Clinical Features of E-cigarette, orVaping, Product Use–Associated LungInjury in TeenagersDevika R. Rao, MD,a,f,j Kendra L. Maple, MPH,i Amy Dettori, MD,a,f,j Folashade Afolabi, MD,a,f,j Jenny K.R. Francis, MD, MPH,b,f,j

Maddy Artunduaga, MD,g,j Tiffany J. Lieu, MD,c,f Kim Aldy, DO, MBA,h,k Dazhe James Cao, MD,h,k Stephanie Hsu, MD,d,f,j

Sing Yi Feng, MD,e,f,k Vineeta Mittal, MD, MBAc,f,j

abstractBACKGROUND: In the United States in 2019, there was an outbreak of electronic cigarette, orvaping, product use–associated lung injury (EVALI). The manifestations of EVALI inadolescents are not well characterized. We describe the diagnosis, evaluation, andmanagement of EVALI in adolescents hospitalized at a tertiary care, university-affiliatedchildren’s hospital.

METHODS: A multidisciplinary committee developed an EVALI algorithm on the basis ofguidelines from the Centers for Disease Control and Prevention. A retrospective chartreview was conducted on patients diagnosed with EVALI. Descriptive analyses includedsociodemographic characteristics, clinical presentation, laboratory and imaging results,pulmonary function testing, oxygen requirements, and clinic follow-up.

RESULTS: Thirteen hospitalized adolescents were diagnosed with confirmed or probable EVALI.The majority were female (54%) with a mean age of 15.9 years. Sixty-nine percent of patientspresented with respiratory symptoms, whereas gastrointestinal symptoms were prominent in85% of patients. Vaping D-9-tetrahydrocannabinol was reported in 92% of patients, andvaping nicotine was reported in 62% of patients. All had bilateral ground-glass opacities onthe chest computed tomography (CT) scan. Treatment with glucocorticoids led to clinicalimprovement in 11 of 12 patients. Treatment with glucocorticoids led to improvement in bothforced expiratory volume in 1 second and forced vital capacity (P , .05). Four patientsrequired home oxygen on the basis of 6-minute walk test results.

CONCLUSIONS: Diagnosis of EVALI should be suspected on the basis of vaping history and clinicalpresentation. Glucocorticoid treatment led to an improvement in symptoms and lung function.The 6-minute walk test may help determine oxygen needs at discharge.

WHAT’S KNOWN ON THIS SUBJECT: The prevalence of electroniccigarette use has more than doubled among eighth- to 12th-graders over the past 2 years. An outbreak of electroniccigarette, or vaping, product use–associated lung injury (EVALI)linked to vaping D-9-tetrahydrocannabinol occurred this fall, andadolescents were among those affected.

WHAT THIS STUDY ADDS: Many teenagers affected by EVALI werefemale, were Hispanic, and had multiple psychosocial stressors.Lung function deficits due to EVALI appear reversible withsteroids. Six-minute walk test results may help identifyadolescents who would benefit from home oxygen.

To cite: Rao DR, Maple KL, Dettori A, et al. Clinical Features ofE-cigarette, or Vaping, Product Use–Associated Lung Injury inTeenagers. Pediatrics. 2020;146(1):e20194104

Divisions of aRespiratory Medicine, bDevelopmental-Behavioral Pediatrics, cPediatric Hospital Medicine, dCriticalCare Medicine, and eEmergency Medicine, fDepartment of Pediatrics, gDivision of Pediatric Radiology, Departmentof Radiology, hDivision of Medical Toxicology, Department of Emergency Medicine and iMedical School, Universityof Texas Southwestern Medical Center, Dallas, Texas; jChildren’s Health Medical Center Dallas, Dallas, Texas; andkNorth Texas Poison Center, Parkland Health and Hospital System, Dallas, Texas

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Among school-aged children, therehas been a rapid increase in the use ofelectronic cigarettes (e-cigarettes),colloquially known as vaping, inwhich a battery-powered coil heatsa carrier fluid producing an aerosolfor inhalation.1 Recent data froma national survey revealed that theprevalence of vaping has more thandoubled among eighth-, 10th-, and12th-graders from 2017 to 2019;25.4% of 12th-graders in 2019reported vaping in the previous 30days.1 Additional data from 2019revealed that 3.9% of eighth-graders,12.6% of 10th-graders, and 14.0%of 12th-graders reported vapingmarijuana in the previous30 days.2 The impact of risinge-cigarette use in children meritsspecial attention becauseneurodevelopmental changes duringadolescence confer particularvulnerability to substance abuse.Inhalational injury is also a concerngiven case reports of adverse effectson the lung, including increasedschool absence due to asthma,3

hypersensitivity pneumonitis,4

eosinophilic pneumonia,5 lipoidpneumonia,6 and diffuse alveolarhemorrhage.7

As of February 18, 2020, the Centersfor Disease Control and Prevention(CDC) described a total of 2807hospitalized patients with electroniccigarette, or vaping, productuse–associated lung injury (EVALI)across 50 states and 2 US territories,of whom 15% were ,18 years ofage.8 The CDC has postulated that theadditive vitamin E acetate (VEA) isa causative factor.9 The severity ofillnesses reported ranges fromminimal or no respiratory support toinvasive mechanical ventilation andICU admission.1,10–14 To ourknowledge, there are no publishedclinically focused case series of EVALIin children. Our objective for this caseseries is to describe our institutionalexperience of diagnosing, evaluating,and managing pediatric EVALI, withspecial attention to psychosocial risk,

clinical presentation, laboratory andimaging findings, pulmonary functiontesting (PFT), and response totherapy.

METHODS

A retrospective chart review on allreported patients with EVALI fromDecember 2018 to November 2019presenting to our tertiary care,university-affiliated children’shospital was conducted. Patientswere identified on the basis ofconsultations received by the medicaltoxicology and/or pulmonologyservice for suspicion of EVALI. Casesmeeting the confirmed or probableCDC case definitions were included inthe analysis.12 After severaladolescents were diagnosed withEVALI, an EVALI steering committeeof key stakeholders was formed andincluded the divisions of pediatricrespiratory medicine, medicaltoxicology, pediatric emergencymedicine, pediatric critical care,pediatric hospital medicine, and adultpulmonology and critical care. Thecommittee collectively reviewed theliterature and devised a clinicalalgorithm to standardize the inpatientmanagement of EVALI (Fig 1). Thiscan be summarized as follows: Aclinician suspects EVALI on thebasis of clinical symptoms,vaping history within the 90 daysbefore admission, and radiographic orimaging findings of bilateral ground-glass opacities. This promptsconsultation of both pulmonology andmedical toxicology followed bya laboratory workup to rule outinfection and other potentialcauses. The results of theworkup should guide the decision tostart antimicrobial agents or movedirectly to treatment with steroids forEVALI.

Data elements collected from anelectronic medical record review aredetailed in Table 1. Descriptivestatistics were performed by usingSAS version 7.12 (SAS Institute, Inc,

Cary, NC). The Wilcoxon rank testwas used to compare PFT resultsbefore and after corticosteroidtreatment by using IBM SPSS version24 (IBM SPSS Statistics, IBMCorporation). Some patients had PFTsobtained for the first time aftersteroid initiation because of inabilityto perform the forced maneuverwhile ill; these PFTs and subsequentPFTs for these patients were notincluded in the analysis ofPFT data. PFTs were performedat an American ThoracicSociety–accredited pulmonaryfunction laboratory and reviewedby the first author for quality.15,16

All data were deidentifiedbefore statistical analysis.Institutional review boardapproval was obtained from theUniversity of Texas SouthwesternMedical Center.

RESULTS

Thirteen patients werediagnosed with confirmed orprobable EVALI. The mean age was15.9 years, 54% of patients werefemale, and 46% of patients wereHispanic. Twelve of 13 patientssought treatment from primary careclinics, urgent care, or outsideemergency departments beforediagnostic admission. One patienthad 2 previous admissions to ourinstitution before a urinetoxicology positive for D-9-tetrahydrocannabinol prompted theteam to consider the diagnosis ofEVALI. EVALI admissions peaked inSeptember 2019.

Vaping D-9-tetrahydrocannabinol wasreported by 92% of patients, with62% also vaping nicotine. Exclusivenicotine vaping was reported by onepatient; however, caregivers hadsuspicion of additional substance use.A urine toxicology screening wasnot performed on this patient.Combustible cigarette use wasreported by 38% of patients.Reported duration of D-9-

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tetrahydrocannabinol vaping rangedfrom 1 month to 2 years. Only onepatient admitted knowingly obtainingproducts from an unregulateddistributor. All others who disclosedtheir sources cited friends andacquaintances. Of note, Texasprohibits retail dispensaries of D-9-tetrahydrocannabinol–containingproducts.

A previous diagnosis of substance usedisorder was present in 31% of

patients. Presence of stressors in atleast 3 of the 5 psychosocial riskdomains was found in 54% ofpatients. Risk domains included homeenvironment, academic difficulty,behavior problems, mental health,and substance use. Two patients hadstressors in all 5 domains, whereasonly 2 patients had no documentedstressors. Six patients receivedpsychiatry consultations, of whom5 received inpatient treatment

recommendations for nicotineor D-9-tetrahydrocannabinolwithdrawal. Symptoms concerningfor D-9-tetrahydrocannabinolwithdrawal were noted in 3patients. Referral to anadolescent-specific addictiontreatment program was providedfor 5 patients.

All patients underwent evaluation forother conditions such as asthma,typical and atypical pneumonia,appendicitis, sepsis, and pulmonaryembolism. Eighty-five percent ofpatients had respiratory symptoms atpresentation ranging from mild tosevere. Cough, shortness of breath,and chest pain were the mostcommon complaints. Gastrointestinal(GI) distress with minimal or norespiratory symptoms characterizedthe presentation of 4 patients. GIsymptoms occurred in 85% ofpatients, with vomiting and nauseapredominating. All patients

FIGURE 1Clinical algorithm for pediatric patients hospitalized for suspected EVALI. The algorithm includes CDC-based diagnostic criteria, recommended con-sultations, laboratory workup and imaging, and recommended treatment and follow-up. a May need to speak with peers and family, especially for patientswho are intubated. b glucocorticoid dosage considerations. CXR, chest radiograph; IV, intravenously; TLC, total lung capacity.

FIGURE 2Fifteen-year-old boy with daily D-9-tetrahydrocannabinol vaping. A and B, Axial chest CT imagesreveal ground-glass opacities involving all lobes with a central, mid, and peripheral distribution(white arrowheads) and subpleural sparing throughout all lobes (black arrows).

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eventually developed respiratorysymptoms.

The urine drug screen was positivefor D-9-tetrahydrocannabinolmetabolites in all 11 patients whoreceived screening. Of 9patients with a subsequenturine comprehensive toxicology panelanalyzed by liquid chromatographyand mass spectroscopy, all had D-9-tetrahydrocannabinol and/or D-9-tetrahydrocannabinol metabolites.A private laboratory analysis of 5D-9-tetrahydrocannabinol cartridgesprovided by 1 patient confirmedthe presence of D-9-tetrahydrocannabinol. D-9-tetrahydrocannabinol madeup 31% of the e-liquid solution

in the patient’s most recently used

cartridge. In this same

cartridge, VEA was detected and

made up 38% of the solution. VEA

was found in 3 of this patient’s

cartridges. This patient reported

obtaining cartridges from friends and

acquaintances.

Chest computed tomography (CT)scans revealed diffuse bilateralground-glass opacities in all patients(Figs 2–4). Notably, abnormal lungfindings were first identified onabdominal CT scans in 23% ofpatients who underwent a primaryworkup for GI symptoms. Fifteenpercent of patients with subtle chestradiograph findings had markedly

abnormal lung findings on the chestCT scan.

The degree of respiratory supportamong patients varied. Nasal cannulawas required by most patients (62%),whereas 2 patients required bilevelpositive airway pressure, 1required intubation with invasivemechanical ventilation, and 1required veno-venousextracorporeal membraneoxygenation (VV-ECMO). The patientwho was the sickest required 2courses of VV-ECMO, chest tubeplacement for persistent air leaksyndrome, and an eventualtracheostomy.

Oral and/or intravenousglucocorticoid treatment wasprovided to 12 of 13 patients(Table 2). Of these, 11 demonstratedclinical improvement within24 hours. One patient who remainedon room air throughout admissionhad minimal abnormalities on thechest CT scan described as “subtlediffuse ground-glass pulmonaryopacities” and improved with low-dose oral steroids. Eleven patientsreceived intravenous steroids, ofwhom 7 received pulse dosing. Thelone patient who did not demonstraterapid improvement fromglucocorticoid therapywas the patient who requiredVV-ECMO. Sixty-nine percent ofpatients received intravenousantibiotics but had no correspondingimprovement.

All patients reported complete ornear-complete resolution of theirprevious constitutional, respiratory,and GI symptoms before discharge;however, 31% were prescribedsupplemental oxygen withactivity at discharge, as indicatedby 6-minute walk test (6MWT)results. The patient who requiredVV-ECMO and a tracheostomy wasdischarged to a rehabilitationfacility with a home ventilator andeventually weaned from ventilatorsupport 110 days after initial hospital

FIGURE 3Seventeen-year-old boy with D-9-tetrahydrocannabinol vaping for one year who reported use ofcartridges from an unregulated distributor. A and B, Axial chest CT images reveal ground-glassopacities throughout all lobes (white arrowheads).

FIGURE 4Sixteen-year-old girl with daily nicotine and D-9-tetrahydrocannabinol vaping. A and B, Chest CTimages in the axial and coronal planes reveal diffuse ground-glass opacities (white arrowheads),a consolidative opacity (large white arrows), interlobular septal thickening (small white arrow), andcrazy paving (black arrowhead) in the left lower lobe.

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admission. The patient is nowdecannulated.

Most patients performed PFTs(Table 3). Spirometry and 6MWTresults were assessed at least once in92% and 77% of patients,respectively. Two out of 13 patientshad an obstructive pattern even aftersteroids were administered. Fivepatients completed the spirometrybefore and after initiation of steroids(Fig 5). Four total patients hadplethysmography, diffusioncapacity testing, and a 6MWTperformed before and afterinitiation of steroids (Figs 5 and 6).All patients who had PFTs beforeand after initiation of steroidsdemonstrated improvement inforced expiratory volume in 1second (FEV1), forced vital capacity(FVC), total lung capacity, anddiffusion capacity of carbonmonoxide (DLCO) (Table 4). Therelative improvement in FEV1ranged from 9% to 35%, witha mean of 23%, and was significant(P = .042).

DISCUSSION

We describe a unique cohort ofpediatric patients diagnosed withEVALI. As in other case series, thenature of the lung injury was notinfectious.12,17 Rather, our patientsdemonstrated a systemicinflammatory process evidenced byelevated inflammatory markers andmultisystem disease. The GI tract wasaffected in 85% of patients, similar toother EVALI case series in whichauthors reported GI symptoms in77% to 92% of patients.12,17 Use ofglucocorticoids was successful inabating this systemic inflammatoryresponse, with clinical improvementnoted in most cases, similar to othercase series.12,17,18 However, ourpatient who was the sickest required2 runs of VV-ECMO despite steroidtherapy and underwenta tracheostomy for long-termmechanical ventilation. This patient’s

TABLE 1 Characteristics of Adolescent Patients Admitted With EVALI

Characteristics Results

No./total No. (%) 13/13 (100)a

Mean age (range), y 15.9 (13–18)Female sex, No. (%) 7 (54)Race and/or ethnicity, No. (%)White 7 (54)Hispanic 6 (46)

E-cigarette or vaping history, No. (%)E-cigarette or vaping use in previous 90 dD-9-tetrahydrocannabinol 12 (92)Nicotine 8 (62)Both nicotine and D-9-tetrahydrocannabinol 7 (54)

Nicotine vaping history, No./total No. (%)Duration3–6 mo 1/8 (13).12 mo 5/8 (63)Unknown 2/8 (25)

FrequencyMultiple times a wk or less 1/8 (13)Daily 1/8 (13)Multiple times per d 5/8 (63)Unknown 1/8 (13)

Cartridges used per wk,1 2/8 (25)2–7 2/8 (25)Unknown 4/8 (50)

Source of cartridgeFriend 3/8 (38)Acquaintance or dealer 1/8 (13)Unknown 4/8 (50)

D-9-tetrahydrocannabinol vaping history, No./total No. (%)Duration3–6 mo 3/12 (25)6–12 mo 1/12 (8).12 mo 8/12 (67)

FrequencyMultiple times a wk or less 5/12 (42)Daily 1/12 (8)Multiple times per d 6/12 (50)

Cartridges used per wk#1 6/12 (50)2–7 1/12 (8)Unknown 5/12 (42)

Source of cartridgeFriend 5/12 (42)Acquaintance or dealer 4/12 (33)Black market 1/12 (8)Unknown 2/12 (17)

Vaping brands reported, No./total No. (%)b

Nicotine brandsJUUL 5/8 (63)NJoy 2/8 (25)Suorin 1/8 (13)Delosi 1/8 (13)

D-9-tetrahydrocannabinol brandsDank 3/12 (25)Rove 2/12 (17)Cali plug 2/12 (17)Chronic carts 1/12 (8)Runtz 1/12 (8)Stig 1/12 (8)EonSmoke 1/12 (8)

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extended course is likely due toprolonged air leak syndrome, and it isunclear what factors in this patient’shistory led to such severe lungdisease. Of note, this patient hadseveral of the known EVALI riskfactors reported by the CDC: use.5 times per day, exclusivevaping of D-9-tetrahydrocannabinol,and use of Dank vapes.19 Inaddition, the patient’s mostrecently used cartridgescontained VEA.

The CDC has reported that the likelyculprit for EVALI is VEA, althoughthe exact mechanism of injury isunknown. In November 2019,the CDC described that residualbronchoalveolar lavage (BAL) fluidfrom 29 patients contained VEA,20

a thickening agent added to diluteD-9-tetrahydrocannabinol oil.21 Morerecently, a study revealed that of 51BAL samples from patients withEVALI, 94% tested positive for VEA,compared with none of the BALsamples from 99 healthy adults.9

The authors suggested thatthe addition of VEA to D-9-tetrahydrocannabinol e-liquidsbecame more popular in 2019,leading to the nationwide peak inEVALI cases in September 2019.

Our patients frequently reportedbuying D-9-tetrahydrocannabinolcartridges from dealers andacquaintances, a standard practice inthis state without legal dispensaries.Products purchased from theunderground economy aresusceptible to adulteration.Adolescents preferentially userefillable vaping cartridges, puttingthem at higher risk for unintendedexposures.22 Although the currentoutbreak appears to be subsiding,13

it is critical that clinicians note thelack of regulation on e-liquidformulations and thate-cigarette cartridges are easilymodifiable with known and unknownadditives.

TABLE 1 Continued

Characteristics Results

Brass knuckles 1/12 (8)Dr Zodiac 1/12 (8)

Reported length of e-cigarette use (range), d 30–730Psychosocial history, No. (%)Stressors identified from psychosocial historyHome environment 6 (46)Academic difficulty 8 (62)Behavior problems 6 (46)History of mood or anxiety disorder 7 (54)History of suicidal or homicidal ideation 5 (38)Nicotine use (other than e-cigarette or vaping) 5 (38)Substance use (other than e-cigarette or vaping) 12 (92)

Symptoms reported at presentationMedian duration of symptoms before presentation (range), d 3 (2–21)Constitutional symptoms, No. (%) 13 (100)Subjective fever 13 (100)Fatigue or malaise 8 (62)Weight loss 6 (46)Excessive sweating 3 (23)

Respiratory symptoms, No. (%) 11 (85)Cough 11 (85)Shortness of breath 10 (77)Chest pain 9 (69)Dyspnea on exertion 6 (46)Wheezing 3 (23)

GI symptoms, No. (%) 11 (85)Vomiting 11 (85)Nausea 10 (77)Diarrhea 8 (62)Abdominal pain 6 (46)

Abnormal vital signs at presentation, No. (%)Respiratory rate $20 breaths per min 11 (85)Oxygen saturation #95% in ambient air 11 (85)Temperature $38°C 10 (77)Heart rate $120 beats per min 9 (69)Blood pressure $135/85 0 (0)

Initial laboratory evaluationWhite blood cell count .11 000 cells per mm3, No. (%) 11 (85)White blood cell count with .80% neutrophils, No./total No. (%) 9/12 (75)C-reactive protein level .1 mg/dL, No./total No. (%) 12/12 (100)Erythrocyte sedimentation rate .15 mm/h, No./total No. (%) 10/11 (91)Erythrocyte sedimentation rate .30 mm/h, No./total No. (%) 8/11 (73)Respiratory viral panel result, No./total No. (%)Negative 10/12 (83)Coronavirus 1/12 (8)Rhinovirus 1/12 (8)

Urine drug screen positive for D-9-tetrahydrocannabinol, No./total No. (%) 11/11 (100)Imaging findings on chest CT scan, No. (%)Bilateral ground-glass opacities 13 (100)Lung bases greater than lung apices 6 (46)

Interlobular septal thickening 2 (15)Pneumomediastinum 2 (15)Crazy paving 1 (8)

Bronchoscopy findingsNegative BAL bacterial culture result, No./total No. (%) 6/6 (100)Lymphocytes, mean (range), % 13.3 (2–32)Neutrophils, mean (range), % 27.8 (2–81)Macrophages, mean (range), % 25.8 (15–69)Eosinophils, mean (range), % 14.0 (1–46)

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The underlying mechanism of toxicityleading to EVALI remains unclear. Onthe basis of our findings, lung injurymay be related to airways disease. Wefound an improvement in FEV1 andFVC after steroid treatment, whichmay reflect improved airflow fromdecreased airway inflammation.Airways disease as a result ofnicotine-containing and nicotine-freee-cigarette use has been previouslydescribed. Airwayhyperresponsiveness, defined asairway obstruction caused by

nonspecific stimuli,23 has been shownin mice after exposure to bothnicotine-free flavored e-cigarettes24

and nicotine-containing flavorede-cigarettes.25 In another study,adults vaped nicotine for 5 minutes,which resulted in airways disease inthe form of increased airwayresistance measured via forcedoscillometry.26 A recent study oftobacco-using adults revealedthat 25 puffs of a nicotine-free vape led to a decrease inthe mean forced expiratory flow

between 25% and 75% of the FVC,a measure of small airways.27 Inaddition to airways disease, wefound evidence of parenchymalpulmonary inflammation fromBAL results that revealeda predominance of lymphocytes andneutrophils as well as chest CTfindings of diffuse bilateral ground-glass opacities.

Although the CDC has acknowledgedthat VEA in D-9-tetrahydrocannabinoloil is a leading suspect in the etiologyof EVALI, other components of thee-cigarette aerosol may contribute tolung disease.20 Murine studies revealthat exposure to both nicotine-containing and nicotine-free aerosolresults in an increase of neutrophils,macrophages, lymphocytes, andpro-inflammatory cytokines inbronchoalveolar fluid.25,28–30 Othere-cigarette aerosol components, suchas vegetable glycerin, propyleneglycol, and flavoring agents, can causelung inflammation and cytotoxicity.One study of human tracheobronchialepithelial cells revealed that exposureto e-cigarette aerosol led to necroticcell death.31 Another study revealedan increased level of the pro-inflammatory cytokine interleukin 6when human bronchial epithelial cellswere exposed to e-liquid withoutnicotine.32 Leigh et al33 found thatexposing human bronchial epithelialcells to various e-cigarette flavoringsled to a significant increase in pro-inflammatory cytokine levels anda decrease in cell viability. Bengalliet al34 demonstrated an increase inpro-inflammatory cytokine levels andcell death in human alveolar and lungendothelial cells exposed toe-liquid–generated aerosolscontaining cinnamon flavoring.Finally, metals found in e-liquids,including chromium, nickel, lead,manganese, aluminum, tin, iron, andcadmium, can also lead to lung injury;cadmium, specifically, is a knownpulmonary toxin.35 Cartridgesprovided by 2 of our patients,including our sickest patient, were

TABLE 1 Continued

Characteristics Results

Normal bronchial mucosa, No./total No. (%) 1/6 (17)Clinical courseHospitalization, No. (%) 13 (100)Admission to ICU 4 (31)

Maximum respiratory support, No. (%)Room air 1 (8)Nasal cannula 8 (62)Bilevel positive airway pressure 2 (15)Intubation with invasive mechanical ventilation 1 (8)VV-ECMO 1 (8)

Duration of hospitalization, median (range), d 7 (2–120)Treatment courseAntibiotics for lower respiratory tract infection, No. (%)Oral antibiotics before hospitalization 6 (46)Intravenous antibiotics during hospitalization 9 (69)

Systemic glucocorticoids, No./total No. (%)Oral and intravenous glucocorticoids 10/12 (83)Oral glucocorticoids alone 1/12 (8)Intravenous glucocorticoids alone 1/12 (8)

Required supplemental oxygen at discharge, No. (%) 4 (31)

a Denominator equals 13 unless otherwise specified.b Each patient may have reported multiple brands; 3 patients had unknown brands.

TABLE 2 Glucocorticoid Treatment Regimen by Patient

Patient IV Glucocorticoids Pulse Dosinga Oral Glucocorticoids Taper Dosing

1 Yes — Yes Yes2 Yes Yes Yes Yes3 Yes Yes — —

4 Yes Yes Yes Yes5 — — — —

6 Yes — Yes Yes7 Yes — Yes Yes8 Yes Yes Yes Yes9 Yes Yes Yes Yes10 Yes Yes Yes Yes11 — — Yesb Yes12 Yes — Yes Yes13 Yes Yes Yes Yes

IV, intravenous; —, not received.a 1000 mg of methylprednisolone every 20 h for 3 d.b 40 mg of prednisone twice daily for 1 d followed by taper dosing.

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tested for cadmium, and results werenegative.

Including 6MWT results in our EVALIalgorithm helped identify residuallung disease in patients who had beenweaned off oxygen because of clinicalimprovement after glucocorticoidtreatment. Four of 8 patients testedafter steroid initiation (including 5patients who did not completea presteroid 6MWT) had abnormaldesaturations with the 6MWT andwere prescribed oxygen for use withactivity at discharge. These patients

were otherwise clinically stable in the

24 to 48 hours before discharge andhad normal oxygenation at rest,

consistent with current CDC guidance

for discharge planning.36 All 4

patients who were discharged onhome oxygen received follow-up inthe pulmonology clinic, wherenormalization of 6MWT results ledto discontinuation of home oxygen.The 6MWT is an assessment ofsubmaximal exercise capacity, akin toactivities of daily living. It isa recommended test to assess

treatment response in lung diseases16

such as pulmonary hypertension,sickle cell disease, and cysticfibrosis.37–39 Abnormal 6MWToxygen saturation may reflect lunginjury at the level of the alveolarepithelium, in which impaired gasexchange manifests during exercise.Impaired gas exchange has beendemonstrated in adult tobaccosmokers who vaped nicotine-freee-cigarettes and had a subsequentdecrease in transcutaneous oxygenmeasurements after a short sessionof use.27

Our pediatric cohort demographicwas more diverse than in previouslydescribed cohorts.12,17 Half of ourcohort was female, and almost halfwere of Hispanic origin, in contrast tothe mostly young, white, and malepopulation described in the adultliterature.12,17,40 A study in whichadult e-cigarette users with EVALIwere compared with e-cigarette userswithout EVALI showed that thosewith EVALI had higher odds ofreporting ethnicity other thanwhite. The reason for Hispanicethnicity as a potential EVALI riskfactor in our cohort is unknown. Itmay be related to underlyingsocioeconomic factors, but may also

TABLE 3 PFT Completion by Patient

Patient Before Glucocorticoidsa After Glucocorticoidsb Clinic Follow-up

Spirometry LV DLCO 6MWT Spirometry LV DLCO 6MWT Spirometry LV DLCO 6MWT

1 — — — — — — — Yes Yes — — Yes2 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes3 — — — Yes Yes Yes Yes Yes — — — —

4 Yes Yes Yes Yes Yes Yes Yes Yes — — — —

5 — — — — — — — — Yes Yes Yes —

6 — — — — Yes Yes — Yes — — — —

7 — — — — Yes Yes Yes Yes — — — Yes8 — — — — Yes Yes Yes Yes Yes Yes Yes Yes9 — — — — Yes Yes Yes Yesc Yes Yes Yes Yes10 Yes Yes Yes Yes — — — — Yes Yes Yes Yesd

11 Yes Yes Yes Yes — — — — Yes Yes Yes —

12 — — — — — — — — — — — —

13 Yes — — — Yes — — — — — — —

LV, lung volume; —, not performed.a Before or within 24 h of initiation of glucocorticoid treatment.b More than 24 h after initiation of glucocorticoid treatment and completed during hospitalization.c Tested with 1 L of oxygen via nasal cannula.d Questionable effort.

FIGURE 5Pulmonary function response to glucocorticoid treatment. The figure reveals the change in PFTresults in response to steroid treatment. Preglucocorticoid values were obtained within 24 hours ofsteroid initiation. Postglucocorticoid values were obtained at the first repeat testing during hos-pitalization or at the clinic follow-up. a n = 5. b P , .05. c n = 4. TLC, total lung capacity.

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simply reflect regional populationdemographics.

Another unique finding among ourpatients was the large percentageof patients with a history ofpsychosocial stressors, includingsubstance use and mooddisorders. Data from the CanadianCommunity Health Survey haverevealed adverse mental healthto be associated with e-cigaretteuse in adolescents and adults.41

Additionally, a recent survey ofstudents at 2 Midwestern universitiessuggested that e-cigarette users weremore likely to engage in illicit druguse; to have a history ofposttraumatic stress disorder,

attention-deficit/hyperactivitydisorder, or anxiety; to have poorerself-esteem; and to have depressivesymptoms.42 A detailed psychosocialscreening was an important partof the evaluation of EVALI andshould be linked with appropriateoutpatient referrals,including for chemicaldependency management.

Our study highlights the severity ofEVALI in adolescents and teenagers,but certain limitations should benoted. Our case series captureda single-center population. However,given that the underground productmarketplace was likely nothomogenous and potentially included

out-of-state sources, our findings maystill be generalizable to cases in otherregions. The evolving nature of ourunderstanding of this diseaseinfluenced our management and mighthave inherently impacted outcomes.We tended toward higher steroiddosages compared with other caseseries, and this decision was based onexpert consensus at our institution.Variation in severity of illnessimpacted our ability to perform BALstudies; however, bronchoscopy andBAL analysis may not be useful toolsand may increase respiratorymorbidity post procedure.43

We lacked sufficient data to drawconclusions on brands or brandchanges in correlation with symptomonset or severity. Samples of vapingdevices were not consistently availablefor testing to determine potentialchemical exposures. Patient effortduring PFTs may have beensuboptimal in some patients and mayhave led to an underestimation of lungfunction, including oxygen saturationduring the 6MWT. To minimize thispossibility, all PFT results werereviewed for adequate quality beforeinclusion in the data analysis.Finally, we have incomplete outpatientfollow-up of our patients, includingseveral who experienced financial orinsurance barriers to return visits.

CONCLUSIONS

In our cohort of adolescentsdiagnosed with EVALI, we found thatthe clinical severity was variable,with some patients requiring nosupplemental oxygen to one patientrequiring invasive mechanicalventilation and extracorporealmembrane oxygenation.Glucocorticoids were a successfultreatment modality, whereasantibiotics did not appear to resultin improvement. Lung functionimproved after glucocorticoidadministration, and the 6MWT wasuseful in identifying patients whocould benefit from oxygen with

FIGURE 66MWT response to glucocorticoid treatment. The figure reveals the mean oxygen saturation duringthe 6MWT by patient, with testing completed both before and after initiation of glucocorticoidtreatment. a Before or within 24 hours of initiation of glucocorticoid treatment. b More than 24 hoursafter initiation of glucocorticoid treatment and completed during hospitalization. SpO2, pulse oxygensaturation.

TABLE 4 PFT Response to Glucocorticoid Treatment

Before Glucocorticoids,Meana

After Glucocorticoids,Meanb

P

FEV1, % predictedc 66.8 89.6 .042FVC, % predictedc 70.4 93.4 .043TLC, % predictedd 83.5 101.3 .066DLCO, % predictedd 78.8 94.3 .0686MWD, % predictedd 62.3 73.3 .0686MWT SpO2

d 84 93.8 .068

SpO2, pulse oxygen saturation; TLC, total lung capacity; 6MWD, 6-min walk distance.a Before or within 24 h of initiation of glucocorticoid treatment.b First repeat testing after initiation of glucocorticoid treatment; completed during hospitalization or at clinic follow-up.c n = 5.d n = 4.

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activity at discharge. The mechanismof lung injury remains unclear, butexposure to D-9-tetrahydrocannabinol adulteratedwith VEA appears likely. All patientswho followed-up in the pulmonaryclinic reported cessation ofe-cigarette use, so it remains to beseen whether the improvement inpulmonary function seen in ourpatients will also persist inadolescents who choose to resumee-cigarette use. The long-term effectsof the other components ofe-cigarette liquid on the lung remainunknown and is an area forfuture study.

ACKNOWLEDGMENTS

We acknowledge the respiratorytechnicians of the PFT laboratoryat Children’s Health Dallas:

Dr Rosechelle Ruggiero from theDepartment of Internal Medicine;members of the Division ofRespiratory Medicine, including DrsAndrew Gelfand, Tanya Martinez-Fernandez, Yadira Rivera-Sanchez,Preeti Sharma, Elisa Basora, Suja Nair,Michelle Caraballo, Kubra MelikeBozkanat, Fayruz Araji, and BayanAbdallah, for their feedback regardingthe clinical algorithm; and membersof the Department of EmergencyMedicine, including Drs KurtKleinschmidt, Mary Billington, JoshuaMcFalls, and Cherie Obilom, for theirfeedback regarding the clinicalalgorithm. We acknowledge Dr GuidoVerbeck and Imesha De Silva of theUniversity of North Texas Laboratoryof Imaging Mass Spectrometry fortheir assistance in analyzing e-liquidsamples.

ABBREVIATIONS

6MWT: 6-minute walk testBAL: bronchoalveolar lavageCDC: Centers for Disease Control

and PreventionCT: computed tomographyDLCO: diffusion capacity of carbon

monoxideE-cigarette: electronic cigaretteEVALI: electronic cigarette, or

vaping, product use–associated lung injury

FEV1: forced expiratory volume in1 second

FVC: forced vital capacityGI: gastrointestinalPFT: pulmonary function testingVEA: vitamin E acetateVV-ECMO: veno-venous

extracorporealmembrane oxygenation

Dr Rao conceptualized and designed the study, performed the retrospective chart review, and drafted the initial manuscript; Ms Maple completed the chart review,

aided in the creation of the database, aided in drafting the initial manuscript, and devised the figures and tables; Drs Dettori and Afolabi aided in the creation of the

database and assisted in the chart review; Dr Francis assisted with statistical analysis and assisted with the initial manuscript draft; Dr Artunduaga reviewed the

radiology findings for all cases, assisting in the initial draft of the manuscript, and secured representative chest computed tomography images; Drs Lieu, Aldy, and

Cao assisted in the chart review and assisted in drafting the initial manuscript; Dr Hsu assisted in drafting the initial manuscript; Drs Feng and Mittal assisted in

the drafting the initial manuscript and organized the references and bibliography; and all authors reviewed and revised the manuscript, approved the final

manuscript as submitted, and agree to be accountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2019-4104

Accepted for publication Apr 6, 2020

Address correspondence to Devika R. Rao, MD, Division of Respiratory Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323

Harry Hines Blvd, Dallas, TX 75290. E-mail: devika.rao@utsouthwestern.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2020 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-0902.

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