Electronic cigarette (e-cigarette) or vaping-associated lung injury (EVALI) refers to an acute lung injury due to inhalation of vaporized liquid, which contains nicotine or cannabis products, with or without added flavorings. Electronic nicotine and cannabis delivery systems are a diverse group of devices that are structurally engineered to aerosolize a liquid, which is then inhaled, or “vaped.” They include a variety of products, including e-cigarettes, vapes, vape pens, and hookah pens. Each device contains four compartments: A battery, a reservoir with liquid formulation, and a vaporizing chamber with a heating element, along with a mouthpiece for inhalation (Fig. E1). The acute lung injury associated with the use of these products is heterogenous, with variable severity, presentation, and duration.

E-cigarette or vaping product use-associated lung injury

(E-cigarette or) vaping-associated pulmonary injury; (E)VAPI

Vaping (product use)-associated lung injury; VALI

“Popcorn lung”-referring specifically to lung injury caused by diacetyl-containing flavor additives

EVALI

• Patients with EVALI may present with symptoms ranging from mild dyspnea to immediately life-threatening respiratory failure. Milder cases generally present with cough, shortness of breath, and dyspnea on exertion. Chest pain and fever are frequently encountered complaints. Patients may also report chills and gastrointestinal symptoms (diarrhea, nausea, and vomiting). Sputum production is less frequent (36% in one case series) and hemoptysis relatively uncommon. More severe cases are marked by profound dyspnea, tachycardia, tachypnea, and hypoxemia.⁷
• Laboratory abnormalities are nonspecific, with elevated leukocyte count, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin. Peripheral eosinophilia is not generally found in EVALI cases.
• Chest imaging findings are also nonspecific, but generally consist of patchy, ground glass opacities, occasionally with subpleural sparing seen on CT scans.
• Although EVALI generally presents with a diffuse alveolar damage phenotype, cases have been reported with more varied presentations, including hypersensitivity pneumonitis, acute eosinophilic pneumonia, organizing pneumonia, and lipoid pneumonia.

• The etiology of EVALI is not fully understood; several mechanisms have been proposed, including direct toxicity of e-liquid components causing lung epithelial necrosis and alteration of the inflammatory state of the lung by increasing proinflammatory cytokine release by macrophages (Fig. E2).
• Vitamin E (tocopherol acetate) is the causative compound most consistently found in bronchoalveolar lavage (BAL) fluid of patients with EVALI and in the vaping products used.⁸ Vitamin E is thought to have a direct toxic effect on pulmonary epithelium.

Because of the nonspecific nature of the history, physical, laboratory, and radiologic findings in EVALI, it is considered a diagnosis of exclusion (in the setting of known or suspected vaping-product use). The differential diagnosis is broad, including the following:

• Infection
  1. Bacterial
     1. Atypical bacterial pneumonia (including Chlamydophila, Mycoplasma, Legionella, and others)
     2. Severe or diffuse typical bacterial pneumonia
  2. Viral
     1. Seasonal influenza infection
     2. COVID-19 infection
     3. Other respiratory viral infections (including common strains of parainfluenza, respiratory syncytial virus, coronavirus, adenovirus, rhinovirus, enterovirus, and metapneumovirus)
  3. Fungal, parasitic, or mycobacterial infection
     1. Including but not limited to Pneumocystis jirovecii pneumonia, strongyloidiasis, miliary tuberculosis, disseminated histoplasmosis, coccidiomycosis, or blastomycosis
     2. More commonly (but not exclusively) a consideration in immunocompromised patients, severe cases can closely mimic EVALI and should be excluded with appropriate laboratory evaluation in the correct setting
• Autoimmune/idiopathic inflammatory conditions
  1. Vasculitis (including granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis)-generally associated with additional extrapulmonary manifestations or a preexisting history of pulmonary disease
  2. Diffuse alveolar hemorrhage
     1. Characterized by increasingly bloody BAL fluid return
• Other inhalational exposures/toxins
  1. Chemical pneumonitis-it is important to question patients and families regarding any other potentially toxic inhalational exposures
  2. Aspiration pneumonitis-due to gastric contents aspiration; of particular concern in patients with a history of dysphagia, reflux, or alcoholism
• Malignancy
  1. Generally excluded by the rapid onset of symptoms; however, some hematologic malignancies may cause leukemic infiltrates that can mimic clinical findings of EVALI
• Cardiogenic pulmonary edema
  1. A transthoracic echocardiogram should be obtained on all patients presenting with severe suspected EVALI to evaluate for cardiac causes of pulmonary edema

• Because there is no specific diagnostic test for EVALI, the majority of the workup is directed at excluding other potential etiologies. Fig. E3 illustrates the management of patients with suspected EVALI.
• If the patient is sufficiently stable, bronchoscopy should be strongly considered to rule out infection in cases of suspected EVALI.
  1. Bronchoscopy should be done with BAL fluid sent for cell count and differential; bacterial, acid-fast bacteria (AFB), and fungal culture.
  2. Mycobacterial polymerase chain reaction (PCR), respiratory viral PCR, and galactomannan of the BAL fluid can be helpful to exclude tuberculous infection, respiratory viral infection, and disseminated aspergillosis, respectively.
  3. If diffuse alveolar hemorrhage is suspected, serial lavage should also be performed, observing for increasingly bloody return.

• In addition to basic lab work (complete blood count, basic metabolic panel, liver function tests, and coagulation tests), we suggest the following for patients hospitalized with suspected EVALI:
  1. Blood culture and sputum culture
  2. Erythrocyte sedimentation rate, C-reactive protein
  3. Legionella antigen
  4. Respiratory viral panel (including assays for COVID-19 and influenza)
  5. Testing for endemic fungal infection (if locally prevalent or patient has had recent travel)
• In addition, we also recommend the following for immunocompromised hosts with suspected EVALI:
  1. Sputum culture (fungal and AFB), as well as TB PCR; recommend induced sputum or bronchoscopy if patient is unable to produce sputum
  2. Silver stain for Pneumocystis jirovecii of induced sputum, tracheal aspirate, or BAL

• Chest x-rays are recommended in all suspected cases of EVALI. Typical findings include diffuse opacities in a central distribution.

CT scans can assist in the diagnosis of EVALI by elucidating parenchymal abnormalities seen on chest x-ray. Findings are also nonspecific, but frequently include diffuse ground glass opacities, with subpleural sparing (Fig. E4).⁹

• The primary treatment of EVALI, regardless of severity, is supportive, and includes supplemental oxygen (via endotracheal intubation if necessary) and close monitoring in the hospital setting.

• No EVALI-specific therapies have been shown to improve outcomes. Therapy is generally supportive.
• Glucocorticoids have been suggested as a possible treatment for severe cases of EVALI, but data concerning their efficacy are limited. No consensus exists on the appropriate dose of steroids, but methylprednisolone 0.5 to 1 mg/kg daily, tapered over 5 to 10 days, is a reasonable approach.¹⁰
• Empiric, broad-spectrum antimicrobial therapy should also be initiated for suspected EVALI cases, pending results of cultures.

• EVALI is an acute presentation; patients either recover or succumb to the effects of the disease. Patients may be left with residual pulmonary dysfunction due to scarring.
• Patients with persistent cough or dyspnea after EVALI can be treated symptomatically with an antitussive.

• Patients with suspected EVALI requiring supplemental oxygen should be managed in a hospital (rather than an outpatient setting).
• Once patients with EVALI are clinically improving and stable for discharge, short-interval follow-up with a primary care provider and pulmonologist should be arranged.¹¹
• Older patients with comorbidities are at higher risk of rehospitalization or death.¹²
• Patients with persistent dyspnea should be evaluated with pulmonary function testing.
• Constrictive bronchiolitis with subepithelial fibrosis has been reported in lung biopsy in patients with long term use of e-cigarettes.¹³

• We recommend follow-up with a pulmonologist for all diagnosed cases of EVALI.
• Patients admitted to the intensive care unit (ICU) may also benefit from evaluation in an ICU Recovery Clinic (if available), to evaluate for symptoms of post-ICU syndrome (including posttraumatic stress disorder, anxiety, weakness, or cognitive dysfunction).

• EVALI emerged as a cause of severe respiratory failure in early 2019, with cases peaking in the fall of 2019.
• Diagnosis of EVALI is based on excluding other potential causes of respiratory failure, including infection or autoimmune disease.
• Treatment is primarily supportive, though glucocorticoids may also be beneficial.
• Reducing the incidence of EVALI depends on decreasing e-cigarette use, particularly among teens and children.
• Young adult users of e-cigatettes are significantly more likely to have wheeze-related respiratory symptoms.¹⁴

• Primary care and pulmonary clinicians should regularly screen for e-cigarette or vaping product use.
• Patients with a personal history of EVALI should be cautioned that they are at high risk of recurrent (and more severe) disease if they again use vaping products.
• Public health efforts to discourage underage use of e-cigarettes show promise in preventing future cases of EVALI.

• Any patient reporting e-cigarette or vaping use should be counseled on the risks, including the risk of EVALI.
• All patients with a personal history of EVALI should be cautioned that they are at high risk of recurrent (and more severe) disease if they again use vaping products.

Acute Respiratory Distress Syndrome (Key Related Topic)