Original Article

Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin — Final Report

List of authors.
  • Jennifer E. Layden, M.D., Ph.D.,
  • Isaac Ghinai, M.B., B.S.,
  • Ian Pray, Ph.D.,
  • Anne Kimball, M.D.,
  • Mark Layer, M.D.,
  • Mark W. Tenforde, M.D., Ph.D.,
  • Livia Navon, M.S.,
  • Brooke Hoots, Ph.D.,
  • Phillip P. Salvatore, Ph.D.,
  • Megan Elderbrook, M.P.H.,
  • Thomas Haupt, M.S.,
  • Jeffrey Kanne, M.D.,
  • Megan T. Patel, M.P.H.,
  • Lori Saathoff-Huber, M.P.H.,
  • Brian A. King, Ph.D., M.P.H.,
  • Josh G. Schier, M.D.,
  • Christina A. Mikosz, M.D., M.P.H.,
  • and Jonathan Meiman, M.D.

Abstract

Background

E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of lung injury associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation.

Methods

We defined case patients as persons who reported use of e-cigarette devices and related products in the 90 days before symptom onset and had pulmonary infiltrates on imaging and whose illnesses were not attributed to other causes. Medical record abstraction and case patient interviews were conducted with the use of standardized tools.

Results

There were 98 case patients, 79% of whom were male; the median age of the patients was 21 years. The majority of patients presented with respiratory symptoms (97%), gastrointestinal symptoms (77%), and constitutional symptoms (100%). All case patients had bilateral infiltrates on chest imaging. A total of 95% of the patients were hospitalized, 26% underwent intubation and mechanical ventilation, and two deaths were reported. A total of 89% of the patients reported having used tetrahydrocannabinol products in e-cigarette devices, although a wide variety of products and devices was reported. Syndromic surveillance data from Illinois showed that the mean monthly rate of visits related to severe respiratory illness in June through August of 2019 was twice the rate that was observed in the same months in 2018.

Conclusions

Case patients presented with similar clinical characteristics. Although the definitive substance or substances contributing to injury have not been determined, this initial cluster of illnesses represents an emerging clinical syndrome or syndromes. Additional work is needed to characterize the pathophysiology and to identify the definitive causes.

Introduction

Electronic cigarettes, or e-cigarettes, include a diverse group of battery-powered devices that allow users to inhale aerosolized substances.1 E-cigarette aerosol generally contains fewer toxic chemicals than conventional cigarette smoke.2 However, e-cigarette aerosol is not harmless; it can expose users to substances known to have adverse health effects, including ultra-fine particles, heavy metals, volatile organic compounds, and other harmful ingredients.2,3 E-cigarettes are commonly used to inhale nicotine but can also be used to deliver substances such as tetrahydrocannabinol (THC), cannabidiol (CBD), and butane hash oils (also known as dabs).4 E-cigarettes entered the U.S. marketplace around 2007 and since 2014 have been the most commonly used tobacco product among youths in the United States.1 During the 2017–2018 period, the prevalence of current use of e-cigarettes (also called vaping) increased from 11.7% to 20.8% among U.S. high school students.5 In contrast, 3.2% of U.S. adults reported current e-cigarette use in 2018.6

Published case reports have detailed a range of severe pulmonary illnesses among persons who have reported use of nicotine or cannabis extracts in e-cigarettes.7-13 No previous case series, however, has described large clusters of temporally related pulmonary illnesses linked to the use of e-cigarette products (e.g., devices, liquids, refillable pods, and cartridges).

Outbreak Surveillance Case Definitions of Severe Pulmonary Disease Associated with E-Cigarette Use — August 30, 2019.

During July 2019, the Wisconsin Department of Health Services (WDHS) and the Illinois Department of Public Health (IDPH) received multiple reports of lung injury of unclear cause that was possibly associated with the use of e-cigarettes and related products, which prompted a coordinated public health investigation. As of September 6, 2019, a total of 98 cases meeting the established case definitions (Table 1) were reported by clinicians in Wisconsin (41 cases) and Illinois (57 cases). As of December 17, 2019, a total of 2506 hospitalized cases have been reported across 50 states, the District of Columbia, and two U.S. territories, and the Centers for Disease Control and Prevention (CDC) is coordinating a nationwide public health response. In this article, we summarize the clinical characteristics and use of e-cigarettes and related products reported among the initial 98 case patients in Wisconsin and Illinois who were identified as being part of this lung injury cluster.

Methods

Outbreak Identification

On July 10, 2019, the Children’s Hospital of Wisconsin notified the WDHS of five previously healthy adolescents who had been admitted during the previous 30 days with progressive dyspnea, fatigue, and hypoxemia. Two patients underwent intubation and mechanical ventilation. Computed tomography (CT) of the chest in four patients revealed bilateral ground-glass opacities, predominantly in the lower lobes. Extensive infectious, rheumatologic, and oncologic workups were unrevealing. All patients reported a history of e-cigarette use in the days or weeks before symptom onset.

On July 25, the WDHS issued an alert to clinicians describing the clinical syndrome and requested that similar cases of lung injury associated with e-cigarette use be reported to public health authorities. The WDHS was subsequently contacted by a physician in Illinois seeking clinical treatment guidance for a patient with similar clinical presentation and e-cigarette product exposure, and the WDHS promptly notified the IDPH on July 31. A joint WDHS–IDPH public health investigation was initiated on August 1 to identify additional case patients and to characterize the pulmonary clinical syndrome related to the use of e-cigarettes and related products. The CDC was consulted for technical assistance early in the investigation, and a CDC epidemiologic assistance field team (Epi-Aid) was deployed to the WDHS and IDPH on August 20, 2019.

Case Definition

An outbreak case definition was initially developed by the WDHS and IDPH and was further refined in coordination with the CDC and the Council for State and Territorial Epidemiologists. Table 1 provides specific details of the probable and confirmed case definitions. All cases described in this article were classified according to and met the working outbreak definitions of confirmed or probable cases that have been mutually accepted by the CDC and the jurisdictions that had been affected earliest in the outbreak (Table 1).

Epidemiologic Investigation

The WDHS and IDPH released their first health alert notices on July 25 and August 2, respectively, to inform clinicians of the initial cases and to request reporting of possible cases to their local health departments. Medical records were requested for all patients with reported cases. A standardized medical record abstraction form was developed in Research Electronic Data Capture software (REDCap, Vanderbilt University) to systematically collect demographic data on the case patients, the signs and symptoms at presentation, laboratory results, imaging findings, reported drug exposures, clinical course, treatments, and medical outcomes. Infectious disease and pulmonary consultations and discharge notes were reviewed to determine whether causes other than vaping were potentially responsible for the clinical syndrome. Medical charts were reviewed by a group of clinicians from the investigative teams (six of the authors) with at least two reviewers for each chart, and discrepancies between reviewers were adjudicated by means of consensus. A standardized interview was administered to case patients to characterize the use of e-cigarettes and related products in the 3 months before symptom onset. Information regarding such use came from clinical documentation and interviews with patients.

Syndromic Surveillance

To assess whether this cluster represented an increase in severe respiratory illness, the IDPH established a baseline rate of severe unexplained respiratory illness by using a syndromic surveillance definition (in contrast to a working outbreak disease-specific case definition). Syndromic surveillance monitors near-real-time prediagnostic data sources (largely from emergency department [ED] visits) to provide early detection of potential public health threats by means of validated algorithms.14 Data from the National Syndromic Surveillance Program15 were searched with the use of the Electronic Surveillance System for the Early Notification of Community-Based Epidemics (ESSENCE) tool, which includes information on vital signs, reported symptoms, ED discharge destination, and diagnosis.15

All ED visits from January 1, 2018, to August 15, 2019, among persons 14 to 30 years of age were searched in order to identify encounters for severe unexplained respiratory illness (defined in Table S2 in the Supplementary Appendix, available with the full text of this article at NEJM.org); searches were limited to counties in Illinois where cases had already been identified. The syndromic definition was designed to capture data on patients who had presented to EDs in Illinois with severe respiratory symptoms and initial pulse oximetry of no more than 96% (or if pulse oximetry was not recorded), who were admitted to the hospital at which they presented or if the discharge disposition was not to home, and who had a discharge diagnosis that was not consistent with a known cause (e.g., bacterial or viral pneumonia or a chronic respiratory disease such as asthma). The formulated query was validated to ensure that it captured data on ED visits by all patients with confirmed or probable cases in Illinois.

Statistical Analysis

Descriptive analyses were performed for all the patients with confirmed or probable cases that were reported in Wisconsin and Illinois. Results were reported as proportions or median values. All analyses were conducted with the use of Stata software, version 16 (StataCorp). Proportions regarding e-cigarette use were limited to the 81 patients who underwent extensive interviews regarding vaping. To calculate the rate of visits for severe unexplained respiratory illness according to syndromic surveillance, a denominator of all ED visits for the same time period, age range, and hospitals was used. The mean monthly rates of ED visits for severe unexplained respiratory illness per 10,000 ED visits for June 1 through August 15, 2018, and for June 1 through August 15, 2019, were compared with a two-sided Student’s t-test.

Results

Demographic Characteristics of the Patients

As of September 6, 2019, a total of 60 patients had cases reported to the WDHS, and 82 to the IDPH. Of the 142 cases reported, 30 were excluded after chart review, and 14 cases were pending case classification because of incomplete medical records or interviews. A total of 98 case patients met the definition of a probable case (48 total, with 21 in Wisconsin and 27 in Illinois) or a confirmed case (50 total, with 20 in Wisconsin and 30 in Illinois). The dates of symptom onset ranged from April 21, 2019, through August 30, 2019, which is outside the typical influenza season. Comprehensive interviews had been conducted for 83% of the 98 patients with a confirmed or probable case.

Demographic Characteristics, Symptoms, Evaluation, and Clinical Course of 98 Case Patients.

The median age of the case patients was 21 years (range, 15 to 53) (Table 2); 26% of the patients were younger than 18 years of age. The majority of case patients were male (79%). Most of the patients had no documented relevant medical history, with no underlying chronic lung disease except for asthma (which was noted in 22% of the patients). Patients resided in multiple urban and rural, noncontiguous counties across both states.

Clinical Presentations

Case patients presented with a combination of respiratory, gastrointestinal, and constitutional symptoms (Table 2). The median duration of symptoms before hospital presentation was 6 days, with a wide range (0 to 155 days) of symptom duration; 71% of patients presented within 7 days after symptom onset. A total of 66% of the hospitalized patients had been seen in outpatient settings (EDs, urgent care clinics, or other outpatient clinics) before admission for related symptoms, and 45% of all the patients who were seen in the outpatient or ED setting received antibiotic agents for presumed respiratory tract infection, primarily oral azithromycin (in 20 of the 44 patients who received antibiotics on an outpatient basis), amoxicillin–clavulanate (in 6), levofloxacin (in 5), or doxycycline (in 4). All the patients who received antibiotics on an outpatient basis had reported progression of respiratory symptoms, which had prompted subsequent hospital admission.

A total of 97% of the patients had respiratory symptoms at hospital presentation. The most common respiratory symptoms were shortness of breath (85%), cough (85%), and chest pain (52%). Reported gastrointestinal symptoms included nausea (66%), vomiting (61%), diarrhea (44%), and abdominal pain (34%). All patients had one or more constitutional symptoms, with the most common being subjective fever (84%). Upper respiratory symptoms such as rhinorrhea, sneezing, or congestion were not commonly reported.

Details of the vital signs at presentation and laboratory findings are shown in Table 2. According to the initial recorded vital signs, 63% of patients had tachycardia (heart rate range, 55 to 146 beats per minute), and 43% had tachypnea (respiratory rate range, 14 to 59 breaths per minute). At presentation, 33% of the patients had oxygen saturation between 89% and 94% while they were breathing ambient air, and 25% had oxygen saturation of less than 89% while they were breathing ambient air. A total of 33% of the patients had a documented fever (temperature, ≥38°C) at triage, and 54% had a fever recorded at some point in their admission, but medical records were incomplete and this may be an underrepresentation of the true proportion with an objective fever.

A high percentage of patients had leukocytosis (83%), defined as a white-cell count of more than 11,000 per cubic millimeter, with a median white-cell count of 16,000 per cubic millimeter (interquartile range, 12,000 to 19,000). A total of 91% of the patients had a neutrophil predominance (neutrophil percentage, >80%). Among the 27 patients who had an eosinophil percent listed, none had a value greater than 2%. The erythrocyte sedimentation rate was more than 30 mm per hour in 90% of the 30 patients in whom it was checked. The median procalcitonin value was 0.53 μg per liter (reference ranges differed among the hospitals). Mildly elevated serum aminotransferase values were noted in 46% of the patients and were transient. Just under one third of the patients had mild hyponatremia, hypokalemia, or both. Acute renal insufficiency was observed in 1 patient, which resolved with intravenous hydration.

Cytopathological Findings

A total of 43 patients underwent bronchoalveolar lavage; the majority of patients received antibiotics, glucocorticoids, or both before the procedure. Of the 26 bronchoalveolar-lavage specimens with reported cell counts, the median values were as follows: eosinophils 1% (range, 0 to 18), neutrophils 58% (range, 10 to 91), lymphocytes 8.5% (range, 1 to 40), and macrophages 22% (range, 2 to 68). A total of 13 of the 23 available cytology reports on bronchoalveolar-lavage specimens noted lipid-laden macrophages (7 were reported with oil red O stain, and 6 mentioned no specific staining); the remaining 10 reports did not comment on the use of oil red O stain. Of the 13 samples with noted lipid-laden macrophages, 4 reports listed moderate lipid-laden macrophages, 8 reports listed scant to minimal, and 1 report did not quantify.

Six patients underwent transbronchial lung biopsy, and two of these patients also underwent an open lung biopsy, which was performed during clinical workup; three of these patients were receiving both antibiotics and glucocorticoids at the time, two were receiving antibiotics, and one was receiving neither before the procedure. Pathologists reported a range of findings, including mild and nonspecific inflammation, organizing pneumonia and bronchiolitis with organizing pneumonia, acute diffuse alveolar damage and foamy macrophages, and interstitial and peribronchiolar granulomatous pneumonitis. Infectious disease evaluations for possible viral, bacterial, and fungal pathogens were negative in nearly all case patients in whom the testing was performed (Table S1 in the Supplementary Appendix).

Imaging Findings

At presentation, 83% of the patients had an abnormal chest radiograph (Table 2). A total of 91 of the 98 case patients underwent CT, and the findings were abnormal for 100% of these patients. Opacities in both lungs were present in 100% of the patients. Ground-glass opacities in both lungs were characteristically observed on CT, sometimes with subpleural sparing. Of the 91 patients who underwent CT imaging, 6 cases of pneumomediastinum, 11 of pleural effusion, and 2 of pneumothorax were present (in 15 patients). Two patients had both a pneumomediastinum and a pneumothorax, and two patients had both a pneumomediastinum and pleural effusion.

Clinical Course

All but 5 patients were hospitalized (93 patients [95%]), and the median duration of hospital stay was 6 days (Table 2). Intensive care unit admission for respiratory failure was common (53% of all patients; 56% of hospitalized patients), and 26% of all patients underwent intubation and mechanical ventilation (27% of hospitalized patients). No patient received a tracheostomy.

A total of 25 case patients had documentation in clinical notes of having acute respiratory distress syndrome (ARDS). Of these 25 patients, the investigative team was able to independently verify that 12 patients (48%) met the Berlin Criteria for ARDS,16 with an average index of partial pressure of arterial oxygen (Pao2) to fraction of inspired oxygen (Fio2) of 189 mm Hg. For the remaining patients, medical records and documentation were insufficient to verify the diagnosis independently. Two patients underwent extracorporeal membrane oxygenation, and one of these patients died. For both patients, there was clinical documentation that the ARDS criteria were met.

Most patients received systemic glucocorticoids (intravenous or oral) during admission (84% of the patients overall; of these, 81% received intravenous administration). Documentation by the clinical team that the respiratory improvement was due to the use of glucocorticoids was found in approximately half the patient notes (51%). All but five patients who began receiving systemic glucocorticoids were treated with at least 7 days of glucocorticoid therapy.

E-Cigarette Use

All patients had a history of use of e-cigarettes and related products within the 90 days before symptom onset, and 92% of those with data (37 of 40 patients) regarding the date of last use reported vaping in the week before symptom onset. Most patients (69 of 78 patients [88%]) reported at least daily e-cigarette use. Of the 81 patients who were extensively interviewed, 73% reported use of nicotine products and 89% reported use of THC products; of the 78 patients who answered the question about CBD products, 9% reported use of CBD products (Table 2). A total of 27% of the patients reported using THC products only, whereas 11% reported using nicotine-containing products only. A total of 60% of the patients reported using both nicotine and THC products. Patients reported using 27 distinct brands of THC products and 25 brands of nicotine products in a wide range of flavors. The most common THC product that was reported was marketed under the “Dank Vape” label (reported by 49 of 73 interviewed patients [67%]). Patients reported use of a number of different e-cigarette devices to aerosolize these products. Of the 72 patients who were extensively interviewed, 12 reported smoking combustible cigarettes as well.

Clinical Series of Selected Patents with Confirmed Cases

Clinical Course and Ventilator Use in Selected Patients with Confirmed Severe Pulmonary Disease Who Were Admitted to an Intensive Care Unit.

Patients were selected if they had a confirmed case of severe pulmonary disease associated with e-cigarette use, according to the August 30, 2019, outbreak surveillance case definitions of the Centers for Disease Control and Prevention (CDC); if they had been intubated; and if ventilatory requirements for the case definition were documented. Patient 5 was admitted to the hospital and discharged and was later readmitted. Fio2 denotes fraction of inspired oxygen, IBW ideal body weight, Pao2 partial pressure of arterial oxygen, PEEP positive end-expiratory pressure, and VT tidal volume.

Figure 1 shows the clinical course of five patients who met the confirmed case definition and who underwent intubation and mechanical ventilation. Representative of the case series in general, most of the patients had previous outpatient visits before admission and ultimately began receiving systemic glucocorticoids.

Select Clinical Vignette with Radiographs

Chest Radiographs and High-Resolution Computed Tomographic Imaging in a 17-Year-Old Male Patient with Diffuse Lung Disease.

In the initial radiograph of the chest at admission (Panel A), the anterior–posterior image shows hazy opacities that are predominant in the mid and lower lungs. An anterior–posterior radiograph of the chest that was obtained approximately 12 hours after presentation (Panel B) shows rapid worsening of diffuse lung opacities with developing consolidation and air bronchograms. Axial (Panels C and D, showing different segments of the lung in order to visualize the extent of the opacities) and coronal reformatted (Panel E) high-resolution CT images of the chest show ground-glass opacities in both lungs and dense consolidation in a peribronchial and perilobular distribution, with relative subpleural sparing — findings consistent with an organizing pneumonia pattern of lung injury.

A 17-year-old male patient with no clinically significant medical history presented to a hospital ED with a 2-day history of shortness of breath, nonproductive cough, and generalized weakness as well as a 1-week history of fever before presentation, nausea, vomiting, abdominal pain, and diarrhea. He sought care with his primary care provider and at multiple EDs for his gastrointestinal symptoms during the week before his admission and was treated with intravenous fluids and given metronidazole, levofloxacin, and an antiemetic agent. His condition worsened, and new respiratory symptoms developed, so he presented again to the ED, where he was found to have hypoxemia with an oxygen saturation of 85% while he was breathing ambient air, tachycardia with a heart rate of 112 beats per minute, and a temperature of 37.9°C. A radiograph of the chest showed opacities in both lungs that were suggestive of infection or acute lung injury (Figure 2A). His laboratory results showed leukocytosis (white-cell count, 18,000 cells per cubic millimeter) with a neutrophil predominance (94%) and no eosinophils (0%), as well as elevated inflammatory markers with a C-reactive protein level of 32 mg per deciliter and an erythrocyte sedimentation rate of 68 mm per hour.

The patient began receiving amoxicillin and azithromycin as empirical therapy for community-acquired and atypical pneumonia and was admitted to the hospital while he was receiving 3 liters of oxygen per minute through a nasal cannula. Within hours, he was transferred to the pediatric intensive care unit owing to respiratory deterioration. He was intubated and mechanically ventilated, receiving a high Fio2 and positive end-expiratory pressure, and met the criteria for moderate ARDS. A radiograph of the chest that was obtained approximately 12 hours after presentation showed rapid worsening of diffuse lung opacities (Figure 2B), and a high-resolution CT image of the chest showed diffuse hazy ground-glass opacities with subpleural sparing, findings consistent with pneumonitis (Figure 2C through 2E). On day 2 of hospitalization, the patient underwent bronchoscopy, which showed normal-appearing bronchi. Cytologic testing of bronchoalveolar-lavage specimens showed a neutrophil predominance (78%) with no eosinophils (0%) and a moderate number of lipid-laden macrophages on oil red O staining. Infectious workup, including blood cultures, testing for the human immunodeficiency virus (HIV), testing for urinary histoplasma and blastomyces antigens, polymerase-chain-reaction (PCR) panel for nasopharyngeal respiratory virus, PCR panel for enteric pathogens, and bronchoalveolar-lavage studies including bacterial and fungal cultures and pneumocystis stain, was negative. He began receiving high-dose intravenous glucocorticoids on day 2 of the hospitalization, and antibiotics were discontinued on day 4 because an infectious cause was deemed to be unlikely. The patient’s clinical condition improved, and he was extubated after receiving intravenous glucocorticoids for 3 days. The patient was discharged home on hospital day 6 with instructions to continue an oral glucocorticoid–tapering regimen for 6 weeks.

Syndromic Surveillance

Emergency Department (ED) Visits for Severe Unexplained Respiratory Illness among Patients 14 to 30 Years of Age, According to Sex, in Illinois Counties in 2018 and 2019.

The periods of January through August in 2018 and 2019 were compared. Outbreak-related cases have been identified since April 2019 and are ongoing.

The mean monthly rate of visits to the ED for severe respiratory illness as identified by syndromic surveillance between June 1 and August 15, 2019, was twice the mean monthly rate that occurred between June 1 and August 15, 2018 (7.4 cases per 10,000 visits vs. 3.8 cases per 10,000 visits), in Illinois counties. This difference was significant for both male and female patients (P<0.05 for both comparisons; P<0.001 for the combined comparison) (Figure 3).

Discussion

In this report, we describe the initial cluster of lung injuries associated with the use of e-cigarettes and related products in the days and weeks before symptom onset in 2 states. Since then, an unprecedented nationwide outbreak of lung injury has occurred, with now more than 2500 cases across all 50 states. Available data on Illinois trends in syndromic surveillance suggest that the increase in the patients presenting with severe lung injury is relatively recent; a national-level syndromic surveillance study has shown similar findings.17 Although the definitive cause or causes of lung injury remain unknown, the severity of the illness and the recent increase in the incidence of this clinical syndrome indicate that these cases represent a new or newly recognized and worrisome cluster of lung injury related to vaping.

E-cigarette liquids and aerosols have been shown to contain a variety of chemical constituents that may have adverse health effects.18 Major declared constituents in nicotine-based e-cigarettes include propylene glycol and glycerin,19 in addition to nicotine. Identified contaminants include polycyclic aromatic hydrocarbons, nitrosamines, volatile organic chemicals, and inorganic chemicals such as toxic metals.19,20 Endotoxins and flavoring compounds such as diacetyl and 2,3-pentanedione have also been detected.21,22 These constituents may also undergo thermal decomposition (pyrolysis) by the metallic e-cigarette heating coils to process new compounds in aerosol with different toxicologic profiles.23,24 The health risks of some constituents remain poorly characterized, and toxicologic assessment of these substances is an active area of ongoing research.19,20 In addition to nicotine, e-cigarette devices can be used to deliver a variety of other recreational drugs, including THC-based oils.4,25

Although the cause or causes of the reported lung injuries remain under investigation, products containing THC are the most commonly reported exposure among these case patients (89%). This finding is consistent with nationwide data.26 Additional studies have shown an association27 and increased risk28 with informally acquired prepackaged THC e-cigarette, or vaping, products. Laboratory analysis conducted by the Food and Drug Administration has identified vitamin E acetate in THC-containing e-cigarette products, and testing by the CDC on clinical bronchoalveolar-lavage samples obtained from case patients has consistently identified vitamin E acetate29 and has not identified vitamin E acetate in control samples.30 Furthermore, a recent study has indicated that vitamin E acetate may be a newly added diluent, on the basis of analysis of THC-containing products seized by law enforcement.31 The accumulation of these findings suggests that vitamin E acetate is associated with these lung injuries. THC-based oils and waxes can be widely purchased, despite the fact that they are illegal in the majority of states, including Illinois and Wisconsin, and the content of these products is largely unknown and unregulated.32

However, in this initial cluster, 11% of the patients reported using only nicotine-based products, and 60% reported using both THC-based and nicotine-based products. Nationwide, a similar proportion of patients have reported the exclusive use of nicotine-based e-cigarette, or vaping, products, and using both product types.26 More in-depth studies have highlighted that case patients use e-cigarette, or vaping, products frequently and that they have used a wide range of products and brand names.26-28 Information on product use is based on reports by the patients, and patients may be reluctant to report illicit drug use; this may explain in part some proportion of patients who have denied the use of THC-based e-cigarette, or vaping, products. Nevertheless, additional substances remain under investigation, and it is possible that there is more than one cause of this outbreak.

Pulmonary illnesses that have been linked to e-cigarette use have been previously limited to individual case reports. Nicotine-containing liquids have been associated with a variety of disease presentations. Diffuse alveolar hemorrhage and exogenous lipoid pneumonia have been observed.33,34 Acute interstitial lung disease, including acute eosinophilic pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and hypersensitivity pneumonitis, has also been associated with use of nicotine-containing liquids.7,8,35 Health effects from dabbing of cannabis concentrates (i.e., superheating of substances containing high levels of THC or CBD in the device) are less frequently reported in the literature. Butane hash oil has been associated with pneumonitis,12,36 and THC oil has been associated with organizing pneumonia.15

In the case series presented here, the population was generally young and healthy, yet acute severe pulmonary illness developed and resulted in critical care and respiratory support. Given the disparate nature of e-cigarette–associated illnesses that have been reported in the literature, it is notable that case patients in Wisconsin and Illinois presented with similar clinical findings and progression of disease, which suggests a similar pathophysiological mechanism of lung injury. However, the definitive pathology for these pulmonary illnesses has not been established, and it is possible that these illnesses represent a range of disease processes.

Of note, eosinophilia was not widely seen in peripheral blood nor observed in bronchoalveolar-lavage specimens, and characteristic radiographic findings of exogenous lipoid pneumonia (e.g., low attenuation consolidations) were not reported in radiograph reports. Among the cytologic reports on bronchoalveolar-lavage specimens that included information on specific oil staining, lipid-laden macrophages were reported as moderate in four and as only “scant” or “minimal” in the others; specific mention of oil staining was not provided in the other cytology reports of bronchoalveolar-lavage specimens. Interestingly, opacities in both lungs were noted on either radiograph or CT of the chest in all the patients. A comprehensive review of imaging by a panel of expert chest radiologists could help to more completely characterize and identify unique radiographic findings.

The CDC released a Clinical Health Advisory37 on August 30, 2019, recommending that all patients who report e-cigarette use within the previous 90 days be asked about signs and symptoms of pulmonary illness. Subsequently, interim guidance for health care providers has been released, encouraging health care providers to ask about the use of e-cigarette, or vaping, products in a confidential and nonjudgmental manner when patients present with respiratory, gastrointestinal, or constitutional symptoms.38 Clinicians should consider the possibility of pulmonary illness associated with vaping when patients report recent use, especially when other causes are not identified. Alternative causes of respiratory illness may be more likely than vaping, and therefore clinicians should also continue to consider and appropriately assess for such possible causes of illness in patients reporting respiratory and gastrointestinal symptoms and e-cigarette use. E-cigarette, or vaping, product use–associated lung injury (EVALI) remains a diagnosis of exclusion.38 Although our current understanding of the appropriate treatment strategies is insufficient to provide clinical recommendations, patients thus far have had clinical improvement with systemic glucocorticoid therapy, and the majority of patients have received prolonged courses.

This article details the clinical spectrums of the initial cluster of 98 case patients from two states. Detailed evaluation of medical records, chest imaging, laboratory results, and exposure information among these cases provided an opportunity to evaluate, characterize, and compare their clinical courses. These data are subject to several limitations. Exposure information was reported by the patients and may be subject to recall error or hesitancy to report vaping practices. Given the emerging nature of this syndrome, this initial series may capture data on patients with more severe cases who presented for evaluation and may not capture data on more mild clinical presentations that were related to the same exposure or disease process.39 Medical chart data were not complete for all patients, especially with regard to respiratory ventilator variables, which limits a more detailed description of disease severity. Not all patients had an exhaustive list of negative findings on serologic tests for infectious causes, cultures, or molecular studies.

In summary, we report the initial cluster of severe lung injury associated with the use of e-cigarettes and related products among generally young, healthy persons in Wisconsin and Illinois who presented between April 21, 2019, and September 6, 2019. Cases continue to be reported to both these health departments and nationwide. The WDHS and IDPH have worked closely with the CDC and the Food and Drug Administration, submitting product and clinical samples for testing.

The findings in this report support several public health recommendations issued by the CDC.38 The CDC recommends that persons not use THC-containing e-cigarette, or vaping, products, particularly from informal sources. However, evidence is not yet sufficient to rule out the contribution of other chemicals of concern. Although it appears that vitamin E acetate is associated with EVALI, there are many different substances and product sources that are being investigated, and there may be more than one cause. Therefore, the best way for persons to ensure that they are not at risk while the investigation continues is to consider refraining from the use of all e-cigarette, or vaping, products. Regardless of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults, or pregnant women.40

Funding and Disclosures

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A preliminary version of this article was published on September 6, 2019, and updated on September 16, 2019, at NEJM.org.

We thank the staff of the Wisconsin Department of Health Services and Illinois Department of Public Health and numerous local health departments and hospitals who played a critical role in this investigation and collected the information provided in this article; members of the investigative team, including Carrie Tomasallo and Barbara Grajewski of the Wisconsin Department of Health Services; Ngozi Ezike, Connie Austin, Judy Kauerauf, and Matt Charles of the Illinois Department of Public Health; and Michael Gutzeit, Lynn D’Andrea, and Lori Loof of the Children’s Hospital of Wisconsin, for their recognition of the cluster and assistance with the public health investigation; Grant T. Baldwin, Debra Houry, Dana Meaney-Delman, and Ileana Arias of the Centers for Disease Control and Prevention (CDC); and the CDC 2019 Lung Injury Response team.

Author Affiliations

From the Illinois Department of Public Health, Springfield (J.E.L., I.G., L.N., M.T.P., L.S.-H.); the Epidemic Intelligence Service, Center for Surveillance, Epidemiology, and Laboratory Services (I.G., I.P., A.K., M.W.T., P.P.S.), National Center for Environmental Health (M.L.), the Division of State and Local Readiness, Center for Preparedness and Response (L.N.), the Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control (B.H., J.G.S., C.A.M.), and the Office on Smoking and Health, National Center for Chronic Disease Prevention and Health Promotion (B.A.K.), Centers for Disease Control and Prevention, and Emory University School of Medicine (M.L.) — all in Atlanta; and the Wisconsin Department of Health Services (I.P., M.E., J.M.), the Wisconsin Division of Public Health, Bureau of Communicable Disease (T.H.), and the Department of Radiology, University of Wisconsin School of Medicine and Public Health (J.K.) — all in Madison.

Address reprint requests to Dr. Layden at the Illinois Department of Public Health, 69 W. Washington St., Chicago, IL 60602, or at .

Supplementary Material

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Citing Articles (507)

    Letters

    Figures/Media

    1. Outbreak Surveillance Case Definitions of Severe Pulmonary Disease Associated with E-Cigarette Use — August 30, 2019.*
      Outbreak Surveillance Case Definitions of Severe Pulmonary Disease Associated with E-Cigarette Use — August 30, 2019.
    2. Demographic Characteristics, Symptoms, Evaluation, and Clinical Course of 98 Case Patients.*
      Demographic Characteristics, Symptoms, Evaluation, and Clinical Course of 98 Case Patients.
    3. Clinical Course and Ventilator Use in Selected Patients with Confirmed Severe Pulmonary Disease Who Were Admitted to an Intensive Care Unit.
      Clinical Course and Ventilator Use in Selected Patients with Confirmed Severe Pulmonary Disease Who Were Admitted to an Intensive Care Unit.

      Patients were selected if they had a confirmed case of severe pulmonary disease associated with e-cigarette use, according to the August 30, 2019, outbreak surveillance case definitions of the Centers for Disease Control and Prevention (CDC); if they had been intubated; and if ventilatory requirements for the case definition were documented. Patient 5 was admitted to the hospital and discharged and was later readmitted. Fio2 denotes fraction of inspired oxygen, IBW ideal body weight, Pao2 partial pressure of arterial oxygen, PEEP positive end-expiratory pressure, and VT tidal volume.

    4. Chest Radiographs and High-Resolution Computed Tomographic Imaging in a 17-Year-Old Male Patient with Diffuse Lung Disease.
      Chest Radiographs and High-Resolution Computed Tomographic Imaging in a 17-Year-Old Male Patient with Diffuse Lung Disease.

      In the initial radiograph of the chest at admission (Panel A), the anterior–posterior image shows hazy opacities that are predominant in the mid and lower lungs. An anterior–posterior radiograph of the chest that was obtained approximately 12 hours after presentation (Panel B) shows rapid worsening of diffuse lung opacities with developing consolidation and air bronchograms. Axial (Panels C and D, showing different segments of the lung in order to visualize the extent of the opacities) and coronal reformatted (Panel E) high-resolution CT images of the chest show ground-glass opacities in both lungs and dense consolidation in a peribronchial and perilobular distribution, with relative subpleural sparing — findings consistent with an organizing pneumonia pattern of lung injury.

    5. Emergency Department (ED) Visits for Severe Unexplained Respiratory Illness among Patients 14 to 30 Years of Age, According to Sex, in Illinois Counties in 2018 and 2019.
      Emergency Department (ED) Visits for Severe Unexplained Respiratory Illness among Patients 14 to 30 Years of Age, According to Sex, in Illinois Counties in 2018 and 2019.

      The periods of January through August in 2018 and 2019 were compared. Outbreak-related cases have been identified since April 2019 and are ongoing.