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Vaping-related Acute Parenchymal Lung Injury: A Systematic Review

Andrea M. Jonas, MD, Rishi Raj, MD

PII: S0012-3692(20)31394-5
DOI: https://doi.org/10.1016/j.chest.2020.03.085
Reference: CHEST 3172

To appear in: CHEST

Received Date: 8 November 2019

Revised Date: 25 March 2020
Accepted Date: 27 March 2020

Please cite this article as: Jonas AM, Raj R, Vaping-related Acute Parenchymal Lung Injury: A
Systematic Review, CHEST (2020), doi: https://doi.org/10.1016/j.chest.2020.03.085.

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Word Counts:
Text: 3,814
Abstract: 239

Title: Vaping-related Acute Parenchymal Lung Injury: A Systematic Review

Short Title: Vaping-related Lung Injury
Authors:
1. Andrea M. Jonas, MD
Pulmonary and Critical Care
Stanford University School of Medicine
Stanford, CA 94305
2. Rishi Raj, MD
Pulmonary and Critical Care
Stanford University School of Medicine
Stanford, CA 94305

Corresponding Author:
Andrea M. Jonas, MD
amjonas@stanford.edu
Pulmonary and Critical Care Medicine
300 Pasteur Dr Rm H3138
Stanford, CA 94305

Conflicts of interest: The authors report no actual or potential conflicts of interest in preparing this work.
Funding Information: None
Notation of Prior Abstract Publication/Presentation: None
Abbreviation List:

ALI Acute Lung Injury

ARDS Acute Respiratory Distress Syndrome

BAL Bronchoalveolar lavage

CBC Complete Blood Count

CBD Cannabidiol

CDC Centers for Disease Control and Prevention

CT Computed Tomography

DAD Diffuse Alveolar Damage

ECMO Extracorporeal Membrane Oxygenation

EVALI E-cigarette or vaping product use Associated Acute Lung Injury

FDA Food and Drug Administration

GGO Ground Glass Opacity

HP Hypersensitivity Pneumonitis

OP Organizing Pneumonia

PMN Polymorphonuclear Leukocyte

RBILD Respiratory Bronchiolitis-associated Interstitial Lung Disease

TBBx Transbronchial biopsy

THC Tetrahydrocannabinol
Abstract

The ongoing U.S. outbreak of vaping-related acute lung injury, recently named EVALI (E-

cigarette or vaping product use associated acute lung injury), has reignited concerns about the health

effects of vaping. Initial case reports of vaping-related lung injury date back to 2012, but the ongoing

outbreak of EVALI began in the summer of 2019 and has been implicated in 2,807 cases and 68 deaths as

of this writing. Review of the scientific literature reveals 216 patient cases spanning 41 reports of

parenchymal lung injury attributed to vaping. In this review, we detail the clinical, radiographic,

pathologic patterns of lung injury attributable to vaping, as well as provide an overview of the scientific

literature to date on the effects of vaping on respiratory health.

Tetrahydrocannabinol was the most common vaped substance and Vitamin E acetate was found

in bronchoalveolar lavage specimens from many affected individuals, however no specific component or

contaminant has conclusively been identified as the cause for the injury to date. Patients present with

cough, dyspnea, constitutional symptoms, and gastrointestinal symptoms. Radiology and histopathology

demonstrate a spectrum of nonspecific acute injury patterns. A high index of suspicion combined with a

good history are the key to an accurate diagnosis. Treatment is supportive, mortality is low, and most

patients recover. Corticosteroids have been used with apparent success in patients with severe disease but

more rigorous studies are needed to clarify their role in treating vaping related lung injury.
Introduction

The ongoing U.S. outbreak of vaping-related acute lung injury, recently named EVALI (E-

cigarette or vaping product use associated acute lung injury), has reignited concerns about the health

effects of vaping. Most recent reports indicate a known 2,807 cases, including 68 deaths in the ongoing

EVALI outbreak1. Public health concern is compounded by the uptake of vaping among the youth and

never smokers,14 some of whom later transition to cigarette use13,15. For the last five years, vaping

prevalence has steadily increased such that vaping has surpassed cigarettes as the most common way to

consume nicotine among youth, and a quarter of high school seniors are regularly vaping. 4,16,17

Originally patented by a pharmacist in China in 2003, vaping has gained in popularity

internationally and there has been an exponential growth in the number of devices, brands, and flavors on

the market.2,3 Vaping was introduced to the U.S. markets in 2007 but only recently has there been

increasing interest among public health groups and medical professionals as to the potential health effects

of vaped products4–6. Vape pens, alternatively called e-cigarettes (e-cigs), e-hookahs, or electronic

nicotine delivery systems (ENDS) are devices which generate aerosols of a variety of substances,

including nicotine, tetrahydrocannabinol (THC), or cannabidiol (CBD). Although early evidence found

reduced carcinogen exposure from vaping compared to smoking conventional cigarettes,7,8 the ongoing

outbreak of lung injury raises serious questions about the safety of vaping 9,10,11,12.

One difficulty in identifying the causative agent of the ongoing EVALI outbreak is the sheer

number of vape products and distributors on the market. Estimates from 2014 found over 450 brands and

8000 different vape flavors on the market, with an average 250 new flavors added each month; these

numbers have almost certainly increased substantially since then.3 Vape shops include both legitimate and

illegitimate distributors who sell a wide array of flavors, THC or CBD oils, and other untested and

unregulated additives whose safety and toxicity profile remains unknown.13

 Vape aerosols harbor a number of toxic substances, including volatile organic compounds, heavy

metals, and ultrafine particles18–21. Sporadic cases of vaping-related respiratory illnesses have been

reported since 2012, however the current outbreak did not occur until the summer of 2019.10 Most

recently implicated in 2,807 cases and 68 deaths, the EVALI (E-cigarette or Vaping product use

associated Acute Lung Injury) outbreak has prompted the formation of a lung injury task force by the

Centers for Disease Control and Prevention (CDC)1.

In this review, we summarize the available literature on the health effects of vaping. Our review

encompasses 216 cases spanning 41 reports involving parenchymal pulmonary disease precipitated by

vaping at the time of this writing (January 23rd, 2020), and represents the largest such compilation of

cases to date.

Methods

Pubmed searches of the terms “vape”, “vaping”, “e-cigarette”, “electronic cigarette”, “EVALI”,

“electronic nicotine device”, “lung”, “injury”, “case”, “ARDS”, “DAD”, “diffuse alveolar damage”,

“bronchiolitis obliterans”, and “lipoid” were performed, yielding a total of 2,270 studies published

through January 23, 2020. Duplicates and irrelevant articles were then screened out. Ultimately 295

studies were assessed for eligibility, of which 169 articles were included in our review. Of these, 41

articles were case reports (Supplemental Figure 1).

Science Behind the Harms of Vaping

Given its potential role in smoking cessation, the health effects of vaping have been the subject of

intense interest in the scientific literature2,22,23. Challenges in reviewing the literature include conflicts of

interest in funding24 and small scale human studies. In the remainder of this section, we will summarize

the work that has been done evaluating the components of a vape aerosol, in vitro and in vivo studies, and

the available studies in human subjects.

The vape pen is composed of a battery-powered heating element, fluid reservoir, and an atomizer

which aerosolizes the vaping solution (Figure 1). Vaping solution, often called vape juice or e-liquid, is

typically composed of a mixture of water, a carrier (commonly propylene glycol or vegetable glycerin),

nicotine and/or THC, and flavorant.2 Vape pen aerosols have been found to harbor a number of toxic

compounds, including carbonyls, toluene, benzene, acrolein, and propylene oxide25,26, as well as the

heavy metals manganese and zinc which arise from the vaping coil itself27. Thermal degradants of

cannabinoids demonstrated a wide array of hydrocarbons and volatile organic compounds.28 Certain vape

pens allow users to adjust the temperature at which aerosolization occurs, resulting in increased

concentrations of formaldehyde production and inducing increased tissue hypoxia and airway epithelial

injury18,29.

Propylene glycol serves as a common carrier of vape solution and provides the characteristic

“smoke” effect of vaping. While propylene glycol is widely considered safe for oral ingestion by the food

industry, the safety of inhaling heated propylene glycol products has been called into question. The CDC

cites reports of propylene glycol-containing fogs causing respiratory irritation among theater workers30,31

and nuclear magnetic resonance studies have demonstrated the presence of formaldehyde as a byproduct

of heating propylene glycol in vape pens32. Additional studies of thermal decomposition of propylene

glycol under the conditions present in a vape pen have shown generation of multiple potentially

carcinogenic compounds including acrolein, acetaldehyde, and glycidol.33

 The flavorants added to vape solution have increasingly garnered attention as a potentially

unrecognized health risk13. Two common flavorants, diacetyl and 2,3-pentanedione, were found to be

present in the majority of a sample of 51 common vape solutions tested.34 The commonality and high

concentrations of diacetyl found were of particular concern as diacetyl was implicated as the likely

causative agent in an outbreak of bronchiolitis obliterans in an occupational setting (microwave popcorn

worker’s lung)35,36. In vitro analysis found that exposure of airway epithelium cells to either diacetyl or

2,3-pentanedione resulted in disruption of genes that direct cilia biogenesis, and directly resulted in

impaired ciliary number and function37,38. Cinnamaldehyde39,40, benzaldehyde41, 2,5-dimethylpyrazine

(chocolate flavoring)42, among other flavorants43 have adverse respiratory effects as well.

Vitamin E acetate has emerged as a potential common exposure amongst patients affected by

EVALI. Generally found as an oil suspension, vitamin E acetate is a common additive to vape pen

solutions, and was likely used as a diluent because of its physical properties and relatively easy

accessibility 44. FDA analysis of vape pens and paraphernalia acquired from EVALI patients found

vitamin E actetate in 51% of THC-containing products45 and vitamin E acetate was identified in 94% of

BAL specimens collected from affected patients46. The exact mechanism by which vitamin E acetate may

mediate lung injury is uncertain however studies suggest vitamin E acetate disruption of pulmonary

surfactant functioning47.

In vitro evaluation of airway epithelium shows that vape condensates cause an increased

oxidative stress48, proinflammatory cytokines49, cytotoxicity50, oxidative DNA damage51, and reduced

cellular viability2,23,52–54. Vaping products also alter lung lipid homeostasis by activating the alveolar

macrophages55 and neutrophils56.

Mice exposed to vaped aerosols have increased airway hyperresponsiveness57, increased airway

eosinophils, elevated cytokine levels, impaired immunological response to infection48,58,59, and increased

lung oxidative stress markers 60. Nicotine-containing vape aerosol exposure in mice causes decreased

mucociliary clearance61 upregulation of pro-fibrotic gene pathways62 and the development of lung
parenchymal changes consistent with COPD.63 Vaping aerosols cause cellular DNA damage in rats64 and

a single vape puff is enough to cause bronchoconstriction in guinea pigs65.

Patients with COPD and chronic bronchitis who use e-cigarettes are at an increased risk of

exacerbations compared to COPD patients who have never used e-cigarettes 66. Spirometric evaluation of

smokers exposed to vape aerosols shows an increase in airflow resistance as well as decreases in exhaled

nitric oxide.67 Inhaled vaped products in adult smokers induce airway epithelial injury as evidenced by

increase in serum CC16 levels, and such results could be replicated even with sham vaping 68.

Airways of chronic vapers are erythematous and friable, and their airway epithelium samples

have differential gene expression, notably in mucin gene pathways 69. Exposure of healthy subjects to

vaping aerosols results in elevation of alveolar fluid neutrophil elastase and matrix metalloprotease, to

levels similar to those seen in subjects exposed to cigarette smoke70, and development of alterations in

airway epithelium and alveolar macrophages71. Figure 2 summarizes the effects of vape aerosol on

respiratory epithelium.

Clinical characteristics of cases reported to date

Vaping can cause a wide array of adverse health effects including nicotine poisoning72, trauma

from device battery explosions, and injury to the GI, cardiovascular, and neurologic systems73.

Respiratory effects include status asthmaticus74 and pneumothoraces75, however diffuse parenchymal lung

disease represents by far the most reported and most serious side effect, and is the focus of this review.

The first reports of vaping-induced acute lung injury date back to 201276, and a handful of

additional cases were reported through 201677–79. The ongoing outbreak of EVALI was first reported in

July 2019 and has most recently been implicated in 2,807 cases and 68 deaths1. In this clinical review, we

report on 216 cases spanning 41 reports of parenchymal lung injury attributable to vaping, including 200

probable and confirmed cases from the ongoing outbreak of EVALI as determined by the CDC case

criteria.80 An overview of common clinical, radiographic, and pathologic manifestations is detailed in

Table 1, and the CDC case definitions are detailed in Table 2. In this section we consider the entire cohort
of parenchymal lung injury cases attributable to vaping, including cases that precede the July 2019

outbreak of EVALI.

Presentation

Patients presenting with EVALI were young (median age between 19-35, age range 14 - 61),

majority male (77%), and generally healthy prior to presentation. Time on vaping ranged from days to

several years and patients presented with approximately one week of symptoms. Nearly all patients

presented with leukocytosis and respiratory symptoms, with dyspnea (81%) and cough (74%)

representing the most common symptoms. A majority (84%) of patients endorsed constitutional

symptoms including fever, and 63% endorsed gastrointestinal symptoms. Hemoptysis was a less common

finding, affecting only 10% of the population. All patients endorsed a history of vaping, often using

multiple products simultaneously. Of 155 cases who underwent more extensive interview THC use was

the most commonly used substance (91%) followed by nicotine (70%) and CBD (8%). One patient

endorsed dabbing marijuana wax (inhaling aerosolized marijuana oil concentrate) in addition to vaping

THC. A minority of patients queried (n = 13) endorsed concurrent use of conventional cigarettes. The

subset of four patients with eosinophilic lung injury pattern had demographics and clinical presentations

similar to the larger group, however notably all presented prior to the start of the July 2019 EVALI

outbreak.

Radiographic Features

Diffuse, multifocal, bilateral ground glass opacities (For example, Figures 3, 4) were seen in

almost all patients. Additional variable findings included areas of consolidation, tree-in-bud nodularity,

discrete lung nodules, and interlobular septal thickening. Distribution of these abnormalities was varied,

and after a detailed review of all the reported cases, no specific pattern of location of radiographic

abnormality could be ascribed. A minority presented with pleural effusions (n=15), pneumomediastinum

(n = 10), and pneumothorax (n = 8) in addition to parenchymal abnormalities.

Cytopathologic and Histologic Features

Biopsy was pursued in 41 patients, with transbronchial biopsy (59%) being the most common

modality. Nonspecific acute lung injury pattern was present in all cases from the current epidemic and

consisted of various combinations of diffuse alveolar damage, organizing pneumonia, or unclassifiable

organizing acute lung injury81,82 . Individual histopathologic features included organizing pneumonia

(59%), foamy macrophages (44%), interstitial inflammation (41%), fibrinous exudates (39%), interstitial

edema (27%), and hyaline membranes (27%). Stains and culture data for alternative infectious etiologies

were negative. Additionally, there were four cases with an eosinophilic lung injury pattern (BAL

Eosinophils 18.5% to 74.0%) 91–94, as well as one case of suspected respiratory bronchiolitis-associated

interstitial lung disease (RBILD)95. None of these cases fell within the cohort of the ongoing outbreak,

and the patient with RBILD had continued to smoke conventional cigarettes as well.

Some of the early cases in the current epidemic were mis-labelled as lipoid pneumonia7,85 based

on the finding of lipid-laden macrophages in bronchoalveolar fluid. These cases demonstrated an acute

injury pattern similar to the other cases, and lacked the hallmark radiographic and pathologic findings of

exogenous lipoid pneumonia including hypoattenuation on CT imaging and foreign body-type reaction to

intra-alveolar lipids81,82. Another case reported as lipoid pneumonia related to vaping was described in

2018 prior to the current epidemic but on further review it did not meet the criteria for exogenous lipoid

pneumonia either 75–77.

Of 106 patients who underwent bronchoalveolar lavage (BAL), cell counts demonstrated a mixed

return of neutrophils, lymphocytes, and macrophages, trending toward neutrophil predominance. In total,

58 BAL samples underwent evaluation for lipid laden macrophages, of which 83% were positive. Three

cases demonstrated sequentially bloodier returns consistent with a diagnosis of diffuse alveolar

hemorrhage.
Clinical Course

The majority of patients (95%) required hospitalization and 27% of admitted patients required

intubation. Admitted patients were managed supportively and a majority (84%) received corticosteroids.

Specific doses and courses of steroids were not detailed. Ten patients required ECMO, of which two died.

Of the 68 deaths reported in the U.S., seven deaths were captured in the cohort studied. The majority of

cases (95%) survived to hospital discharge.

Subset analysis: Cases prior to July 2019 EVALI outbreak:

Though the EVALI outbreak was first reported in July 2019, our literature review revealed 16

cases published prior to the commencement of the EVALI outbreak. In evaluating those 16 cases we

found that the patients reported were on average slightly older (median age 34.5), had less male

predominance (50% female), and only one patient endorsed use of cannabis products. Similar to the

EVALI outbreak, patients presented with a median one week of dyspnea (88%) and cough (69%). In

contrast to the EVALI cohort, constitutional symptoms affected only 44% of patients and GI symptoms

were only reported in one patient. Notably hemoptysis was more common in this cohort, affecting 31% of

patients.

Radiographic appearance was varied with GGOs (63%) and nodular opacities (25%) reflecting

the most common findings. BAL was pursued in 14 of the cases and revealed neutrophil predominance in

the majority (63%) of samples reporting the BAL differential. Lipid laden macrophages were reported in

5 of the cases reported. Biopsy was pursued in half of cases most commonly demonstrating organizing

pneumonia (38%). Clinical course was similar to the overall group, with 63% of patients receiving

steroids and 31% requiring intubation. One patient required ECMO and survived, and one patient died,

for an overall survival rate of 94%.

Discussion

The clinical presentation of EVALI cases is nonspecific, and includes cough, dyspnea, and

constitutional symptoms. The radiographic and histopathologic findings associated with EVALI are

consistent with an acute lung injury pattern. These findings are nonspecific, and can be seen as a result of

a wide variety of insults including drugs, irritative inhalants, gastric acid aspiration, and viral infections,

among others. Therefore, the diagnosis needs to be based on a thorough history, appropriate clinical

context, and exclusion of other etiologies which may have a similar presentation. This is much like the

process of diagnosing drug-induced pulmonary toxicity where the symptoms, radiologic, and pathologic

findings are often nonspecific and diagnosis rests on a high index of suspicion and exclusion of other

causes.

The mechanism and culprit agent underlying the ongoing outbreak of EVALI remains elusive. A

diagnosis of exogenous lipoid pneumonia was incorrectly applied to early cases on the basis of lipid-laden

macrophages found on BAL among affected patients. The finding of foamy lipid-laden macrophages in

BAL fluid is not specific for aspirated or inhaled lipid82, and can be seen in many cases of acute lung

injury regardless of etiology83. Further, cases to date have lacked hallmark radiographic and pathologic

features which would be expected in exogenous lipoid pneumonia, including fat attenuation on CT

images and chronic foreign body reaction to exogenous lipids84. The presence of foamy macrophages,

foamy pneumocytes, and pigmented macrophages on BAL are felt to represent non-specific features that

correlate with exposure to vaporized lipids.81

The high frequency of THC exposure among reported cases raises the question of a common

contaminant in THC-containing vape solutions. The thermal decomposition of vape solution ingredients

has been found to harbor a range of respiratory irritants, and it is unknown the potential respiratory effects

of chronic vaping of THC and the substances found in third party vape solution additives. Various culprits

have been nominated as the common thread among EVALI cases reported to date, including THC itself,

particular cartridge brands (particularly those sold under the brand name “Dank Vapes”)85, vitamin E
acetate86, and various flavorants. The brand “Dank Vapes” has come under particular scrutiny as it has

emerged as the most commonly used brand in affected patients, yet efforts to identify a centralized

distribution source have been unsuccessful and it is possible that “Dank Vapes” packaging is used for a

variety of counterfeit products85. Vitamin E acetate has emerged as a potential common exposure amongst

affected patients, and further evaluation of the effects of vitamin E acetate on the respiratory epithelium is

warranted.

Efforts are ongoing to identify the common element, and it remains possible that contamination is

taking place at a common upstream source in the vape solution supply chain. Such upstream

contamination could lead to development of EVALI among people using a wide range of vape solution

brands and flavors, as is being seen. Alternatively, the occurrence of EVALI with a diverse array of

flavors and sources raises the question of toxic thermal degradation products of common ingredients such

as propylene glycol, vegetable glycerol or other oil-rich additives, rather than specific contaminant being

the culprit. Inhalation or aspiration of even relatively small amounts of volatile organic compounds causes

an intense chemical pneumonitis which is distinct from lipoid pneumonia due to nonvolatile organic

liquids 87,88. Volatile organic compounds generated by heating/vaporization of oily vaping solutions could

potentially be minor contributors to the parenchymal injury noted with vaping.

An eosinophilic BAL return serves as the hallmark of eosinophilic lung injury, an uncommon

manifestation of vaping related lung disease. Four cases were identified that were consistent with a

diagnosis of acute eosinophilic pneumonia. Notably, none of these cases were a part of the ongoing

outbreak of EVALI, and no patients reported THC exposure. They bear a close resemblance to case

reports of acute eosinophilic pneumonia secondary to conventional cigarette use; similarities include

acute onset of hypoxemic respiratory failure within weeks to months of cigarette initiation, CT imaging

demonstrating bilateral diffuse GGOs, eosinophil-rich BAL returns, absence of peripheral eosinophilia,

and rapid clinical improvement upon steroid initiation.89 The presence of lipid laden macrophages in these

cases further supports the notion that lipid laden macrophages likely serve as a marker of ongoing vape

use, rather than a pathophysiologic finding.

 It is important to consider that the cases reported here reflect a selection bias toward more

symptomatic patients who presented for care. It is likely that vaping-related lung injury includes a wide

spectrum of disease severity, and that a considerable number of cases may go unrecognized and untreated.

Clinicians must incorporate taking a vaping history into their clinical practice, including vaping products,

brands, and wattage settings, to ensure that potential exposures to vape product and high risk vaping

behaviors (such as use of Dank Vape branded THC products) are identified in a timely manner.

New questions have arisen regarding the safety of vaping as its prevalence is on the rise among

the youth and never smokers. Vaping aerosols have been found to be a pro-inflammatory respiratory

irritant, and carry a risk of exposure to a wide range of chemicals which have demonstrated carcinogenic

potential. Clinical evidence supports a wide array of clinical manifestations of acute lung injury in the

context of exposure to vape aerosols, as detailed above and as evidenced by the ongoing outbreak of

respiratory failure attributable to vaping. The chronic manifestations of vaping exposure remains to be

seen, and the medical community must be prepared to manage the sequelae of vaping-related respiratory

illnesses for decades to come.

Future directions will entail continued work in epidemiology, basic science, and public policy.

Ongoing work is directed toward the identification of the common element underlying the ongoing

outbreak of EVALI. As potential culprit agents such as vitamin E acetate are identified contaminated

products can be removed from circulation; this however will not mitigate against the outlined numerous

other harmful effects of vaporized solutions containing nicotine, THC, or other chemicals for recreational

use. Abstaining from inhaling all forms of vaporized solutions therefore seems a prudent and reasonable

recommendation. Further basic science and clinical studies identifying the mechanism of injury of

vaping-related lung disease may help inform public policy decisions. The ethical balance favoring e-

cigarette use as a tool of risk reduction among smokers90 has now been counterbalanced by the uptake of

vaping among the youth and never smokers, and the subsequent potential public health implications.91

Ultimately, agencies such as the FDA will be tasked with the decision whether to reclassify vape pens as
drug delivery devices which will necessitate more rigorous pre-market testing of vape solutions to ensure

their safety.

Conclusions

In sum, we report on 216 patient cases spanning 41 articles of parenchymal lung injury

attributable to vaping, including 96 cases from the ongoing outbreak of EVALI. Patients generally present

with approximately one week of nonspecific signs and symptoms of cough, dyspnea, respiratory distress

and hypoxia after a few weeks to months of vaping. Imaging demonstrates a combination of ground glass

opacities, consolidations and nodular opacities in various distribution patterns, and no specific radiologic

finding is pathognomonic. Similarly, lung biopsy almost always shows a nonspecific acute lung injury

pattern which can be centered around the airways. Lipid-laden macrophages on BAL are favored to

reflect a marker of exposure to vape aerosols, and these patients do not meet the diagnostic criteria for

lipoid pneumonia on radiology or histopathology.

Bronchoscopy and BAL can be performed to exclude infections but bronchoscopic or surgical

lung biopsy are unlikely to provide any additional actionable information, and are therefore not routinely

recommended. Diagnosis therefore hinges on a high index of suspicion in the context of appropriate

clinical history especially when vaping exposure is endorsed or suspected.

Management for affected individuals entails vaping cessation and supportive care. Corticosteroids

were administered to patients with severe disease with apparent success but properly designed prospective

studies are needed to clarify their role in vaping associated lung injury. Recent evidence links Vitamin E

laced vaping solutions to EVALI but no specific component or contaminant has definitely been identified

as the primary causative agent for the syndrome, and it is best to avoid any and all vaping.Relatively little

is known about the spectrum of subclinical disease, natural history, and potential chronic health effects of

vaping, and it may take decades for such effects to become apparent.92
Acknowledgements:

Contributions of authors: A.J. and R.R. both contributed to the completion of the systematic review and

compilation of the manuscript. R.R. is the guarantor of the manuscript.

Financial/nonfinancial disclosures: None declared.

Figure and Table Legends:

Table 1. Summary of case reports of vaping-induced lung injury presentations. Median values reported

unless otherwise indicated. Percentage calculations excluded unspecified or unreported data.

Table 2. CDC Lung Injury Surveillance Case Definitions. For use by public health departments in

identification and tracking of cases, and not for use in diagnosis. Last updated September 18, 2019.

*Vape use defined as use of vape pen, e-cigarette, or dabbing

** Absence of pulmonary infection defined as a minimum of negative respiratory viral panel and negative

influenza PCR or rapid test (if influenza testing warranted by season). Additional infectious work up may

include urine antigens, BAL, blood culture, and sputum culture as clinically warranted.

Figure 1 Components of a common, second generation type vape pen. Photography reprinted with

modification from the public domain.

Figure 2. Components of a vape pen aerosol and downstream effects of vaping on the respiratory system.

(Current revision contains Author edits of professionally rendered image for inclusion in the final

manuscript)

Figure 3 - Radiographic and pathologic features of vaping-related lung injury.

(A) CT demonstrating multifocal GGOs. Pathology demonstrating features consistent with

organizing pneumonia. Reprinted with permission from Khan, et al.

(B) Diffuse GGOs on CT imaging. Biopsy with intra-alveolar giant cells, organization, and

eosinophils consistent with ALI. Reprinted with permission from Itoh, et al.

(C) Diffuse GGOs and patchy consolidation on imaging with diffuse alveolar hemorrhage on biopsy.

Reprinted with permission from Agustin, et al.

 (D) Ground glass centrilobular nodules with golden-tan intra-alveolar macrophages on biopsy.

Reprinted with permission from Flower, et al.

Figure 4 - Radiology and corresponding pathology from cases of EVALI. (A) Patchy bilateral GGOs;

cytopathology revealing lipid-laden macrophages on Oil-Red-O stain. Reprinted with permission from

McCauley, et al. (B) CT with upper lobe bronchocentric GGOs. Pathology demonstrating organizing ALI

and severe bronchiolitis. (C) Extensive bilateral GGOs and consolidation. Pneumocyte vacuolization and

edematous alveolar septa. B and C reprinted with permission from Butt, et al.

Supplementary Figure 1. PRISMA diagram demonstrating article selection for the systematic review.

See Methods section for further details.

Supplementary Table 1. Summary table of all reported cases of parenchymal lung injury attributable to

vape exposure.
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Vape Pen Components:
Atomizer Mouth
Heating element for Piece
vaporizing solution

Battery Button Fluid Reservoir

Rechargeable Lithium Ion Battery Controls Refillable or
On/Off exchangeable chamber
to hold vape solution
 Radiographic
Demographics Presentation Vape Exposure Appearance Pathologic Findings Course

2019 EVALI Outbreak:

Non-specific Lung Age: 19 - 35 1 week of symptoms: 10 months of 80% Diffuse GGOs 92 cases underwent BAL: 94% Admitted
Injury Pattern Gender: 79% 95% Any respiratory vaping 24% Bilateral infiltrates 42/52 Positive for lipid-laden macrophages 82% Steroids
n = 200 male symptoms 80% THC 9% Pleural effusion 33/53 Neutrophil predominant BAL return 24% Intubated
81% Dyspnea 60% Nicotine 5% Pneumomediastinum 20/53 Macrophage predominant BAL return 5% ECMO
75% Cough 7% CBD 33 underwent biopsy: 3% Died
9% Hemoptysis 61% Organizing Pneumonia
87% Constitutional symptoms 55% Inflammation
73% GI symptoms 52% Foamy macrophages
49% Fibrinous exudates
37% DAD

Prior cases:

Non-specific Lung Age: 37.5 2 - 4 weeks of symptoms: 7 months of vaping 67% Diffuse GGOs 10 cases underwent BAL: 92% Admitted
Injury Pattern Gender: 58% 92% Any respiratory 83% Nicotine 33% Nodular opacity 3/3 Positive for lipid-laden macrophages 50% Steroids
n = 12 male symptoms 17% CBD 3/4 Neutrophil predominance 33% Intubated
83% Dyspnea 1/4 Macrophage predominance 8% ECMO
67% Cough 7 underwent biopsy: 8% Died
42% Hemoptysis 4/7 Organizing Pneumonia
42% Constitutional symptoms 2/7 Alveolar Hemorrhage
8% GI symptoms 1/7 Giant cell foreign body reaction

Eosinophilic Lung Age: 19 2.5 days of symptoms: 1 month of vaping 50% Upper lobe GGOs 4 cases underwent BAL: 100%
Injury Pattern Gender: 50% 100% Any respiratory 50% nicotine 25% Dependent GGOs 2/2 Positive for lipid-laden macrophages Admitted
n=4 male symptom 50% unspecified 25% Diffuse GGOs Median Eosinophil 24% (range 18.5% - 100% Steroids
100% Dyspnea 25% Pleural effusion 74%) 25% Intubated
75% Cough 1 underwent TBBx: 0% Died
50% Pleuritic chest pain Intra-alveolar eosinophils and
50% Constitutional symptoms multinucleated
giant cells
 CDC Lung Injury Surveillance
Primary Case Definitions

Confirmed Case
• Vape use* in 90 days prior to symptom onset; and
• Pulmonary infiltrate on chest x-ray or ground glass opacities on chest CT; and
• Absence of pulmonary infection**; and

• Absence of alternative plausible diagnosis (e.g. cardiac, rheumatologic, or neoplastic

process).

Probable case
• Vape use* in 90 days prior to symptom onset; and
• Pulmonary infiltrate on chest x-ray or ground glass opacities on chest CT; and

Infection has been identified however is not thought to represent the sole cause of lung injury;
• OR minimum criteria** to exclude infection have not been performed but infection is not
thought to be the sole cause of lung injury

• Absence of alternative plausible diagnosis (e.g. cardiac, rheumatologic, or neoplastic

process).