Vaping Associated Lung Injury (EVALI): An Explosive United States Epidemic

Abstract

As of November 5, 2019, there have been 2051 cases of e-cigarette, or vaping, product use associated lung injury (EVALI), with 39 deaths reported in the United States, over four months. The rapidly increasing popular habits of vaping and e-cigarette use has suddenly turned deadly in the United States. This epidemic of vaping-associated illness appears to be limited to the United States with few reported cases and no deaths from the rest of the world.

Introduction

Electronic cigarettes are battery-powered devices that produce an inhaled aerosol by heating a liquid that contains nicotine, flavorings, and other chemicals¹ (Figure 1). Commercially available devices are available to purchase legally for adults that contain various amounts of nicotine and flavors. The term vaping is used because of the perception that the exhaled smoke is water vapor. It actually consists of fine particles of chemicals.¹ The vaping device consists of a mouthpiece, a battery, a cartridge for containing the e-liquid or e-juice, and a heating component for the device. When the device is used, the battery heats up the heating component, which turns the contents of the e-liquid into an aerosol that is inhaled into the lungs and then exhaled.¹ Vaping devices include not simply e-cigarettes, but also vape pens and personal vaporizers (also known as ‘MODS’).¹ The e-liquid in vaporizer products usually contains a propylene glycol or vegetable glycerin-based liquid with nicotine, flavoring, and other chemicals and metals but not tobacco.¹

Figure 1.

Schematic Diagram of the Elements of an Electronic Cigarette and Pictures of Three Generations of Electronic Cigarette Devices

Source: Journal of the American College of Cardiology 2015

The electronic cigarette company, JUUL, has developed a product that resembles a USB flash drive to deliver high doses of nicotine.² One pod contains the same amount of nicotine as 20 cigarettes. JUUL entered the U.S. market in 2015 and their design has become popular with teenagers as they are easy to hide from parents and teachers.² The JUUL product has become the most popular vaping device on the market, accounting for 72% of vaping products in the U.S² (Figure 1).

Electronic cigarettes were approved for use in Europe in 2006 and in the United States in 2007.³ The use of electronic cigarettes and vaping has exploded in the United States over the last 12 years. In 2018, more than 3.6 million U.S. middle and high school students had used electronic cigarettes in the previous 30 days.¹ In 2015 the CDC reported more than nine million Americans vaped on a regular basis. ¹

Vaping stores provide customized e-juices that can be used in devices to deliver various combinations of flavors and nicotine concentrations. Tetrahydrocannabinol (THC), the psycho-active component of cannabis, is added to electronic cigarettes alone and in combination with nicotine. Many of the products containing THC are purchased from illicit dealers and often contain potentially toxic substances such as Vitamin E and Cannabidiol (CBD) oils.^{3, 4} In states with legalized marijuana for medical or recreational use, commercially manufactured products containing THC are sold legally. Highly concentrated THC or nicotine concentrates prepared in a wax like substance and smoked in a pipe is a process called “dabbing”. Vaporizing extracts of a concentrate of butane hash oil or nicotine that has been placed on a hot surface is called “dripping”.^{4, 5}

Clinical Vignette

A 27-year-old Caucasian female with no prior history of asthma or other lung diseases was admitted to the intensive care unit with a five-week history of dyspnea associated with dry cough and bilateral sharp chest pain increased with deep inspiration. She was evaluated in the emergency department (ED) two weeks prior to admission. Her oxygen saturation at the first ED visit was initially 84% on room air with wheezes auscultated on lung exam. After nebulized treatments with albuterol and ipratropium, her oxygen saturation improved to 97% on room air. A CT angiogram of the chest identified no pulmonary emboli. Bilateral upper lobe ground glass infiltrates were noted on the CT chest. White blood cell count was 24,400 with 47% eosinophils. She was treated as an outpatient with an albuterol inhaler and a five-day course of azithromycin. Her cough and dyspnea initially improved and then increased two days prior to admission.

She reported vaping for at least three years. Initially she vaped both nicotine and THC products, but over the three months prior to admission she was vaping exclusively JUUL pods with 5% nicotine (about 2 pods/day) blueberry and mint flavors. She also occasionally smoked tobacco cigarettes and marijuana joints. After her first emergency department visit, two weeks prior to admission, she stopped vaping and noted less cough and dyspnea. She then started vaping JUUL pods a few hits per day up to the day of admission when she presented with increased cough, dyspnea, and pleuritic chest pain.

In the emergency department on the day of admission, she was found to be hypoxic requiring six liters per minute supplemental oxygen to maintain oxygen saturations of 93%. She was admitted to the ICU for management. Arterial blood gas on FiO2 of 40% revealed pH of 7.287, PaCO2 52 mmHg, PaO2 of 64 mmHg, HCO3 24 mEq/L, O2 saturation 93%. Alveolar arterial gradient of 161 mmHg. Her initial vital signs were temperature 98.3, blood pressure: 109/74 mmHg, heart rate 102, oxygen saturation of 93% on 6 liters of supplemental O2, and respiratory rate of 20. Physical exam was only remarkable for diffuse bilateral crackles with end expiratory wheezes on lung exam. The chest x-ray revealed subtle patchy heterogeneous opacities bilaterally (Figure 2). The CT of the chest revealed increased ground glass opacities of bilateral lungs, predominantly in the upper lobes (Figure 3). White blood cell count was 23,000 with 18% eosinophils. Urine streptococcus and legionella antigens negative, serum mycoplasma antibody was negative, T spot for tuberculosis and HIV were both negative.

Figure 2.

(second ED CXR) Chest x-ray at time of admission showing subtle bilateral patchy infiltrates.

Figure 3.

(second ED CT scan) Chest CT at time of admission showing bilateral upper lobe ground glass opacities.

She was treated with oral prednisone 50 mg daily for a total of 5 days. Given the concern for infection, the patient was also started on oral doxycycline 100 mg twice a day for a period of five days. During hospitalization, she had significant improvement of her symptoms. She was treated for one day in the intensive care unit and an additional three more days in the hospital. Her oxygen requirements continued to decrease and the patient was discharged to home off supplemental oxygen after a total of four days of hospitalization. She had no oxygen desaturation on room air with a six-minute walk the day of discharge. The patient was scheduled for follow-up in the pulmonary clinic two weeks after discharge for repeat imaging, complete blood count, and pulmonary function testing. She did not keep her appointment.

With the presence of significant peripheral eosinophilia, patchy ground glass infiltrates, hypoxemia, and a history of vaping, this patient most likely had acute eosinophilic pneumonia associated with electronic cigarettes. Acute eosinophilic pneumonia has been reported in individuals using nicotine containing electronic cigarettes.^6,7,8 In idiopathic acute eosinophilic pneumonia the duration of corticosteroid treatments is usually at least two weeks.⁹ Once the patient we described had completely stopped vaping during her hospitalization her symptoms improved rapidly and she only required five days of oral corticosteroids.

E-cigarette, or Vaping, Product Use Associated Lung Injury: EVALI

The number of reported cases of EVALI in the United States has exploded over a four month time period. As of November 5, 2019, 2051 cases of EVALI have been reported with 39 deaths.¹⁰ Seventy percent of cases were in males and 79% in patients less than 35-years old.¹⁰ Fourteen percent of cases were less than 18-years old.¹⁰ Eighty-six percent of patients reported using THC-containing products and only 11% reported using nicotine products exclusively.¹⁰ Thirty-four percent of patients reported exclusive use of THC-containing products.¹⁰ Patients may be reluctant to report use of THC or purchasing products from illicit dealers.

The vast majority of patients (95%) present with respiratory symptoms of cough, chest pain, and shortness of breath.¹¹ Many patients will reduce, but not eliminate, vaping after the onset of respiratory symptoms. Constitutional symptoms of fever, chills, and weight loss occur in 85% of patients.¹¹ Gastrointestinal symptoms of abdominal pain, nausea, vomiting, and diarrhea occur in 77% of patients and can be the initial symptoms preceding respiratory symptoms.¹¹ Symptoms usually progress in severity over one to two weeks.¹¹ Tachycardia and tachypnea associated with pulse oximetry less than 95% are common.¹¹ Auscultation on lung exam is often normal. Non-specific findings of leukocytosis, elevated erythrocyte sedimentation rate and elevated liver transaminases have been reported.¹¹ The chest radiograph is abnormal in the majority of cases revealing patchy infiltrates.¹² CT of the chest commonly demonstrates basilar-predominant consolidation and ground-glass opacities, often with areas of lobular or sub pleural sparing.¹²

The clinical course is usually associated with progressive hypoxemia requiring high flow oxygen and in 22% of cases mechanical ventilation for Acute Respiratory Distress Syndrome (ARDS).¹¹ Most patients have been treated with antibiotics to treat severe community acquired pneumonia, and varying doses and duration of corticosteroids.¹¹ Microbiology specimens for bacteria, viral, and fungal organisms are usually negative. When Broncho-alveolar-lavage (BAL) specimens are obtained, lipid-laden macrophages have been identified.¹¹

Eosinophils have been identified in broncho-alveolar lavage or peripheral blood specimens in a few cases, such as the one reported in this article, suggesting acute eosinophilic pneumonia.^6,7,8 Surgical lung biopsies reveal mild and nonspecific inflammation, acute diffuse alveolar damage, organizing pneumonia, acute fibrinous pneumonitis, chemical pneumonitis, foamy macrophages, lipoid pneumonia, and interstitial and peribronchiolar granulomatous pneumonitis.¹³ Lipoid pneumonia has been reported from the use of THC-containing vaping cartridges and pens.¹⁴ Hypersensitivity pneumonia with ARDS was reported in an 18-year-old nicotine-only electronic cigarette user.¹⁵

EVALI Diagnosis Is by Exclusion

Specific diagnostic criteria for EVALI have not been established.¹¹ It is a diagnosis of exclusion in patients presenting with a recent history of electronic cigarette use or vaping nicotine, and/or THC containing products with respiratory, constitutional, and/or gastrointestinal symptoms. Oxygen saturations less than 95% are reported in 57% of cases.¹¹ Evaluation for infectious and inflammatory causes of the illness should be investigated based on the clinical history.

Management of EVALI

Physicians should routinely question patients about vaping and use of electronic cigarettes. Hospital admission is recommended for patients with oxygen saturations less than 95% on room air with suspected EVALI.¹¹ Patients may develop severe hypoxemia and respiratory failure 24–48 hours after presenting with mild symptoms.¹¹ A detailed history and physical should be performed. Rapid testing for influenza should be performed during the influenza season, as this may have a similar presentation to EVALI. All patients should have a chest x-ray and patients with moderate and severe symptoms or hypoxemia should have a CT of the chest. A complete blood count with manual white blood cell differential should be performed to detect peripheral eosinophilia. Microbiology specimens from sputum and blood should be obtained.

It is important not to miss other causes of respiratory and gastrointestinal symptoms. Treatment with antibiotics directed against organisms causing severe community-acquired pneumonia should be started at the time of presentation. Oral or intravenous corticosteroids should be started in consultation with a pulmonologist recognizing that some infections may worsen with corticosteroids.¹¹ The dose and duration of corticosteroids has not been established. Once the patient has clinically improved, with oxygen saturations greater than 89% on room air, they should be considered for discharge. Patients should have a follow-up visit after discharge in one to two weeks, with a chest x-ray and pulse oximetry. The long-term consequences of EVALI are unknown, so pulmonary function tests, six-minute walk pulse oximetry, and CT chest may be considered one to two months after discharge.

Unanswered Questions About EVALI

Unanswered questions remain about the recent explosion of EVALI cases. Why are we seeing these cases now and not over the preceding 12 years? The majority of cases are related to use of THC-containing products.¹⁰ It is possible this epidemic of acute lung injury cases is related to a recent widespread adulteration of THC-containing illicit vaping products. A common finding in published case series is the prevalence of use of a cannabis product known as “Dank Vape.”^4,5 Dank Vapes are counterfeit brands available online and used by distributors to market THC-containing cartridges.^4,5 How do we explain EVALI cases in patients, like the one we reported, who claim to only use commercially available nicotine electronic cigarettes? Was our patient being truthful? Has there been a change in the manufacturing of these products? Are the lung injury cases a result of the marked increased number of electronic cigarette users in the USA? Why are we not seeing more EVALI cases reported in countries other than the USA? The United Kingdom (UK) has placed restrictions on the import of selected vaping products, limits the amount of nicotine within these products, and has placed restrictions on the advertising of electronic cigarettes.¹⁶ Electronic cigarettes are promoted as an acceptable smoking cessation tool in the UK and are not as popular with youth as they are in the USA¹⁶ What causes the gastrointestinal symptoms common among patients presenting with EVALI? It is possible gastrointestinal symptoms are related to synthetic marijuana as the source of the THC vaping fluid.

Conclusion

We report a case of acute eosinophilic pneumonia associated with commercially available electronic nicotine cigarettes, responding to a short course of oral corticosteroids and cessation of vaping. There are likely multiple mechanisms of lung injury in EVALI cases. Acute eosinophilic pneumonia and hypersensitivity pneumonitis appear to be more associated with nicotineonly electronic cigarettes. Acute eosinophilic pneumonitis may be underreported due to the unavailability of a manual white blood cell differential to accurately identify peripheral eosinophilia. Lipoid pneumonia, diffuse alveolar damage, acute fibrinous pneumonitis, and chemical pneumonitis appear to be more associated with THC containing products. Physicians should be vigilant in identifying and reporting cases of EVALI and strongly discourage the use of electronic cigarettes and vaping products.