E-cigarette or vaping product use-associated lung injury (EVALI)

INTRODUCTION — "Vaping" is the process of inhaling an aerosol that is created by heating a liquid or wax containing various substances, such as nicotine, cannabinoids (eg, tetrahydrocannabinol, cannabidiol), flavoring, and additives (eg, glycerol, propylene glycol) [1]. Several devices are available to generate this aerosol including battery-operated electronic cigarettes (also called e-cigarettes), vape pens, or vape mods [2]. E-cigarette, or vaping, product use-associated lung injury (EVALI; originally called vaping-associated pulmonary injury), initially described in 2019, is an acute or subacute respiratory illness that can be severe and life-threatening [3-6].

The epidemiology, clinical features, evaluation, and management of EVALI will be reviewed here. The use of e-cigarettes for smoking cessation and potential health consequences of cannabis use are described separately. (See "Vaping and e-cigarettes" and "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects".)

Our approach is similar to that set out in the American Thoracic Society workshop guideline [7].

EPIDEMIOLOGY — EVALI was initially recognized in the summer of 2019 [3,8-11]. More than 2800 hospitalized cases of EVALI were reported to the Centers for Disease Control and Prevention (CDC) as of February 18, 2020, and, among those, there have been 68 deaths [5]. The CDC stopped collecting these data in February 2020; epidemiologic statistics can be found at the CDC website. Approximately 66 percent of reported cases were male, and nearly 80 percent were younger than 35 years old (range 13 to 85 years) [6]. Approximately 22 percent of patients had underlying asthma [3].

Data obtained from emergency department visits associated with possible EVALI, Google searches, and case reports to the CDC confirmed similar trends in all three databases for potential cases of EVALI [12]. Peaks were seen between June and September of 2019, with a subsequent reduction in trends since then.

Sporadic cases of EVALI have been reported in Europe and in individuals traveling from the United States to Europe [13-15].

PATHOGENESIS AND RISK FACTORS — The pathogenesis of EVALI is not known. EVALI appears to be a form of acute lung injury with pathologic findings of acute fibrinous pneumonitis, diffuse alveolar damage, or organizing pneumonia, usually bronchiolocentric and accompanied by bronchiolitis [16]. EVALI may reflect a spectrum of disease processes rather than a single process. Individual reports of vaping-associated lung diseases have described acute eosinophilic pneumonia [17], diffuse alveolar hemorrhage [18], lipoid pneumonia [19-21], and respiratory-bronchiolitis interstitial lung disease, suggesting that more than one mechanism of injury may be involved. No evidence of an infectious etiology has been identified, and studies of e-cigarette fluids used by patients with EVALI have not found bacterial contamination [22].

The key risk factor for EVALI is use of an e-cigarette or similar product [23]. Examination of products used by affected patients and bronchoalveolar lavage fluid (BAL) samples has found tetrahydrocannabinol (THC) and/or vitamin E acetate in the majority [3,6,8,16,22,24-27]. However, other additives might be involved including nicotine, cannabinoid (CBD) oils, and other substances such as coconut oil and limonene [22,24]. It remains possible that other unknown additives may be responsible, and further work is needed to determine whether a causal link and specific mechanism can be established.

●THC – The majority of patients with EVALI report use of products containing THC (75 to 80 percent) [3,6,8,26]. One study compared BAL samples from 51 patients who had confirmed or probable EVALI with BAL from 99 healthy individuals from 16 states [28]; the healthy control group was comprised of asymptomatic patients who did not have EVALI, 52 of whom did not smoke or use vaping products and 47 of whom smoked cigarettes or were e-cigarette users. THC (or its metabolites) was identified in 94 percent of patients with EVALI but was undetectable in BAL from healthy individuals.

●Vitamin E acetate – Vitamin E acetate, a synthetic form of vitamin E, was initially identified in BAL samples from 29 patients with EVALI from 10 different states [25]. In a larger study of 51 patients with EVALI, vitamin E acetate was identified in 94 percent of patients compared with zero in BAL fluid from healthy individuals, one-half of whom were tobacco smokers or e-cigarette users and one-half of whom were nonusers [28]. The mechanism of vitamin E acetate toxicity is not known but may be related to byproducts of pyrolysis [29].

●Nicotine – Approximately 13 to 58 percent of patients with EVALI report having used nicotine-containing products with or without THC in the 90 days preceding symptom onset [3,6,8]. In a study that compared BAL fluid in patients with EVALI, nicotine or its metabolites were detected in 64 percent of patients compared with zero in healthy nonsmoking or non-vaping individuals. However, nicotine was also identified in the BAL samples of asymptomatic individuals who smoked tobacco or used e-cigarettes.

●Other – Other oils thought to be potential culprits (eg, CBD or other plant oils, medium-chain triglycerides, petroleum distillates, terpenes) have not been consistently found in products smoked by patients or in BAL fluid from patients with EVALI [28].

In terms of the device used for aerosolization, among 573 affected individuals, the majority used products obtained from illicit (off-the-street) or informal (eg, friends and family member) sources [6,24]. Other patients reported use of commercially available e-cigarette products (ie, bottles, cartridges, or pods) and also addition of homemade liquids to previously used cartridges or pods. While most used aerosolized products, some dripped the substance onto the heating element (called "dripping") and others used highly concentrated nicotine or THC prepared in a waxlike substance and smoked in a pipe (called "dabbing"). It is also possible that the process of mixing and heating active and inactive components could lead to production of toxic new agents [22].

Whether underlying comorbidities increase the risk is unclear, but one study reported that 68 percent had at least one comorbidity [2].

An animal model of EVALI has been described and may shed light on the pathogenesis of this disease [30].

CLINICAL FEATURES — Information about the clinical presentation of EVALI is largely derived from a case series of 98 patients who met a case definition for EVALI (table 1) [3]. A similar pattern of symptoms is reported in other series, including adolescents [2,11,23,26,31-35].

The median patient age was 21; 78 percent were males, and 68 percent had at least one comorbidity. No patients died during the initial hospital admission.

Respiratory symptoms included shortness of breath (85 percent), cough (85 percent), chest pain (52 percent), pleuritic chest pain (36 percent), and hemoptysis (8 percent) [3]. Constitutional symptoms of subjective fever and chills were reported by 84 and 60 percent, respectively.

Gastrointestinal symptoms were common (77 percent) and included nausea (66 percent), vomiting (61 percent), diarrhea (44 percent), and abdominal pain (34 percent) [3]. Rarely, gastrointestinal symptoms predominate [36], as in one teenage boy with presumed EVALI who reported nausea, vomiting, weight loss, and fever but denied respiratory symptoms despite imaging findings consistent with EVALI [37].

On physical examination, fever was present in 33 percent, tachycardia in 63 percent, and tachypnea in 43 percent [3]. Approximately 58 percent were hypoxemic, with a pulse oxygen saturation ≤88 percent in 25 percent.

Progression to respiratory failure is common. (See 'Prognosis' below.)

EVALUATION — EVALI should be suspected in patients who have a history of vaping or other use of e-cigarette-related products and have a pneumonia-like syndrome, progressive dyspnea, and/or worsening hypoxemia (see 'Clinical features' above). Useful questions include the following (table 2):

●What type(s) of vaping device were used (eg, bottle, cartridge, pod)?

●What products (eg, nicotine, tetrahydrocannabinol [THC], cannabidiol, flavored liquid) were vaped?

●Were cartridges or pods reused? If so, were they filled with homemade, unlicensed, or commercially licensed products?

●Was the product concentrated prior to use (eg, dabbing)?

●When did the patient start vaping relative to the onset of symptoms?

●How often was the patient vaping (eg, number of cartridges or pods per day, frequency of puffs)? Did they Valsalva at end-inhalation (thought to increase the rate of absorption)?

●Were they also smoking tobacco?

The specific steps in the evaluation depend on the acuity of illness, other exposures (eg, influenza, coronavirus disease 2019 [COVID-19], coccidioidomycosis, travel, medications known to cause lung toxicity, occupations or other activities associated with hypersensitivity pneumonitis), evidence of underlying disease (eg, heart failure, rheumatic disease, immunodeficiency), and presence of opacities on imaging.

Laboratory — The laboratory evaluation of suspected EVALI is designed to exclude processes in the differential diagnosis, most importantly, community-acquired pneumonia, COVID-19 pneumonia, and also acute eosinophilic pneumonia. We typically obtain complete blood count and differential, blood urea nitrogen, and creatinine. Gastrointestinal symptoms might prompt liver function tests. Microbiologic testing is based on the severity of respiratory impairment and site of care. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Microbiologic testing' and "COVID-19: Diagnosis".)

While there is general interest in using biomarkers such as C-reactive protein and procalcitonin to discriminate bacterial infection from other causes of pneumonitis, these studies are not routinely obtained. A single-center study of 24 patients with EVALI related to THC noted elevated markers of coagulation (eg, international normalized ratio) and inflammation (C-reactive protein, erythrocyte sedimentation rate, procalcitonin), although the significance is uncertain [38,39]. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Laboratory evaluation' and "Procalcitonin use in lower respiratory tract infections".)

Imaging — The majority of patients (83 percent) presenting with suspected EVALI have a chest radiograph that shows diffuse hazy or consolidative opacities [3,34,40]. For those with progressive dyspnea or hypoxemia, the next step is often computed tomography pulmonary angiography (CTPA) to exclude pulmonary embolism or high-resolution CT (HRCT) in those without risk factors for pulmonary embolism. (See "Approach to the adult with dyspnea in the emergency department" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Bilateral opacities are typical in EVALI [34,41-45]. In a series of 98 patients, bilateral opacities were noted in 100 percent, either on the chest radiograph or chest CT [3]. The CT opacities were typically ground glass in density and sometimes spared the subpleural space. Pleural effusions were less common (approximately 10 percent). These features are consistent with diffuse alveolar damage, as is seen in acute respiratory distress syndrome. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Imaging'.)

A separate series confirmed bilaterality and also noted basilar predominance of consolidative and ground glass opacities [41].

Spontaneous pneumothorax and pneumomediastinum associated with vaping has been described [46,47].

In addition, a variety of radiographic patterns have been noted with features suggestive of one or more of the following processes [41,42,48] (see 'Differential diagnosis' below):

●Diffuse alveolar damage – Dependent consolidation, diffuse ground glass, air bronchograms.

●Acute eosinophilic pneumonia – Nodular areas of consolidation, diffuse ground glass, septal thickening, small amount of pleural fluid.

●Hypersensitivity pneumonitis – Centrilobular ground glass opacities anteriorly and more confluent ground glass opacities in dependent areas, and lobules of mosaic attenuation.

●Organizing pneumonia – Diffuse, multifocal discrete and confluent.

●Lipoid pneumonia – Ground glass and consolidative opacities in the dependent portions of the lungs, with areas of fat attenuation (<-30 Hounsfield units) are characteristic features of lipoid pneumonia, but areas of fat attenuation are typically absent in EVALI even when bronchoalveolar lavage (BAL) fluid has a high number of lipid-laden macrophages [31].

Flexible bronchoscopy and bronchoalveolar lavage — Flexible bronchoscopy with BAL can be helpful in excluding other causes of nonresolving or progressive pneumonitis (eg, infection and acute eosinophilic pneumonia) and is generally performed in patients with progressive or severe symptoms. Samples of BAL fluid should be sent for cell counts, cytopathology, and studies to exclude bacterial, mycobacterial, fungal, and viral pathogens. (See "Basic principles and technique of bronchoalveolar lavage" and "Nonresolving pneumonia", section on 'Bronchoscopy'.)

Reported cell counts in EVALI are variable but tend to show an increase in neutrophils (58 percent, with a range 10 to 91 percent), although eosinophils have been reported in isolated cases [3,17]. Identification of lipid laden-macrophages (eg, positive Oil-red-O stain) is a common but nonspecific finding [3,31,34,49-51].

Pathology — Only a few patients with EVALI have undergone lung biopsy or autopsy, so a full description of the range of histopathologic features awaits further study. Reported findings are consistent with acute lung injury and include features such as acute fibrinous pneumonitis, diffuse alveolar damage, foamy (lipid-laden) macrophages (seen in all cases), and organizing pneumonia (usually bronchiolocentric and accompanied by bronchiolitis) [3,4,16,49,52,53]. Peribronchiolar granulomas (with negative testing for infectious pathogens) were noted in one series [3] but not in a larger series [16]. Neutrophils are often prominently present; eosinophils are rare [16]. One autopsy report described type 2 pneumocyte hyperplasia and scattered atypical mitotic figures [54]. Whether features represent various stages of lung injury is unknown.

Individual case reports have described multinucleated giant cells that suggested a foreign body reaction to lipophilic material [41,55]. In addition, one case of diffuse alveolar hemorrhage has been reported [14].

DIAGNOSIS — Formal diagnostic criteria for EVALI have not been agreed upon, and the heterogeneous presentations suggest that EVALI comprises several different forms of lung injury. EVALI is a diagnosis of exclusion and requires particular attention to the exclusion of lung infection and other causes of progressive respiratory insufficiency. (See 'Differential diagnosis' below.)

Criteria used as a case definition for EVALI provide a reasonable foundation for a "probable case" or a "confirmed case" (table 1) [3,8]. Criteria for a confirmed case include the following:

●Use of an e-cigarette or related product (eg, "vaping" or "dabbing") in the previous 90 days.

●Lung opacities on chest radiograph or computed tomography. (See 'Imaging' above.)

●Exclusion of lung infection based on negative influenza polymerase chain reaction or rapid test (unless out of season), viral respiratory panel, and, as clinically indicated, urine antigen tests for Legionella and Streptococcus pneumoniae, blood cultures, sputum culture (if producing sputum), bronchoalveolar lavage (if performed), and testing for human immunodeficiency virus (HIV)-related opportunistic infections.

●Absence of a likely alternative diagnosis (eg, cardiac, neoplastic, rheumatologic). (See 'Differential diagnosis' below.)

Similar criteria, but without conclusive exclusion of infection, are used for a probable diagnosis of EVALI (table 1).

It is important to note that criteria used for a case definition were developed prior to the COVID-19 pandemic [56]. The California Department of Public Health has provisionally changed the definition of a confirmed EVALI case to require a negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test. We encourage clinicians to be familiar with their state health departments information on diagnostic requirements.

DIFFERENTIAL DIAGNOSIS — A variety of respiratory diseases are in the differential diagnosis of EVALI. All patients with suspected EVALI should undergo an evaluation for community-acquired pneumonia and COVID-19, which are much more common. Other processes that are listed here have occasionally been described in association with vaping but did not figure prominently in the cluster of cases of EVALI reported in 2019 [3,16]. Thus, they are considered in the differential diagnosis, rather than as manifestations of EVALI.

Chest CT may provide clues to the presence of these disorders but is generally not diagnostic. Bronchoscopy with bronchoalveolar lavage (BAL) and, sometimes, lung biopsy may be needed when a definitive diagnosis is needed.

●Community-acquired pneumonia (CAP) – It is important to exclude CAP when evaluating a patient with suspected EVALI as prompt and directed antimicrobial treatment is essential to successful treatment. The presentation of CAP overlaps with EVALI and ranges from mild pneumonia with fever and productive cough to severe pneumonia with acute respiratory distress syndrome and sepsis. Like EVALI, gastrointestinal symptoms are common among patients with CAP.

The selection of microbiologic tests and initiation of empiric antibiotic therapy for CAP depends on the severity of illness, risk factors for resistant or atypical pathogens, comorbidities, and local patterns of antibiotic resistance. The presentation, evaluation and management of CAP are described separately. (See "Overview of community-acquired pneumonia in adults" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

●COVID-19 – COVID-19, a cause of CAP, has clinical features similar to EVALI, such as cough, dyspnea, fever, and diarrhea [57]. (See "COVID-19: Diagnosis" and "COVID-19: Management in hospitalized adults".)

●Acute eosinophilic pneumonia (AEP) – AEP has a similar time course of symptom onset and is typically associated with BAL eosinophilia (>25 percent eosinophils) and has been reported in association with vaping and use of heat-not-burn cigarettes, as well as a number of other potential irritants and toxins (see "Idiopathic acute eosinophilic pneumonia", section on 'Etiology'). However, BAL eosinophilia was not reported in a series of 98 patients with EVALI of whom 26 underwent BAL [3], nor in a separate report of six patients with EVALI [31].

●Organizing pneumonia – Organizing pneumonia, a diffuse interstitial lung disease (ILD) that affects the distal bronchioles, respiratory bronchioles, alveolar duct, and alveolar walls, has been reported in a few patients after use of e-cigarettes [58,59]. In one patient, dyspnea, chest pain, and hypoxemia developed after using e-cigarettes for a month as part of a smoking cessation program and progressed to acute respiratory failure [58]. Organizing pneumonia was diagnosed by surgical lung biopsy after less invasive studies were negative. Improvement followed systemic glucocorticoids and e-cigarette abstinence. The evaluation and management of organizing pneumonia are discussed separately. (See "Cryptogenic organizing pneumonia".)

●Lipoid pneumonia – Lipoid pneumonia is most commonly reported after aspiration of ingested mineral oil [60] but has also been reported after vaping with products containing vegetable oil [19-21,61]. High-resolution CT findings of lipoid pneumonia typically include consolidative and ground glass opacities, a crazy paving pattern, interlobular septal thickening, and nodular or mass-like consolidation [62]. Areas with negative attenuation (eg, -17 to -114; similar to nearby adipose tissue) are seen in approximately one-half to two-thirds of patients with mineral oil-associated lipoid pneumonia [60]. However, areas of negative attenuation have not been reported with EVALI, even among patients with lipid-laden macrophages in the bronchoalveolar lavage fluid [31]. (See 'Flexible bronchoscopy and bronchoalveolar lavage' above and "Aspiration pneumonia in adults", section on 'Lipoid pneumonia'.)

●Diffuse alveolar hemorrhage (DAH) – DAH is in the differential diagnosis of EVALI and is a reported consequence of EVALI. As an example, one patient developed dyspnea, hemoptysis, and hypoxemia after approximately one month of frequent vaping with a variety of flavored vaping solutions [18]. CT revealed patchy areas of consolidation; sequential bronchoalveolar lavage revealed progressively more hemorrhagic returns, and a surgical lung biopsy confirmed alveolar hemorrhage with capillaritis and diffuse alveolar damage. Treatment with pulse dose steroids led to complete radiographic clearing over two weeks. A separate report described onset of DAH in a patient who vaped large volumes of cinnamon-flavored nicotine solution daily; vaping cessation led to resolution [63]. The evaluation of DAH is discussed separately. (See "The diffuse alveolar hemorrhage syndromes".)

●Hypersensitivity pneumonitis (HP) – The possibility that vaping can cause HP has been raised, although supportive information is limited [41,64-66]. HP would be in the differential diagnosis of upper lung zone opacities and centrilobular nodules that are seen in some cases of EVALI. The clinical features and diagnosis of HP are discussed separately. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

●Respiratory bronchiolitis ILD (RBILD) – RBILD is generally associated with chronic inhalation of tobacco smoke. A single patient has been reported in association with vaping nicotine. While the patient was continuing to smoke cigarettes, the appearance and resolution of symptoms and radiographic evidence of RBILD temporally followed onset and cessation of vaping [67]. CT features of RBILD include diffuse or patchy ground glass opacities, centrilobular nodules, bronchial wall thickening, and air trapping. The evaluation and diagnosis of RBILD is discussed separately. (See "Respiratory bronchiolitis-associated interstitial lung disease".)

●Giant cell pneumonitis – Giant cell pneumonitis, typically associated with heavy metal exposure, was described in a single patient with progressive ILD over a six-month period of vaping [41]. CT demonstrated peripheral reticulation, ground glass opacities, and mild traction bronchiectasis that developed. Lung biopsy revealed giant cell pneumonitis that was believed to be due to cobalt exposure from the vape pen used by the patient [41]. Cobalt-related ILD is associated with multinucleated giant cells on histopathology; other ILD patterns, such as usual interstitial pneumonia, desquamative interstitial pneumonia, or hypersensitivity pneumonia, can also be present [68]. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

TREATMENT — The optimal treatment of EVALI is not known. The most important step is to ensure that community-acquired pneumonia (CAP), including COVID-19, is not overlooked or undertreated, as infectious pneumonias are much more common than EVALI. (See 'Differential diagnosis' above.)

Hospitalization is advisable for any patient with suspected EVALI who has respiratory distress, decreased oxygen saturation (eg, <95 percent on room air), significant comorbidity that compromises lung reserve, and/or suboptimal access to follow-up within 24 to 48 hours [69]. Patients not admitted to the hospital should be advised of the risk of rapid deterioration and instructed to completely avoid vaping and to seek medical care if they experience worsening symptoms.

Empiric antibiotics — For the majority of patients with EVALI, empiric antibiotics are initiated to cover likely pathogens of CAP, pending the results of the initial evaluation and response to therapy. Antiviral therapy (eg, COVID-19, influenza) may also be appropriate. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization" and "COVID-19: Management in hospitalized adults".)

Systemic glucocorticoids — Systemic glucocorticoids have been used in the majority of patients with EVALI [3,21,31,70], but the efficacy has not been formally studied. As EVALI appears to reflect a spectrum of responses to lung injury, it is possible that the various presentations of EVALI will respond differently to glucocorticoids.

The decision regarding initiation of glucocorticoid therapy is challenging and requires individualized assessment [2,3,16]. We do not advise routine use of glucocorticoids, because the efficacy in EVALI is unknown. However, given the potentially life-threatening nature of EVALI, we suggest initiation of systemic glucocorticoids for patients who meet criteria for EVALI and have progressively worsening symptoms and/or hypoxemia. For patients with less severe presentations, it is reasonable to withhold initiation of glucocorticoids because of the greater likelihood of an infectious cause in patients with fever, dyspnea, and chest pain; the potential adverse effects of glucocorticoids; and the potential for resolution with supportive care.

As exceptions, patients with imaging, bronchoalveolar lavage, or biopsy evidence of acute eosinophilic pneumonia or cryptogenic organizing pneumonia should be treated with systemic glucocorticoids according to the usual management of those processes. (See "Idiopathic acute eosinophilic pneumonia" and "Cryptogenic organizing pneumonia".)

If the decision is made to administer glucocorticoids for EVALI, we favor a short course, starting with the equivalent of methylprednisolone 0.5 to 1 mg/kg per day and tapering over 5 to 10 days, guided by the clinical course [2,3,21,31]. Commonly prescribed glucocorticoid regimens consist of 40 to 60 mg of prednisone ranging from three days up to two weeks [34]. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)

The evidence regarding the benefit of systemic glucocorticoids is observational. In a large case series of 98 patients, 78 (84 percent) received systemic glucocorticoids (81 percent intravenously) and the treating clinicians attributed clinical improvement to the glucocorticoids [3]. In a detailed analysis of five of these patients, extubation from mechanical ventilation occurred 5 to 10 days after initiation of treatment with glucocorticoids. The exact dose of glucocorticoids was not provided, but the duration of therapy among the 46 treated patients was ≥7 days.

In a report of five patients, intravenous methylprednisolone 120 to 500 mg was administered daily; all five patients survived (one required mechanical ventilation, three required intensive care unit admission) [21]. Clinical improvement was noted by 24 to 72 hours after initiation of methylprednisolone.

In a separate series of six patients, one patient developed progressive respiratory failure despite methylprednisolone (1 mg/kg) and required extracorporeal membrane oxygenation (ECMO), although the relative timing of treatment initiation and worsening of hypoxemia was not provided [31]. In the same series, two of six patients whose hypoxemia was managed with oxygen by nasal cannula did not receive systemic glucocorticoids and improved spontaneously and one patient had progressive respiratory insufficiency despite glucocorticoids, so this therapy was stopped, and the patient improved with supportive care.

Supportive care — Approximately 95 percent of patients with EVALI have required hospitalization [10]. Supportive care initially focuses on supplemental oxygen with a target pulse oxygen saturation of 88 to 92 percent. If nasal cannula are insufficient to achieve this target, high-flow oxygen can be provided through a face mask or, possibly, high-flow nasal cannula (HFNC). If hypoxemia worsens, management follows that for acute respiratory distress syndrome. In the largest series, mechanical ventilation was required in approximately 26 percent of patients; rarely, ECMO has been needed [3,31]. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults" and 'Prognosis' below.)

Discharge and follow-up — Based on concerns about recurrent disease, it is prudent to ensure that vital signs, oxygenation, and exercise tolerance are stable for 24 to 48 hours prior to discharge after hospitalization for EVALI [71]. In addition, symptoms should have resolved and comorbid conditions that may have been exacerbated by EVALI reassessed. Follow-up examination should be scheduled within 48 hours of discharge or sooner if the patient's condition deteriorates. This advice is based on a report that 13 of 1139 patients discharged after an episode of EVALI (2.7 percent) required rehospitalization and seven patients died [71]. Patients who died or required rehospitalization were typically older and had one or more underlying chronic condition. All of those who died after discharge had required mechanical ventilation. Rehospitalization typically occurred at a median of four days after discharge and death at a median of three days.

Few studies have reported follow-up data. We suggest follow-up evaluation clinically and radiologically to ensure resolution of the process is appropriate. In one study of 31 patients, the majority had improved symptoms at two weeks, although two-thirds had some residual symptoms [34]. Follow-up chest radiographs in 10 showed complete or near-complete resolution of abnormalities, while pulmonary function tests showed a mild reduction in diffusing capacity. Follow-up for long-term sequelae of mechanical ventilation or critical illness is discussed separately. (See "Post-intensive care syndrome (PICS) in adults: Clinical features and diagnostic evaluation".)

If glucocorticoids have been used to treat EVALI, they should be tapered as quickly as possible (eg, over 5 to 10 days) and discontinued.

Until the exact mechanism of EVALI is known, it is reasonable to advise patients with EVALI to completely avoid vaping in the future.

COMMUNICATION WITH HEALTH DEPARTMENT — The Centers for Disease Control and Prevention (CDC) encourages reporting of hospitalized patients with possible EVALI to local or state health departments and provides links to state health departments for information on reporting requirements [72]. Additionally, the CDC suggests that clinical details about the patient's vaping practices be obtained and recorded (table 2) [73]. (See 'Evaluation' above.)

Residual samples of the vaping product used by the patient may help to determine the causative substance, but this is not always necessary. Testing can be coordinated with the local or state health department and/or the US Food and Drug Administration [72,74].

PROGNOSIS — EVALI is a serious respiratory illness [3,8-10]. As of February 18, 2020, over 2800 patients have been hospitalized with EVALI in the United States and, among those, 68 have died [5]. Among 1604 patients admitted to the intensive care unit, 36 percent required intubation and mechanical ventilation and 7 percent required extracorporeal membrane oxygenation (ECMO); most patients (93 percent) survived to discharge [70]. Updated epidemiologic statistics can be found at the Centers for Disease Control and Prevention website.

When comparing fatal and nonfatal cases of EVALI, the proportion of fatal cases was higher among patients over age 35 years and (when the medical history was available) among those with a history of asthma (23 versus 8 percent), cardiac disease (47 versus 10 percent), or a mental health condition (65 versus 41 percent) [75]. Among patients who died, 52 percent were obese.

Data describing long term outcomes suggest significant morbidity [2,76-78]. A retrospective review assessed one-year outcomes of 41 patients diagnosed with confirmed or probable EVALI [2]. Ten (24 percent) patients had at least one emergency department visit and 10 (24 percent) patients had at least one readmission within a year of initial hospital admission. Six (60 percent) of the readmissions were due to respiratory diagnoses (persistent or recurrent EVALI, asthma, or bacterial pneumonia). During follow-up, 13 (45 percent) remained symptomatic at the first outpatient visit, but nine became asymptomatic within the first year. Nine patients had abnormal pulmonary function tests (restriction, obstruction, mixed, or abnormal diffusion) [2]. In six patients who had repeat pulmonary function testing within one year after initial admission, abnormalities in pulmonary function testing had resolved. Other case series among adolescents suggest residual lung dysfunction, mainly diffusion abnormalities in the short term (<2 months post-discharge) but do not provide long-term data [76,77]. Of 33 patients with a documented subsequent health care encounter after hospitalization for EVALI, 16 (48 percent) patients had stopped vaping, 4 (12 percent) reported continued use of e-cigarettes, and 13 (39 percent) patients did not have a vaping assessment recorded [2].

PREVENTION — Until more is known about the specific cause(s) of EVALI, the Centers for Disease Control and Prevention advise complete avoidance of tetrahydrocannabinol-containing e-cigarettes or vaping products [8]. Furthermore, they advise avoidance of all e-cigarette or vaping products by youths, young adults, pregnant women, and adults who do not currently use tobacco products.

For those who wish to continue use of tobacco-containing e-cigarette products to help with tobacco smoking cessation, it appears safer to purchase commercially prepared products, rather than purchasing unlicensed products, although legally purchased products may contain potentially harmful substances.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults" and "Society guideline links: Pediatric pneumonia" and "Society guideline links: COVID-19 – General guidelines for diagnostic testing" and "Society guideline links: COVID-19 – Pediatrics".)

SUMMARY AND RECOMMENDATIONS

●Definition – E-cigarette, or vaping, product use-associated lung injury (EVALI) is an acute or subacute respiratory illness that can be severe and life-threatening. Vaping is the process of inhaling an aerosol created by heating a substance such as nicotine or tetrahydrocannabinol (THC) with a battery-operated electronic device such as an electronic cigarette (e-cigarette). (See 'Introduction' above.)

●Epidemiology – More than 2000 cases have been reported; approximately two-thirds are male, and approximately 80 percent are under 35 years old (range 13 to 75 years). The incidence has declined since the original outbreak in the summer of 2019. (See 'Epidemiology' above.)

●Pathogenesis and risk factors

•The exact pathogenesis of EVALI is unknown. The various presentations of EVALI suggest acute lung injury, possibly reflecting a spectrum of disease processes rather than a single process. No evidence of an infectious etiology has been identified. (See 'Pathogenesis and risk factors' above.)

•The key risk factor for EVALI is use of an e-cigarette or similar product; no single constituent has been identified that is common to all cases. Potential candidate toxins include THC and vitamin E acetate, although other compounds including nicotine and other unknown additives have been implicated. (See 'Pathogenesis and risk factors' above.)

●Clinical features – The mean duration of symptoms prior to presentation is six days with a range of zero days to two months. Respiratory symptoms include dyspnea, cough, chest pain (sometimes pleuritic), and hemoptysis. Approximately one-third of patients may progress to acute respiratory failure requiring mechanical ventilation. Subjective fever is reported by 85 percent; gastrointestinal symptoms are also common and include nausea, vomiting, diarrhea, and abdominal pain. (See 'Clinical features' above.)

●Diagnostic evaluation – Criteria used as a case definition provide a reasonable foundation for a clinical diagnosis as formal diagnostic criteria for EVALI have not been agreed upon (table 1); a negative nucleic acid test for SARS-CoV-2 should also be included. The case definition criteria include the following (see 'Diagnosis' above):

•Use of an e-cigarette or related product in the previous 90 days.

•Lung opacities on chest radiograph or CT.

•Exclusion of lung infection based on negative influenza polymerase chain reaction or rapid test (unless out of season), viral respiratory panel, and, as clinically indicated, urine antigen tests for Legionella and Streptococcus pneumoniae, blood cultures, sputum culture (if producing sputum), bronchoalveolar lavage (if performed), and testing for HIV-related opportunistic infections.

•Absence of a likely alternative diagnosis (eg, cardiac, neoplastic, rheumatologic).

●Differential diagnosis – A variety of respiratory diseases are in the differential diagnosis of EVALI. Community-acquired pneumonia (including COVID-19) should be carefully evaluated. Other processes, such as acute eosinophilic pneumonia, organizing pneumonia, lipoid pneumonia, and diffuse alveolar hemorrhage have occasionally been described in association with e-cigarette product use but either did not figure prominently in the reported cases of EVALI or have some unique features. (See 'Differential diagnosis' above.)

●Management – The optimal treatment of EVALI is not known. However, the following are appropriate:

•Empiric antibiotics – For the majority of patients with EVALI, empiric antibiotics are initiated to cover likely pathogens, pending the results of the initial evaluation and response to therapy. (See 'Treatment' above.)

•Selective use of glucocorticoids – The efficacy of systemic glucocorticoids is unknown, and we do not advise routine use in EVALI. However, for patients who meet criteria for EVALI and have progressively worsening symptoms and hypoxemia, we suggest initiation of systemic glucocorticoids (Grade 2C). Pending further data, it is reasonable to use an initial dose of methylprednisolone (or equivalent) 0.5 to 1 mg/kg per day and taper over 5 to 10 days. (See 'Systemic glucocorticoids' above.)

•Supportive care – Supportive care focuses on oxygenation and, when indicated, noninvasive or invasive ventilation. (See 'Supportive care' above and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

•Patients should be followed clinically and radiologically until the point of resolution. (See 'Discharge and follow-up' above.)

●Prognosis – The prognosis is variable, with many cases resolving completely, while a small number progress to death. Risk factors for disease progression and death are unknown. (See 'Prognosis' above.)

●Resources – In many states, EVALI cases are being collected and reviewed. The Centers for Disease Control and Prevention (CDC) has links to state health departments for information on reporting requirements. (See 'Communication with health department' above.)

●Prevention – Until more is known about the specific cause(s) of EVALI, the CDC advises complete avoidance of THC-containing e-cigarettes or vaping products and avoidance of all e-cigarette or vaping products by youths, young adults, pregnant women, and adults who do not currently use tobacco products. (See 'Prevention' above.)