The 2018 US Food and Drug Administration Youth Tobacco Survey suggested use of e-cigarette devices in roughly 1 in 5 high school students.1 According to preliminary self-report data from 2019, this number may be as high as 25% of 11th graders.2,3 Additionally, about one-quarter of high school students in a large Arizona cohort reported lifetime use of tetrahydrocannabinol (THC) concentrates, the psychoactive component in marijuana.4 In light of the substantial escalation of vaping among youth, federal law was signed to prohibit sales of e-cigarette and other tobacco-related products to individuals younger than age 21 years and to curb the sales of some flavors of e-cigarette cartridges.5,6
E-cigarette or vaping–induced pulmonary syndromes have been observed over the past few years as the use of electronic devices with inhaled aerosols has increased.7–11 However, by January 14, 2020 more than 2,600 patients in the United States had been recently diagnosed with e-cigarette or vaping product use-associated lung injury (EVALI) according to the US Centers for Disease Control and Prevention (CDC), with 60 EVALI-associated deaths.12 It is probable that more cases occurred but were not recognized or reported. Nicotine and THC-based aerosols are the vaping products most commonly associated with either acute or subacute lung injury.13,14 Most EVALI cases so far have reported some THC-based product use, although this has been seen as a marker or risk, rather than a known singular cause of the illness thus far. E-cigarette devices produce an aerosol subsequent to heating an indwelling liquid that may contain multiple chemicals including glycerin, propylene glycol, diacetyl, aldehydes, formaldehyde, vitamin E acetate, terpenes, organic compounds, and trace metals.15,16 E-cigarette devices range in design and modifiability (Figure 1). Flavoring of these liquids has made them more desirable for teens and young adults, thus the preponderance of cases in people younger than age 35 years.1,17 Flavoring substances such as cinnamonaldehyde and vanillin have been reported to cause immune dysfunction.18–21 Furthermore, variable heating properties and the resultant chemical reactions and degradation of ingredients may further complicate our understanding of the causes of EVALI.22,23
Examples of various e-cigarette models.
A previously healthy 16-year-old girl presented to her family physician with complaints of dizziness, nausea, mild cough, and intermittent vomiting. She appeared well hydrated and had no fever or abnormal pulmonary findings. She was diagnosed with a presumed viral syndrome causing vertigo and discharged on supportive care of clear liquids and anti-emetics. Within 48 hours she worsened, with complaints of dyspnea, anorexia, mild diarrhea, and headache. She was admitted to her local hospital for intravenous (IV) fluids, and a screening chest radiograph showed bilateral pulmonary infiltrates. Her O2 saturation was 85% on room air. She was treated for community-acquired pneumonia with IV ceftriaxone, azithromycin, and supplemental oxygen. Over the next 24 hours she worsened, with increasing hypoxemia and respiratory distress. She was transferred to Children's Hospitals of Minnesota and admitted to the pediatric intensive care unit. Further history revealed social stressors and anxiety. She had recently started using e-cigarettes and had been vaping a THC-containing liquid through her refillable device. This liquid had been given to her by a friend. She had been vaping one cartridge daily for 5 days prior to this onset of symptoms.
Her respiratory distress worsened despite oxygen, diuretic, and fluid therapy. She required intubation and mechanical ventilatory support with plateau pressure of 28 cm H2O, positive-end expiratory pressure of 12 cm H2O, and inspired fractional oxygen concentration (FiO2) of 0.7. Due to hypotension, she was treated with a norepinephrine drip. Her echocardiogram was normal without evidence of pulmonary artery hypertension or myocardial dysfunction. A computed tomography (CT) scan of her chest revealed patchy bilateral ground glass changes with septal thickening and pleural sparing (Figure 2). A bronchoscopy was performed at the bedside without evidence of pulmonary hemorrhage or purulent pneumonia. Seventy-five milliliters of saline were used in bronchoalveolar lavage (BAL), and effluent testing demonstrated a predominant neutrophilia (polymorphonuclear cells 60%, lymphocytes 10%, alveolar macrophages 25%, and eosinophils 5%). Cytology showed no evidence of malignancy. Gram stain and fungal smears were negative for bacteria or fungi. An oil red O stain on BAL was positive for lipid-laden macrophages (lipid-laden macrophage index 260/400), and viral/fungal/acid-fast bacillus polymerase chain reaction tests were negative. All cultures were ultimately negative.
(A) Chest radiograph and (B, C) computed tomography scans of diffuse lung disease caused by e-cigarette or vaping product use.
Given the level of ventilator support and continued high oxygen requirement, a thoracoscopic lung biopsy was obtained to rule out endovascular fungal disease, pulmonary vasculitis, or occult malignancy. Pulmonary biopsy findings indicated a component of necrotizing pneumonia, vacuolated macrophages in alveoli (evaluation for lipid was limited by use of formalin in tissue preparation), type II pneumocyte hyperplasia, and diffuse alveolar damage (Figure 3 and Figure 4).
Low-power view of left lingula biopsy showing multiple areas with diffuse lung injury characterized by diffuse inflammation and extensive obliteration of the alveolar spaces.
(A) Hematoxylin and eosin stain showing findings of organizing pneumonia with obscuration of the alveolar spaces with neutrophilic infiltrate and increased alveolar consolidation. (B) Diffuse alveolar damage with reactive type II pneumocytes, foamy histiocytes, interstitial edema, and fibrin disposition.
After the biopsy, she was started on IV methylprednisolone sodium succinate at a dose of 1 g daily for 3 days, then transitioned to prednisone at a dose of 60 mg daily. She had rapid resolution of pulmonary infiltrates and was extubated within 5 days of her biopsy.
When seen in the pulmonary clinic 1 month after discharge, the patient was asymptomatic with normal lung function and chest radiograph findings consistent with recent surgical biopsy. Corticosteroid therapy was transitioned to hydrocortisone and weaned over the next 2 to 3 weeks, and she remained asymptomatic. She was referred for addiction counseling and will have ongoing pulmonary follow-up in the pediatric pulmonology clinic.
Clinical Presentation and Differential Diagnosis
Most patients with EVALI present to a health care provider with symptoms of dyspnea, cough, and chest pain. Prominent gastrointestinal symptoms include nausea, vomiting, and diarrhea with nonspecific abdominal pain. Constitutional symptoms including perceived fever, fatigue, headache, and weight loss are not unusual (Table 1). Presumably due to mimicry of typical infectious symptoms, patients may seek medical care more than once prior to the diagnosis of EVALI being made.
Common Symptoms and Vital Signs of EVALI
Symptoms may develop rapidly over hours or days, or the presentation may be subacute and indolent over weeks. Physical examination is usually nonspecific with absent adventitial sounds. Commonly, patients are hypoxemic with oxygen saturations less than 95% in room air and may require supplemental oxygen to maintain normal oxygen saturation. Patients requiring intubation have lower oxygen saturations on admission (87% vs 92%).24
Chest radiographs often show bilateral infiltrates that are confirmed by a CT scan of the chest. These scans are useful to rule out pulmonary embolic disease and often show bilateral ground glass changes indicating diffuse lung disease. Other findings may include centrilobular nodules, interstitial and septal thickening, and patchy mosaic attenuation compatible with air trapping or subpleural sparing.25
Laboratory data usually show an elevated white blood cell count with a predominance of neutrophils and elevated inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein.24 Chemistries generally show normal renal function but with occasional hyponatremia or hypokalemia. Alanine aminotransferase is elevated in approximately 50% of patients.
The CDC surveillance case definition of confirmed EVALI includes diffuse lung disease with a history of vaping within 90 days of presentation with no evidence of infectious, rheumatologic, or malignancy diagnoses that could explain the lung disease.26 It is a diagnosis of exclusion, and rapid viral panel testing, including for influenza, is important during viral season. Other infections to consider and rule out include Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, endemic mycoses, and opportunistic infection of the lungs. CDC surveillance cases labeled as “probable” EVALI are defined as someone who underwent partial work-up or has an infection that was identified but not thought to be the sole cause of the person's illness. It is important to note that these stringent criteria were intended for collection of surveillance data and epidemiologic investigation rather than for clinical diagnostic distinction.
Bronchoscopy with lavage is frequently performed to understand the inflammatory nature of the lung disease, to assess for intrapulmonary infection, and to rule out pulmonary hemorrhage syndromes or malignancy. BAL in patients with EVALI reveals a neutrophilia in the BAL without a preponderance of lymphocytes, hemosiderin macrophages, or eosinophils. In some cases, there is an elevated lipid-laden macrophage index indicating macrophage activation and ingestion of endogenous or exogenous lipid; this finding has not been consistently seen in all cases, regardless of disease severity.
When the bronchoscopy is compatible with inflammatory lung disease triggered by vaping and without evidence of other causes, further evaluation is unnecessary. However, in atypical or rapidly progressive cases a tissue diagnosis may be necessary using either transbronchial or thoracoscopic lung biopsy to make a definitive diagnosis. Biopsy findings can be nonspecific and may include diffuse alveolar damage with foamy macrophages and hyaline membrane formation, peribronchiolar granulomatous inflammation, and organizing pneumonia.27–29
Included in the differential diagnosis should be non-EVALI causes of acute respiratory distress syndrome with diffuse alveolar damage, acute or subacute hypersensitivity pneumonitis, eosinophilic pneumonia, Mycoplasma, viral or Legionella pneumonia, and exogenous lipoid pneumonia. There may be variable pathology in EVALI such that treatment should be tailored to the patient's clinical condition.
Treatment and Follow-Up
Most patients are admitted to the hospital due to multiple symptoms and a ventilation perfusion mismatch requiring oxygen therapy. Usual supportive care is provided with IV fluids and supplemental oxygen to improve dyspnea and eliminate hypoxemia. Most patients initially receive IV antibiotics for community-acquired and atypical pneumonia coverage, pending blood and airway cultures. Most patients, especially those requiring intensive care admission, are given corticosteroid therapy, which may result in rapid improvement in lung function. There is no consensus as to the standard IV dose of methylprednisolone or oral prednisone, and the duration of therapy is unknown. We at Children's Minnesota have been rather aggressive in treating these patients with high-dose IV methylprednisolone for 3 days and a prednisone weaning schedule over the next 4 weeks. Some patients will require a hydrocortisone dosing schedule for secondary adrenal suppression pending an adrenocorticotropic hormone stimulation test. This approach has appeared effective, as our patients have recovered normal lung function by their follow-up at 2 to 4 weeks post-discharge. Removal of the offending trigger is mandatory, and all patients should be given appropriate counseling and nicotine withdrawal treatment if nicotine vaping has been prolonged. It should be mentioned that this disease is incompletely understood and as further information becomes available, other therapies may be necessary.
Currently there is not a clear understanding of the mechanism of lung injury in patients with EVALI. Initially, clinicians felt that aerosolized vegetable oil from cannabis or other liquids was inducing a lipoid pneumonitis with associated hypoxemia and dyspnea.30 A recent CDC report identified vitamin E acetate in BAL samples from all patients studied, raising concern about the effects of inhaled vitamin E on the lung.24 As this epidemic has progressed and more tissue samples have become available, it is not obvious that aerosolized organic matter is the trigger for this disease. Some experts feel that this disorder resembles a chemical pneumonitis or a hypersensitivity reaction to vaporized particles and chemicals,25,27,31 whereas others have focused on the end result of acute lung injury.28 Unfortunately, there are multiple vaping fluids that are heated to different temperatures and inhaled at different pressures. The addition of flavoring is another variable that may cause pulmonary or immune dysfunction.21,22 All of these variables can affect the dose delivered to the lung and the subsequent degree of lung injury. Much further study is necessary to identify the primary pathophysiology and various mechanisms of both airway and alveolar injury.
It is encouraging that some of the sickest patients have responded dramatically to corticosteroid therapy with normalization of their lung function and gas exchange. Nevertheless, these patients need to be observed for the long-term to understand the lung's response to a severe insult and whether progressive late-onset deterioration will develop. Additionally, many of these patients have nicotine addiction and will be predisposed to return to tobacco smoking. What effect this will have on their ongoing lung function is unclear, but most studies would suggest progressive detrimental effect. Therefore, addiction counseling and treatment is imperative for these patients.17
- Cullen KA, Ambrose BK, Gentzke AS, Apelberg BJ, Jamal A, King BA. Notes from the field: use of electronic cigarettes and any tobacco product among middle and high school students–United States, 2011–2018. MMWR Morb Mortal Wkly Rep. 2018;67(45):1276–1277. doi:10.15585/mmwr.mm6745a5 [CrossRef] PMID:30439875
- Minnesota Department of Health. 2019 Minnesota student survey: e-cigarette and cigarette findings. https://www.health.state.mn.us/communities/tobacco/data/docs/2019_mss_tobacco.pdf Accessed January 20, 2020.
- Minnesota Department of Health. Tobacco data highlights from the 2019 Minnesota student survey. https://www.health.state.mn.us/communities/tobacco/data/docs/2019_mss_data_highlights.pdf. Accessed January 20, 2020.
- Meier MH, Docherty M, Leischow SJ, Grimm KJ, Pardini D. Cannabis concentrate use in adolescents. Pediatrics. 2019;144(3):e20190338. doi:10.1542/peds.2019-0338 [CrossRef] PMID:31451609
- US Food & Drug Administration. FDA finalizes enforcement policy on unauthorized flavored cartridge-based e-cigarettes that appeal to children including fruit and mint. https://www.fda.gov/news-events/press-announcements/fda-finalizes-enforcement-policy-unauthorized-flavored-cartridge-based-e-cigarettes-appeal-children. Accessed January 27, 2020.
- US Food & Drug Administration. Newly signed legislation raises federal minimum age of sale of tobacco products to 21. https://www.fda.gov/tobacco-products/ctp-newsroom/newly-signed-legislation-raises-federal-minimum-age-sale-tobacco-products-21. Accessed January 27, 2020.
- Sommerfeld CG, Weiner DJ, Nowalk A, Larkin A. Hypersensitivity pneumonitis and acute respiratory distress syndrome from e-cigarette use. Pediatrics. 2018;141(6):1–5. doi:10.1542/peds.2016-3927 [CrossRef] PMID:29773665
- Khan MS, Khateeb F, Akhtar J, et al. Organizing pneumonia related to electronic cigarette use: a case report and review of literature. Clin Respir J. 2018;12(3):1295–1299. doi:10.1111/crj.12775 [CrossRef] PMID:29392888
- Arter ZL, Wiggins A, Hudspath C, Kisling A, Hostler DC, Hostler JM. Acute eosinophilic pneumonia following electronic cigarette use. Respir Med Case Rep. 2019;27:100825. doi:10.1016/j.rmcr.2019.100825 [CrossRef] PMID:30963023
- Viswam D, Trotter S, Burge PS, Walters GI. Respiratory failure caused by lipoid pneumonia from vaping e-cigarettes [published online ahead of print July 6, 2018]. BMJ Case Rep. doi:10.1136/bcr-2018-224350 [CrossRef]
- He T, Oks M, Esposito M, Steinberg H, Makaryus M. “Tree-in-bloom”: severe acute lung injury induced by vaping cannabis oil. Ann Am Thorac Soc. 2017;14(3):468–470. doi:10.1513/AnnalsATS.201612-974LE [CrossRef] PMID:28248584
- US Centers for Disease Control and Prevention. Outbreak of lung injury associated with the use of e-cigarette, or vaping, products. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html#latest-outbreak-information. Accessed January 27, 2020.
- Moritz ED, Zapata LB, Lekiachvili A, et al. Lung Injury Response Epidemiology/Surveillance GroupLung Injury Response Epidemiology/Surveillance Task Force. Update: characteristics of patients in a national outbreak of e-cigarette, or vaping, product use-associated lung injuries – United States, October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(43):985–989. doi:10.15585/mmwr.mm6843e1 [CrossRef] PMID:31671085)
- Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin – preliminary report [published online ahead of print September 6, 2019]. N Engl J Med. doi:10.1056/NEJMoa1911614 [CrossRef] PMID:31491072
- Perrine CG, Pickens CM, Boehmer TK, et al. Lung Injury Response Epidemiology/Surveillance Group. Characteristics of a multistate outbreak of lung injury associated with e-cigarette use, or vaping—United States, 2019. MMWR Morb Mortal Wkly Rep. 2019;68(39):860–864. doi:10.15585/mmwr.mm6839e1 [CrossRef] PMID:31581168
- National Academies of Sciences, Engineering, and MedicineHealth and Medicine Division; Board on Population Health and Public Health PracticeCommittee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public health consequences of e-cigarettes. http://nationalacademies.org/hmd/Reports/2018/public-health-consequences-of-e-cigarettes.aspx. Accessed January 22, 2020.
- Siegel DA, Jatlaoui TC, Koumans EH, et al. Lung Injury Response Clinical Working GroupLung Injury Response Epidemiology/Surveillance Group. Update: interim guidance for jealthcare providers caring for patients with suspected e-cigarette, or vaping, product use associated lung injury–United States, October, 2019. MMWR Morb Mortal Wkly Rep. 2019;68(41):919–927. doi:10.15585/mmwr.mm6841e3 [CrossRef] PMID:31633675
- Meehan-Atrash J, Luo W, Strongin RM. Toxicant formation in dabbing: the terpene story. ACS Omega. 2017;2(9):6112–6117. doi:10.1021/acsomega.7b01130 [CrossRef] PMID:28983528
- Kaur G, Pinkston R, Mclemore B, Dorsey WC, Batra S. Immunological and toxicological risk assessment of e-cigarettes. Eur Respir Rev. 2018;27(147):170119. doi:10.1183/16000617.0119-2017 [CrossRef] PMID:29491036
- Hua M, Omaiye EE, Luo W, McWhirter KJ, Pankow JF, Talbot P. Identification of cytotoxic flavor chemicals in top-selling electronic cigarette refill fluids. Sci Rep. 2019;9(1):2782. doi:10.1038/s41598-019-38978-w [CrossRef] PMID:30808901
- Clapp PW, Pawlak EA, Lackey JT, et al. Flavored e-cigarette liquids and cinnamaldehyde impair respiratory innate immune cell function. Am J Physiol Lung Cell Mol Physiol. 2017;313(2):L278–L292. doi:10.1152/ajplung.00452.2016 [CrossRef] PMID:28495856
- Hickman E, Herrera CA, Jaspers I. Common E-cigarette flavoring chemicals impair neutrophil phagocytosis and oxidative burst. Chem Res Toxicol. 2019;32(6):982–985. doi:10.1021/acs.chemrestox.9b00171 [CrossRef] PMID:31117350
- Chen W, Wang P, Ito K, et al. Measurement of heating coil temperature for e-cigarettes with a “top-coil” clearomizer. PLoS One. 2018;13(4):e0195925. doi:10.1371/journal.pone.0195925 [CrossRef] PMID:29672571
- Schuchat A. Outbreak of lung injury associated with the use of e-cigarette, or vaping, products. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html#. Accessed January 20, 2020.
- Lechasseur A, Altmejd S, Turgeon N, et al. Variations in coil temperature/power and e-liquid constituents change size and lung deposition of particles emitted by an electronic cigarette. Physiol Rep. 2019;7(10):e14093. doi:10.14814/phy2.14093 [CrossRef] PMID:31140749
- US Centers for Disease Control and Prevention. For state, local, territorial, and tribal health departments. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/health-departments/index.html. Accessed January 27, 2020.
- Henry TS, Kanne JP, Kligerman SJ. Imaging of vaping-associated lung disease. N Engl J Med. 2019;381(15):1486–1487. doi:10.1056/NEJMc1911995 [CrossRef] PMID:31491070
- Butt YM, Smith ML, Tazelaar HD, et al. Pathology of vaping-associated lung disease. N Engl J Med. 2019;381(18):1780–1781. doi:10.1056/NEJMc1913069 [CrossRef] PMID:31577870
- Mukhopadhyay S, Mehrad M, Dammert P, et al. Lung biopsy findings in severe pulmonary illness associated with e-cigarette use (vaping). Am J Clin Pathol. 2020;153(1):30–39. doi:10.1093/ajcp/aqz182 [CrossRef] PMID:31621873
- Davidson K, Brancato A, Heetderks P, et al. Outbreak of e-cigarette–associated acute lipoid pneumonia - North Carolina, July-August 2019. MMWR Morb Mortal Wkly Rep. 2019;68(36):784–786. doi:10.15585/mmwr.mm6836e1 [CrossRef] PMID:31513559
- Riario Sforza GG, Marinou A. Hypersensitivity pneumonitis: a complex lung disease. Clin Mol Allergy. 2017;15(1):6. doi:10.1186/s12948-017-0062-7 [CrossRef] PMID:28286422
- Siegel DA, Jatlaoui TC, Koumans EH, et al. Lung Injury Response Clinical Working GroupLung Injury Response Epidemiology/Surveillance Group. Update: interim guidance for health care providers evaluating and caring for patients with suspected e-cigarette, or vaping, product use associated lung injury — United States, October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(41):919–927. doi:10.15585/mmwr.mm6841e3 [CrossRef]
Common Symptoms and Vital Signs of EVALI
|Symptoms and Signs||Number of Patients (%)||Total Number Used in Calculation|
| Years of age, median (range)||22 (13–71)||338|
| Any respiratory||323 (95)||339|
| Any gastrointestinal||262 (77)||339|
| Any constitutional||289 (85)||339|
| Oxygen saturation <95% while breathing room air||143 (57)||253|
| Tachycardia (heart rate >100 beats/min)||169 (55)||310|
| Tachypnea (respiratory rate >20 breaths/min)||77 (45)||172|