
crackles. CXR on admission showed patchy alveolar opacities
in the mid and lower lungs bilaterally (Figure 6). CT chest
demonstrated basal-predominant bilateral ground-glass
opacities with subpleural sparing, in addition to pneumome-
diastinum and slightly prominent bilateral hilar lymph nodes
(Figures 7 and 8). He was started on broad-spectrum antimi-
crobial therapy with vancomycin, piperacillin-tazobactam,
azithromycin, and fluconazole with coverage to treat poten-
tial coccidioidomycosis and presumed bacterial pneumonia,
all of which were discontinued after cultures were sterile
(Table 1). BAL of the right lower lobe revealed macro-
phages with neutrophils and lymphocytes (Figure 9). A
transbronchial tissue biopsy of the right lower lobe showed
an acute fibrinous and organizing pneumonia pattern with
no prominent eosinophils, granulomas, or malignancy
(Figures 1013). Six-minute walk before discharge was
notable for oxygen desaturation with activity, and subse-
quently, he was discharged on one-liter oxygen via nasal
cannula and prednisone 40mg daily tapering over four
weeks. He reported a resolution of his symptoms at the
time of his clinic follow-up visit about six weeks following
discharge. Repeat chest high-resolution CT (HRCT) at that
time showed remarkable improvement in the aeration of his
Figure 1: Case 1 CXR on presentation.
Figure 2: Case 1 chest CT scan on presentation (axial view).
Figure 3: Case 1 chest CT scan on presentation (coronal view).
2 Case Reports in Pulmonology
lungs and resolution of the bilateral ground-glass opacities
(Figures 14 and 15).
3. Discussion
Since the 2000s, when E-Cigarette made its initial appear-
ance, the vaping industry has shown rapid emergence. Its
popularity and prevalence have been driven by an appar-
ent improved nicotine delivery system with attractive fea-
tures for users and a wide variety of flavors. E-Cigarette
marketing-related expenditure in the United States increased
from $3.6 million in 2010 to $125 million in 2014 [7]. At the
same time, the prevalence of vaping has been on the rise, with
Table 1: Lab work on admission.
Case 1 Case 2
Infectious workup
White cell count 11.3K/l 14.3K/l
Sedimentation rate (ESR) 80mm/hr 91mm/hr
Procalcitonin 0.21 ng/ml 0.40 ng/ml
Legionella urine antigen Negative Negative
Pneumococcal urine antigen Negative Negative
Histoplasma urine antigen Negative Negative
Blood culture for aerobic & anaerobic
growth
Negative Negative
Respiratory viral pathogen screen Negative Negative
Sputum culture Negative Negative
Sputum AFB smear Negative Negative
HIV AG/AB Negative Negative
ANCA Negative Negative
1,3-b-d-Glucan Negative Negative
BAL cell count and differentials Normal Normal
BAL total nucleated cells 440/l 640/l
BAL RBCs <10.000/l <10.000/l
BAL neutrophils 49% 39%
BAL lymphocytes 28% 5%
BAL monocytes 17% 8%
BAL phagocytes 6% 48%
BAL fungal culture with special Negative Negative
BAL vulture viral reflex Negative Negative
BAL bacterial culture Negative Negative
BAL Aspergillus antigen Negative Negative
Miscellaneous workup
Lyme disease serology Negative
Rapid strep A Negative
West Nile antibodies Negative
Glomerular basement membrane (GBM)
antibodies
Negative
Mononucleosis screen Negative
Complement levels Normal
LDH level Normal
ProBNP 74 pg/ml
CRP >375mg/l
Coccidioides antibodies Negative
Hypersensitivity pneumonitis panel Negative
BAL AFP culture and smear Negative
BAL PCR for Legionella Negative
Figure 4: Case 1 transbronchial biopsy of upper division of left
upper lobe with benign bronchial mucosa.
Figure 5: Case 1 transbronchial biopsy of left lingula with benign
bronchial mucosa.
Figure 6: Case 2 CXR on presentation.
3Case Reports in Pulmonology
more than a quarter (25.4%) of 12th-grade students in 2019
saying that they had vaped in the last 30 days, more than
double the rate in 2017 [8]. A study developed to describe
advertising claims made on branded E-Cigarette reported
that it is marketed as a healthier and cheaper alternative to
conventional smoking. And the appeal of the wide array of
flavors, perception of modernity, enhanced social appearance
and celebrity use, and avoidance of smoking policy were
appealing to many [9].
Based on largely observational data on the current out-
break, the majority of reported cases were young males
[1013]. The commonly reported clinical symptoms include
fever, chills, and a headache. Respiratory symptoms include
shortness of breath, cough, and chest pain. Gastrointestinal
symptoms include nausea, vomiting, diarrhea, and abdomi-
nal pain [1013]. Fever was present in 29%, tachycardia in
64%, and tachypnea in 43%, with oxygen saturation < 88%
in 31% of the cases in one report [10]. There are no clear
guidelines regarding the management of EVALI, although
glucocorticoids and empiric systemic antimicrobial therapy
have been prescribed in the majority of cases [10, 11, 13].
The improvement in respiratory symptoms has been attrib-
uted to glucocorticoids [10, 12].
Figure 7: Case 2 chest CT scan on presentation (axial view).
Figure 8: Case 2 chest CT scan on presentation (coronal view).
Figure 9: Case 2 bronchioalveolar lavage (BAL) of right lower lobe.
Macrophages (red arrow) and neutrophils (yellow arrows).
Figure 10: Case 2 transbronchial biopsy of right lower lobe.
Macrophages containing blackish brown pigmented particles (red
arrows).
Figure 11: Case 2 transbronchial biopsy of right lower lobe with
multiple neutrophils.
Figure 12: Case 2 transbronchial biopsy of right lower lobe.
Eosinophilic fibrin exudate between cells, typical for pneumonia.
4 Case Reports in Pulmonology
86% of the 867 EVALI patients report using THC-
containing products in the three months preceding symptom
onset with mild elevations in white cell count, sedimentation
rate, and procalcitonin [14]. Both of our patients were young
males who vaped THC and met a confirmed diagnosis of
EVALI set by the CDC. The clinical characteristics and pre-
sentation were consistent with previously reported cases [15].
A wide range of imaging patterns has been described in
EVALI [16, 17], including hypersensitivity pneumonitis, dif-
fuse alveolar damage, acute lung injury, acute eosinophilic
pneumonia, organizing pneumonia, lipoid pneumonia, and
giant cell interstitial pneumonia. Imaging obtained during
the acute phase for both our patients demonstrated diffuse
ground-glass opacities slightly more prominent at the lower
lung zones, with subpleural and peribronchovascular spar-
ing. Our patients had a pattern most consistent with organiz-
ing pneumonia, which has been described in the EVALI
literature. Peribronchovascular sparing, as was seen in our
patients, is not a well-described feature that may represent
clearing by the peribronchovascular lymphatics related to a
subacute process with vaping. Of note, 100% of the cases in
the report of 53 cases had bilateral infiltrates on chest radio-
graph or CT [10].
The pathology of EVALI continues to be poorly under-
stood with no specific histopathological findings. A recent
review described lung biopsies from 17 patients with either
a confirmed or probable diagnosis of EVALI. All showed
a pattern of acute lung injury, including acute fibrinous
pneumonitis, diffuse alveolar damage, or organizing pneu-
monia. While other reports suggested an exogenous lipoid
pneumonia-like process, the authors suggested that the pat-
terns resemble a chemical pneumonitis [18]. Nevertheless,
both findings do not provide clarity while making a histolog-
ical diagnosis for EVALI. Our second patient showed similar
histopathology, as described in the literature, with findings
suggestive of acute pneumonia/inflammation with macro-
phages containing blackish brown pigmented material. Our
first patient did not show any histological pattern of lung
injury despite meeting a confirmed diagnosis of EVALI
by the CDC [15]. However, the biopsy showed predomi-
nantly bronchial mucosa and not adequate alveolar tissues;
thus, whether the patient had normal lung histopathology is
inconclusive.
E-Cigarette aerosol contains different harmful sub-
stances, including carbonyls, volatile organic compounds,
toluene, benzene, and heavy metals [19, 20]. Their constitu-
ents undergo thermal decomposition by the metallic coils,
which then release new compounds that can be toxic [21].
In one study, E-Cigarette products contained microbial
toxins, which included endotoxin concentrations above the
limit of detection (LOD) in 17 of the 75 products tested
and glucan concentrations greater than the LOD in 61 of 75
products tested [22]. Certain pesticides, such as chlorpyrifos
ethyl and trifluralin, have been detected in high concentra-
tions in some E-Liquid samples [23].
Triantafyllou et al. described several proposed mecha-
nisms of EVALI, which include alteration in the expression
of bronchial epithelial proteins, inducing airway remodeling,
and macrophage activation [12]. Marijuana smoke inhala-
tion has been associated with damage to the pulmonary epi-
thelial barrier, and even the flavoring component has been
linked to lung injury [23]. Compounds such as diacetyl,
2,3-pentanedione, and acetoin can impair ciliary function
and have been evaluated and linked to bronchiolitis
Figure 13: Case 2 transbronchial biopsy. Macrophages (red arrows)
and neutrophils (yellow arrows) in a background of exudative
material.
Figure 14: Case 2 chest CT scan 6 weeks post discharge (axial view).
Figure 15: Case 2 chest CT scan 6 weeks post discharge (coronal
view).
5Case Reports in Pulmonology
obliterans, the popular term being popcorn lung, which
causes severe respiratory diseases among workers inhaling
these heated vapors [2426].
Recently, samples of THC-containing products have
been analyzed to identify the potential contributing sub-
stance resulting in harmful effects on the lung. Different sub-
stances were identified, which have included vitamin E
acetate, medium-chain triglyceride oil (MCT oil), and other
lipids [27] (Personal communication, D.T. Heitkemper,
FDA Forensic Chemistry Center, November 2019). Vitamin
E acetate, in particular, has been identified in the majority
of the THC cartridge samples tested in various states and
facilities [14, 28]. Vitamin E acetate is a compound that is
used as an additive to E-Cigarette and as a thickening agent
in THC products [29]. Vitamin E acetate was further impli-
cated when a breakthrough report from CDC on November
8, 2019, showed that it was detected in 100% of the BAL sam-
ples of the 29 cases with EVALI that were sent to the CDC
from 10 different states across the United States, while THC
was identified in 82% and nicotine in 62% of the samples.
Of note, no other suspected substances (plant oils, MCT oil,
petroleum distillates, and diluent terpenes) were detected in
those 29 BAL samples [30]. Inhaling vitamin E is not as
benign as ingesting vitamin E, as it can impair lung function
[31]. This provides strong evidence that vitamin E acetate
might be a potential agent, though further studies are needed
to validate this link.
4. Conclusion
EVALI can be devastating and even fatal, as was seen by the
recent outbreak. Although various substances have been
investigated, vitamin E acetate appears to be a risk factor.
More data is needed to establish causality. With this report
of two cases with radiologic and pathological findings, we
hope to enrich the growing database and increase our knowl-
edge of this disorder.
Abbreviations
EVALI: E-Cigarette or vaping product use-associated lung
injury
THC: Tetrahydrocannabinol
CBD: Cannabidiol
CDC: Centers for Disease Control and Prevention
CXR: Chest X-ray
CT: Computed tomography
BAL: Bronchoalveolar lavage
HRCT: High-resolution computed tomography
ESR: Sedimentation rate
ANCA: Antineutrophil cytoplasmic antibody
AFB: Acid-fast bacillus
HIV: Human immunodeficiency virus
AG: Antigen
AB: Antibody
GBM: Glomerular basement membrane
LDH: Lactate dehydrogenase
BNP: B-Natriuretic peptide
PCR: Polymerase chain reaction
LOD: Limit of detection
MCT: Medium-chain triglyceride.
Consent
Consent for publication of patient information was obtained.
Conflicts of Interest
The authors declare no conflict of interest or financial
disclosure.
Acknowledgments
We thank Laurel Preheim, MD, for assistance with editing
and formatting.
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Review of Cases of E-Cigarette or Vaping Product Use-Associated Lung Injury (EVALI) and Brief Review of the Literature
1. Introduction
2. Case Presentation
2.1. Case 1
2.2. Case 2
3. Discussion
4. Conclusion
Abbreviations
Consent
Conflicts of Interest
Acknowledgments
