key: cord-0788295-rdg31p17 authors: Rice, Shawn J.; Hyland, Victoria; Behera, Madhusmita; Ramalingam, Suresh S.; Bunn, Paul; Belani, Chandra P. title: Guidance on the clinical management of E-cigarette or Vaping Associated Lung Injury (EVALI)? date: 2020-08-29 journal: J Thorac Oncol DOI: 10.1016/j.jtho.2020.08.012 sha: d0df66eb768f67fba0ebfda78f0b0f0ad9a23f97 doc_id: 788295 cord_uid: rdg31p17 In the summer of 2019 there was a rise in clusters of adolescents and young adults in the United States reporting to emergency departments with acute respiratory distress related to e-cigarette or vaping usage. The number of patients with E-cigarette or Vaping Associated Lung Injury (EVALI) continued to rise through the summer before peaking in September 2019. Through the efforts of state and federal public health agencies, officials were able to define the condition, identify the relationship of the respiratory injury to tetrahydrocannabinol (THC)-containing products, and stem the rise in new cases. In this report, we present a comprehensive review of the clinical characteristics and features of EVALI patients and present guidelines for patient care and management to inform and navigate clinicians who may encounter these patients in their clinical practice. Beginning in early 2012 a disturbing trend was building in the background of the public health arena, and it would develop into one of the largest public health mysteries of the decade. Sporadic cases of lung injury associated with vaping began in 2012 1 , and in July of 2019 clusters of young people (ages 10-19 years) began entering hospital emergency departments (ED) with complaints of shortness of breath and chest pains associated with vaping 2 . While the early cases are not necessarily reflective of the etiology of the 2019 EVALI series, they suggest that unregulated development of inhaled devices have the potential for significant health consequences in some proportion to individual risk coupled with the breadth of distribution. The cases in the summer of 2019 were particularly worrisome because the increase in ED visits was primarily among young males from up to 10 states with no known cause for respiratory distress or illness 3 . E-cigarette and Vaping Associated Lung Injury (EVALI) usually presents with symptoms of dyspnea, fever, nausea, and cough 4 . A common theme in these patients is that they reported the use of electronic-cigarette (e-cigarette) or vaping products within 90 days of their ED visit. Through February 18 2020, 2807 cases and 68 deaths from a mysterious lung injury have been reported in the United States of America and involved all 50 states 5 . The outbreak of EVALI was primarily limited to the USA. These cases developed before the current COVID-19 pandemic although many of the symptoms and radiographic findings are J o u r n a l P r e -p r o o f overlapping. While it is possible to diagnose viral infections with PCR testing, the current state of testing in the US is prone to false negatives and positives for both PCR-based and antibodybased methods. Therefore, careful consideration must be applied when EVALI and COVID-19 are the possible diagnoses. Identifying the EVALI causative agent and characterizing the lung injury from vaping became a top public health priority. Vaping or e-cigarettes involves high-temperature heating of a liquid to generate an aerosol vapor that can deliver substances like nicotine or THC to the lungs. Generally, these liquids contain flavoring agents, diluents, nicotine, THC, nicotine and THC, or less commonly, neither nicotine nor THC; the ingredients can vary greatly in the chemical composition, especially between manufacturers or homemade mixtures. It became apparent early in the outbreak that most patients (86-92%) admitted to using THC vaping liquids within three months of developing the disease 3,4 . This proved to be an important observation, as laboratory analyses of these vaping liquids sought to identify candidate agents resulting in EVALI. Vitamin E acetate, medium-chain triglyceride oil, and other lipids rose to the top of the list of causative agents 4 . By mid-December 2019 a causative agent for EVALI was finally identified. Using bronchoalveolar-lavage (BAL) fluid from EVALI patients and healthy donors who have not used THC-containing products, researchers used isotope dilution mass spectrometry and identified vitamin E acetate in over 90% of EVALI cases versus none in the healthy controls. According to the Center for Disease Control and Prevention (CDC), new cases of EVALI in the USA have continued to decline through February 2020, since its' peak in mid-September 2019. Guidelines on the clinical management of EVALI is important for these acutely ill patients. A timely diagnosis and treatment course can improve patient experiences and outcomes. Here we present a comprehensive review of EVALI to aid physicians in the management of these patients. A Pubmed search was performed on March 21 using the keywords "vaping", "lung injury" to collect references that included EVALI and those that may report respiratory injuries prior to the naming of the condition EVALI, leading to retrieval of 116 J o u r n a l P r e -p r o o f articles. Review articles and commentaries were excluded from the dataset of articles. We reviewed the remaining literature with a focus on the patient characteristics, clinical features, and guidance for patient care and management. In 2019, clusters of patients with severe acute respiratory symptoms began to appear in the US among Midwest states (Minnesota, Illinois, Indiana, and Wisconsin) and western states (Utah and California). The respective states and national health agencies created the Lung Injury Response Clinical Working Group, to track and monitor these patients resulting in the emergence of numerous case studies and reports. These clusters indicated a larger issue existed. We identified 27 case reports or case series related to the description of EVALI patients in our dataset of EVALI literature from 2017-2020 as shown in Table S1 . While these studies provide insight into the characteristics of EVALI patients, the limited number of patients in these studies does not allow for definitive conclusive recommendations about the disease and its' management. Therefore, we focused our attention on the larger observational studies. The CDC established case definitions for the surveillance of EVALI to identify and track patients (Table 1) . Cases are classified as confirmed or probable based on the presence or absence of signs of other etiologies for the respiratory symptoms, i.e. other infectious agents. Probable cases are those where infectious agents may present in a patients airway, but the clinical team deems that the agent is likely not the cause of the respiratory symptoms. EVALI cases began to rise in the USA throughout the summer of 2019 before peaking in September, and they continued to decline through February of 2020 ( Figure 1A ). As of February 18, 2020, 2807 EVALI patients have been reported to the CDC and 68 confirmed deaths have J o u r n a l P r e -p r o o f been attributed to the disease ( Figure 1B ). EVALI cases have been identified in all 50 states, and deaths have occurred in 29 states and the District of Columbia ( Figure 1B ). The CDC published monthly reports on the characteristics of EVALI cases for the US and summaries for limited state clusters have also been reported, which are summarized in Table 2 . Patients across all the datasets tended to be male (62-79%), less than 30 years old (median age 23-27 years) and have used THC-containing products within the last 90 days (76.9-91%). Affected cases were primarily non-Hispanic whites (46-79%) and Hispanic (12-47%), with California having a lower number of non-Hispanic whites (46%) and a higher proportion of Hispanic (47%) cases, which may be due to the small sample size (n=160) and demographics of the state 27 . @. These were early and partial studies that apparently were published quickly to get the word out to the general population. The sharp and sustained decline in new EVALI cases is a testament to the effectiveness of this approach in putting a halt to the outbreak. 1 Vaping or E-cigarette use among EVALI patients 2 As e-cigarette and vaping became associated with lung injury in youths, it is important to 3 understand how this group of patients were using these devices. EVALI patients report using 4 various types of vaping liquids containing products of THC, nicotine, and cannabidiol (CBD) 34 . For EVALI patients in the US, most use THC or nicotine-containing products daily, 74% and 6 85%, respectively 34 . The use of THC containing products more than 5 times a day is associated 7 with a higher risk for developing EVALI (aOR 3.1, 95% CI 1.6-6.0) 31 . The source of products 8 differed between THC and nicotine-containing liquids. Most patients report getting THC 9 products from only informal sources (78%), i.e. family or friends, while most nicotine products 10 were acquired from commercial sources (69%) 34 . Youths, <18 years, primarily acquire either 11 THC or nicotine products through informal channels. This is problematic because informal 12 sources can be dangerous and also difficult to track. A comparative analysis of symptomatic It is worth noting that while most cases of EVALI report use of THC containing products, a 18 minority of cases (8-24%) report use of only nicotine products or neither nicotine nor THC 19 products (2-7%)( Table 2) . Some of this discrepancy may be attributable to patient recall error, J o u r n a l P r e -p r o o f secondhand inhalation, or some other unknown explanation, but it could suggest that there may 1 be two or more agents able to effect EVALI symptoms. The CDC recommends that people 2 abstain from e-cigarette and vaping products, but if one must use such a product, they should 3 be acquired through formal commercial channels. Table 2 . While the CDC reports provide an overview of characteristics across 10 the entire US, three state-level studies provide more in-depth clinical and outcome data. Therefore, we will focus our discussion on the clinical presentation of EVALI patients of Illinois 12 and Wisconsin 32 , Utah 33 , and California 27 datasets ( The above histological and imaging features represent observations from adult patients, 20 but since EVALI also affects many adolescent patients it is important to consider this group of 21 patients separately. Adolescents tend to display similar features as adult patients with EVALI, but additional common imaging findings are noted in these patients, including pleural effusions 23 (50%), mild thickening of the bronchial wall(50%), and enlarged lymph nodes (75%) 44 . In 14 These findings support the assertion that vitamin E acetate is a likely cause of EVALI, but they 15 do not rule out other possible agents, as some EVALI patients did not have detectable vitamin E 16 acetate in BAL samples and 8-24% EVALI patients report smoking nicotine only (Table 2 ). Vitamin E acetate is used as a diluent for vaping products that contain THC because it has the 18 advantageous characteristics of being inexpensive and tasteless 54 . While vitamin E acetate seems to be a strong candidate for causing EVALI, our 20 understanding of the mechanism behind the lung damage is limited. Vitamin E acetate can form 21 a non-covalent complex with THC in aerosols produced during vaping, which would allow the 22 complex to be delivered to the lungs 55 . However, the effect of this complex on the lung is not 23 known and warrants further investigation to establish a possible mechanism of lung toxicity. Vaping involves aerosolizing a liquid containing many constituents (nicotine, THC, flavorings, 3 Mice were exposed to77.3 to 167.5 µg vitamin E acetate, propylene glycol and vegetable glycol 4 (PG-VG), or air. Following a two week exposure period, BAL fluid and lung tissue were 5 harvested from the mice. Mice exposed to vitamin E acetate display similar phenotype to 6 human EVALI patients including a rise in albumin levels, and elevated leukocytes and lipid-7 laden macrophages in BAL fluid, relative to the PG-VG and air groups. Mice exposed to vitamin 8 E acetate displayed profuse oil red O stained alveolar macrophages within the pneumocytes of 9 the alveoli. This model could be used to prove that vitamin E acetate does in fact cause EVALI, 10 establish a mechanism of action, and identify other agents that cause lung injury. symptoms should be evaluated for EVALI using definitions in Table 1 . The CDC offers 20 suggestions on questions to ask during the initial clinical assessment to obtain information 21 essential for an EVALI diagnosis (https://www.cdc.gov/tobacco/basic_information/e-22 cigarettes/severe-lung-disease/healthcare-providers/pdfs/dont-forget-to-ask-assessing-the-risk- of-lung-injury-508.pdf). Once EVALI is suspected, patients should be assigned for inpatient or 4 During hospitalization, patients should abstain from e-cigarette and vaping products, and 5 initiation of antimicrobial agents and corticosteroids as the condition warrants. The previous steps are important for managing the acute effects of EVALI, but 7 generating a thorough plan for discharging the patient may be important for reducing 8 readmission and death 40,58 . The CDC has established an "EVALI Discharge Readiness 9 Checklist" to aid clinicians in the discharge planning process 10 (https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/evali-discharge-readiness-11 checklist-508.pdf). The treatment team should screen patients for substance abuse disorders 12 and provide the patient with contact information for the appropriate support that the patients will Vaping-associated Lung Injury Severe E-Cigarette, or Vaping Requiring Venovenous Extracorporeal Membrane Oxygenation Anaerobic 6 Necrotizing Pneumonia: Another Potential Life-threatening Complication of Vaping? 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