Epiglottitis Associated With Intermittent E-cigarette Use: The Vagaries of Vaping Toxicity Michael J. Bozzella, DO, MS,a Matthew Magyar, MD,b Roberta L. DeBiasi, MD, MS,a,c Kathleen Ferrer, MDa,b,c

An adolescent female patient presenting with subacute onset of dysphagia abstract and hoarseness underwent a direct laryngoscopy, which revealed epiglottitis. After 2 hospitalizations and multiple consultations and biopsies, all infectious testing results for viral, bacterial, fungal, and acid-fast bacilli etiologies were negative. The patient’s use of electronic cigarettes was the only exposure elicited with a likely role in her presentation. This case, combined with the growing body of evidence revealing the toxic effects of vaping and the increasing use of electronic cigarettes among adolescent patients, highlights the many unknowns and risks regarding the biological effects of this practice. aDivisions of Pediatric Infectious Diseases and bHospitalist Medicine, Children’s National Health System, Washington, District of Columbia; and cDepartment of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia CASE intravenous ampicillin and sulbactam. Dr Bozzella performed the initial chart and literature A previously healthy 15-year-old girl Results of both a rapid group A Streptococcus reviews and wrote the initial draft of the case report; with no history of asthma, chronic test and monospot test Dr Magyar contributed to the hospital summary and respiratory illness, or inhaled were both negative. Her respiratory the discussion of the available literature; Drs DeBiasi medication use presented to an outside complaints prompted a bedside and Ferrer provided supervision for the chart laryngoscopy by Otolaryngology, reviews and provided critical editing and revision to emergency department with the final drafts of the report; and all authors complaints of acute respiratory distress revealing moderately severe edema of approved the final manuscript as submitted. the epiglottis and arytenoids. She was and severe dysphagia. Her symptoms DOI: https://doi.org/10.1542/peds.2019-2399 started subacutely 2 months before transferred to our hospital, a pediatric Accepted for publication Oct 10, 2019 with mild hoarseness and increased quaternary care facility. The pediatric throat clearing. Over the next 3 to 4 otolaryngology team repeated the Address correspondence to Michael J. Bozzella, DO, MS, Division of Infectious Diseases, Children’s weeks, her symptoms evolved to laryngoscopy and again noted “ National Medical Center, 111 Michigan Ave NW, include dysphagia (including moderate edema of the epiglottis Washington, DC 20010. E-mail: mbozzella@ a sensation that food was stuck in her extending along the aryepiglottic folds” childrensnational.org “ throat), early-morning voice loss, and mild/moderate edema of the PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, episodes of regurgitation, and food hypopharyngeal mucosa with partial 1098-4275). avoidance. Her pediatrician attributed obstruction of the airway at the level of Copyright © 2020 by the American Academy of her symptoms to allergies and the epiglottis. Mucosa is pink with Pediatrics prescribed loratadine, which had no scattered area of thick chartreuse FINANCIAL DISCLOSURE: The authors have indicated effect. Three weeks later, she presented mucus draped over epiglottis.” Cultures they have no financial relationships relevant to this to an urgent care center with similar were not obtained because of the article to disclose. symptoms and was prescribed a 3-day concern for potentiating airway FUNDING: No external funding. course of prednisone. Her symptoms compromise. She was admitted to POTENTIAL CONFLICT OF INTEREST: The authors have temporarily improved, but 2 days after the PICU. indicated they have no potential conflicts of interest completing the steroid course, she to disclose. worsened, feeling “as if she were Infectious Diseases was consulted on breathing through a straw,” prompting the day of admission. A detailed history To cite: Bozzella MJ, Magyar M, DeBiasi RL, the emergency department visit. She did not reveal any personal or family et al. Epiglottitis Associated With Intermittent received intravenous dexamethasone, history suggestive of an autoimmune E-cigarette Use: The Vagaries of Vaping Toxicity. Pediatrics. 2020;145(3):e20192399 inhaled racemic epinephrine, and disorder or immunodeficiency. Physical

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 3, March 2020:e20192399 CASE REPORT examination features were not hospital day 7 to complete a 10-day and was discharged from the hospital supportive of an abscess or viral course of antibiotics. on hospital day 6. In the year period infection. Fever was absent since her presentation and full throughout her illness, although One day after discharge, she recovery, the patient has not returned previous treatment with steroids may developed odynophagia and noted to our institution for subsequent or have masked a febrile response. She white streaks on her pharyngeal recurrent episodes or other had received all immunizations for mucosa. She returned for evaluation, symptoms; it is not known if she her age and had no history of travel and her examination suggested continues to practice vaping. or animal exposures. She denied possible candidal infection. A mucosal Final cultures from biopsies yielded sexual activity, illicit substance use, swab was sent for herpes simplex only normal flora. The final pathology traditional cigarette use, or virus polymerase chain reaction of the samples from her arytenoid secondhand smoke exposure, but testing, and throat swabs were sent and soft palate revealed only admitted to using a JUUL, an for repeat bacterial and fungal fl ulcerated squamous mucosa with electronic cigarette (e-cigarette). She culture. Oral uconazole and nystatin rinses were started, and she was marked acute inflammation and reported at least 3 to 5 uses with readmitted to the hospitalist service. reactive epithelial changes with friends over 1 to 2 months with Within 24 hours of admission, she abundant suppurative debris. The different fruit- or candy-flavored developed a diffuse body rash that pathology from her tongue revealed cartridges, none loaded with was erythematous, blanching, similar reactive squamous mucosal tetrahydrocannabinol, with the last papular, and nonpruritic. Infectious changes with focal erosions. There use ∼2 weeks before symptom onset. Diseases, Otolaryngology, was no evidence of fungal organisms, viral inclusion bodies, other The result of a neck computed Dermatology, and Rheumatology infectious agents, or malignancy. tomography scan was consistent with were consulted, and the differential Despite multiple detailed histories by epiglottitis, without focal abscess. diagnosis was broadened to include systemic inflammatory conditions, several consulting services, the only Otolaryngology aspirated a sample of drug reaction, and unusual plausible trigger for her presenting fluid from her epiglottic region for fi presentations of common disease symptoms and ndings was bacterial and fungal cultures; final processes. Dermatology suspected inhalation of chemical vapor via culture results yielded only normal her rash to be a b-lactam antibiotic e-cigarette use. Her clinical course respiratory flora. A nasopharyngeal fi drug reaction, and amoxicillin and and biopsy ndings were highly swab specimen was tested for clavulanate was discontinued. With suspicious for direct chemical injury respiratory pathogens by using fl low suspicion for a bacterial process, and/or subsequent in ammatory a multiplex polymerase chain reaction no further antibiotics were reaction. Without knowing the panel, including human rhinovirus administered, and her rash gradually precise cartridges she used the exact and enterovirus, respiratory syncytial resolved. Laboratory and clinical exposure is unknown, although as we fl virus A and B, in uenza A and B, evaluation for rheumatologic discuss in the following section, fl parain uenza 1 to 4, human disorders, including antinuclear e-vapors can contain a myriad of Mycoplasma metapneumovirus, antibody, antineutrophil cytoplasmic potentially toxic substances. pneumoniae Chlamydia , and ; all test antibody screen, complement protein results were negative. Results for C3 and C4 levels, anti-proteinase-3, DISCUSSION serologies for cytomegalovirus, and myeloperoxidase antibodies, Epstein-Barr virus, HIV, and rapid were not consistent with systemic Epiglottitis is an acute, life- plasma reagent were negative. vasculitis, sarcoidosis, or threatening condition classically Results of throat swabs for gonorrhea polychondritis. Repeat throat cultures associated with infection. It is part of Chlamydia and were negative. The yielded normal respiratory flora, and the differential diagnosis of any total peripheral white blood cell herpes simplex virus testing results febrile child presenting with signs of count was mildly elevated, but the were negative. Given the ongoing respiratory distress involving the C-reactive protein level, erythrocyte diagnostic uncertainty, biopsies of her upper airway, along with tracheitis, sedimentation rate, and complete oropharynx and epiglottis were croup, and peritonsillar or metabolic panel were normal. She obtained. With no yeast forms retropharyngeal abscess. Although remained afebrile throughout her present on the initial review of the Haemophilus influenzae type b is stay and slowly improved biopsy specimen or any cultures, characteristically associated with symptomatically. She transitioned to nystatin and fluconazole were epiglottitis, widespread routine oral amoxicillin and clavulanate and discontinued. After the biopsy, she childhood vaccination has led to was discharged from the hospital on slowly improved symptomatically a shift in epidemiology. The incidence

Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 BOZZELLA et al of epiglottitis due to Hinfluenzae type cigarettes.10,18 Because the amount of smokers, after 5 minutes, e-cigarette b has fallen, in some studies by nicotine delivered by each device can use increased airway resistance and 90%.1–4 Other organisms, such as be adjusted, their use can decrease decreased fractional exhaled nitric streptococci, staphylococci, Moraxella, symptoms of nicotine withdrawal.10 oxide.27 An adolescent study found and other types of Haemophilus, are Although some data suggest that potentially carcinogenic compounds more common etiologies.1–5 overall, e-cigarettes may be less in the urine of e-cigarette users.28 It is Additionally, the age of affected cytotoxic than traditional cigarettes, reasonable to suspect that there is patients has shifted from school age the full toxicological effects are not potential for allergenicity as well, to adolescence and adulthood.1–3,5 fully understood.8 although little direct research has been published on that topic. Although age and etiology have In a review of studies analyzing the shifted, initial management remains vapor produced, one group reported In an adolescent with signs and focused on rapid assessment, airway that nicotine levels fluctuated widely symptoms of subacute epiglottis, the management, imaging or direct between “puffs” from the same differential should expand beyond visualization of anatomy, and cartridges and that vapor was found infectious etiologies. E-cigarettes are antibiotic therapy.4,5 Empirical to contain substances similar to those increasingly being used by our therapy with ceftriaxone or found in traditional cigarette smoke, adolescent patients and should be a combination b-lactam and including heavy metals, tobacco a consideration in the evaluation of b-lactamase inhibitor is alkaloids, volatile organic compounds, ororespiratory complaints. suggested.1,2,4 and aldehydes, many of which have potential or known detrimental E-cigarettes, also known as vape health effects.6,13 Additionally, the ABBREVIATION pens, are devices designed to deliver nicotine levels in the vapor from nicotine (or other substances) for e-cigarette: electronic cigarette some products were on par with inhalation via aerosolization of an – those produced from traditional often flavored liquid.6 9 They are cigarettes.14 frequently marketed as a healthier alternative to smoking tobacco As work continues to understand the products.6,10,11 Use of these devices, chemical exposures associated with REFERENCES JUUL in particular, has become e-cigarette use, researchers are also 1. Faden H. The dramatic change in the increasingly prevalent in the investigating its biological effects. epidemiology of pediatric epiglottitis. adolescent population,9,11,12 and Vaping liquid, with or without Pediatr Emerg Care. 2006;22(6):443–444 there is mounting evidence nicotine, can cause inflammatory 2. Shah RK, Roberson DW, Jones DT. 19 describing their toxicities and health changes in nasal cell mucosa and Epiglottitis in the Hemophilus – risks,7 9,13,14 including potential cytotoxic effects in other cell influenzae type B vaccine era: changing microbial contamination.15 types20,21 through the oxidants and trends. Laryngoscope. 2004;114(3): reactive oxygen species, which are 557–560 Data obtained from the 2011–2018 produced in varying quantities from National Young Tobacco Survey 3. Isakson M, Hugosson S. Acute different flavors of fluid (higher levels epiglottitis: epidemiology and revealed that e-cigarette use among detected in fruit- and candy-based Streptococcus pneumoniae serotype US middle and high school students is flavors).22 These oxidative stresses distribution in adults. J Laryngol Otol. on the rise. In 2018, 20.8% of all high may explain the increased 2011;125(4):390–393 school students and 4.9% of middle secretion of pro-inflammatory 4. Gorga SM, Gilsdorf JR, Mychaliska KP. school students admitted to using the cytokines,7,19,22,23 the observed Haemophilus influenzae serotype f devices, making them the most increased rates of viral replication, epiglottitis: a case report and review. commonly used tobacco product in and decreased antimicrobial activity Hosp Pediatr. 2017;7(1):54–56 those age groups.16 A longitudinal of neutrophils and macrophages.7,24 5. Belfer JA. Case 2: sore throat and study of Connecticut high school Unsurprisingly, e-cigarette use causes dysphagia in a 6-year-old boy. Pediatr students found that the use of immunosuppression in the nasal Rev. 2018;39(5):260 e-cigarettes among teenagers was mucosa at a level consistent with associated with an increased odds 6. Cheng T. Chemical evaluation of traditional cigarettes.25 E-cigarette electronic cigarettes. Tob Control. 2014; ratio of future traditional cigarette users also have an increased 23(suppl 2):ii11-ii17 use.17 prevalence of mucosal lesions, 7. Chun LF, Moazed F, Calfee CS, Matthay In adults, the use of e-cigarettes with including nicotine stomatitis, hairy MA, Gotts JE. Pulmonary toxicity of nicotine-containing solutions may tongue, and angular cheilitis, similar e-cigarettes. Am J Physiol Lung Cell Mol decrease the use of traditional to former tobacco smokers.26 In adult Physiol. 2017;313(2):L193–L206

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 3, March 2020 3 8. Orr MS. Electronic cigarettes in the USA: 16. Cullen KA, Ambrose BK, Gentzke AS, cigarettes and e-juices with flavorings a summary of available toxicology data Apelberg BJ, Jamal A, King BA. Notes induce toxicity, oxidative stress, and and suggestions for the future. Tob from the field: use of electronic inflammatory response in lung Control. 2014;23(suppl 2):ii18-ii22 cigarettes and any tobacco product epithelial cells and in mouse lung. PLoS 9. Walley SC, Wilson KM, Winickoff JP, among middle and high school One. 2015;10(2):e0116732 students - United States, 2011-2018. Groner J. A public health crisis: 23. Wu Q, Jiang D, Minor M, Chu HW. MMWR Morb Mortal Wkly Rep. 2018; electronic cigarettes, vape, and JUUL. Electronic cigarette liquid increases 67(45):1276–1277 Pediatrics. 2019;143(6):e20182741 inflammation and virus infection in 10. Gualano MR, Passi S, Bert F, La Torre G, 17. Bold KW, Kong G, Camenga DR, et al. primary human airway epithelial cells. Scaioli G, Siliquini R. Electronic Trajectories of e-cigarette and PLoS One. 2014;9(9):e108342 conventional cigarette use among cigarettes: assessing the efficacy and 24. Scott A, Lugg ST, Aldridge K, et al. Pro- youth. Pediatrics. 2018;141(1): the adverse effects through inflammatory effects of e-cigarette e20171832 a systematic review of published vapour condensate on human alveolar studies. J Public Health (Oxf). 2015; 18. Callahan-Lyon P. Electronic cigarettes: macrophages. Thorax. 2018;73(12): 37(3):488–497 human health effects. Tob Control. 2014; 1161–1169 23(suppl 2):ii36-ii40 11. Balbo S, Stepanov I. The wild west of 25. Martin EM, Clapp PW, Rebuli ME, et al. e-cigarettes. Chem Res Toxicol. 2018; 19. Kim M, Baumlin N, Dennis JS, et al. E-cigarette use results in suppression 31(9):823–824 Never-smokers develop mucosal of immune and inflammatory-response 12. Singh T, Arrazola RA, Corey CG, et al. inflammation and CFTR dysfunction genes in nasal epithelial cells similar to Tobacco use among middle and high upon vaping nicotine-free e-liquid for cigarette smoke. Am J Physiol Lung Cell school students–United States, 2011- one week. In: Proceedings from the Mol Physiol. 2016;311(1):L135–L144 American Thoracic Society International 2015. MMWR Morb Mortal Wkly Rep. 26. Bardellini E, Amadori F, Conti G, Conference; May 18–23, 2018; San 2016;65(14):361–367 Majorana A. Oral mucosal lesions in Diego, CA 13. Pisinger C, Døssing M. A systematic electronic cigarettes consumers versus review of health effects of electronic 20. Bahl V, Lin S, Xu N, Davis B, Wang YH, former smokers. Acta Odontol Scand. cigarettes. Prev Med. 2014;69:248–260 Talbot P. Comparison of electronic 2018;76(3):226–228 cigarette refill fluid cytotoxicity using 14. Geiss O, Bianchi I, Barahona F, Barrero- 27. Vardavas CI, Anagnostopoulos N, embryonic and adult models. Reprod Moreno J. Characterisation of Kougias M, Evangelopoulou V, Connolly Toxicol. 2012;34(4):529–537 mainstream and passive vapours GN, Behrakis PK. Short-term pulmonary emitted by selected electronic 21. Farsalinos KE, Romagna G, Allifranchini effects of using an electronic cigarette: cigarettes. Int J Hyg Environ Health. E, et al. Comparison of the cytotoxic impact on respiratory flow resistance, 2015;218(1):169–180 potential of cigarette smoke and impedance, and exhaled nitric oxide. electronic cigarette vapour extract on Chest. 2012;141(6):1400–1406 15. Lee MS, Allen JG, Christiani DC. cultured myocardial cells. Int J Environ Endotoxin and [formula: see text] 28. Rubinstein ML, Delucchi K, Benowitz NL, Res Public Health. 2013;10(10): contamination in electronic cigarette Ramo DE. Adolescent exposure to toxic 5146–5162 products sold in the United States. volatile organic chemicals from Environ Health Perspect. 2019;127(4): 22. Lerner CA, Sundar IK, Yao H, et al. e-cigarettes. Pediatrics. 2018;141(4): 47008 Vapors produced by electronic e20173557

Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 BOZZELLA et al Epiglottitis Associated With Intermittent E-cigarette Use: The Vagaries of Vaping Toxicity Michael J. Bozzella, Matthew Magyar, Roberta L. DeBiasi and Kathleen Ferrer Pediatrics 2020;145; DOI: 10.1542/peds.2019-2399 originally published online February 5, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/145/3/e20192399 References This article cites 27 articles, 9 of which you can access for free at: http://pediatrics.aappublications.org/content/145/3/e20192399#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Adolescent Health/Medicine http://www.aappublications.org/cgi/collection/adolescent_health:me dicine_sub Pharmacology http://www.aappublications.org/cgi/collection/pharmacology_sub Toxicology http://www.aappublications.org/cgi/collection/toxicology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 Epiglottitis Associated With Intermittent E-cigarette Use: The Vagaries of Vaping Toxicity Michael J. Bozzella, Matthew Magyar, Roberta L. DeBiasi and Kathleen Ferrer Pediatrics 2020;145; DOI: 10.1542/peds.2019-2399 originally published online February 5, 2020;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/145/3/e20192399

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 1, 2021