EVALI

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Classification according to ICD-10
U07.0 Vaping-related disorder
ICD-10 online (WHO version 2019)

EVALI is an acute lung damage that occurred mainly in the USA from the consumption of certain products that are inhaled using e-cigarettes . The abbreviation also used in German stands for the English technical term e-cigarette, or vaping, product use associated lung injury . Sometimes there is also the expression VALI, which describes the form of absorption into the lungs ("vaping"), but leaves the devices used open.

As of August 2019, the United States saw a surge in cases of severe lung damage, which is associated with shortness of breath , which can lead to lung failure and death. In the majority of cases, the consumers inhaled tetrahydrocannabinol (THC), but also nicotine (11%) and identified vitamin E acetate, which is sometimes even the main component in the products consumed, as the main cause.

Pathogenesis and technical basis

In the case of e-cigarettes, liquids (“liquids”, “flavors”, “juices”) are heated and inhaled primarily as an aerosol and sometimes as a vapor, which usually contains nicotine. Due to the long-standing release of cannabis products in some US states, the technical principle of e-cigarettes has been optimized for the consumption of medicinal cannabis, but also for recreational use. For this purpose, specially modified products as so-called "E-Joints" with tetrahydrocannabinol and cannabidiol were developed and brought onto the market. These are pre-filled disposable vaporizers which can be screwed onto commercially available batteries (for e-cigarettes). The high level of acceptance corresponds to the consumer's desire for an uncomplicated, easy-to-use product that enables ash-free and almost odor-free consumption to be interrupted at any time without prior preparation. What is important for 'medical use' (available in 'Dispensaries') is the absence of harmful combustion components that occur in the smoke of a classic joint. Due to these properties, the demand grew particularly in states in which the acquisition is prohibited by regulations and therefore procurement was only possible from illegal sources.

The basic or carrier of the liquid used in e-cigarettes is a mixture of propylene glycol and glycerine . Due to their lipophilic properties, tetrahydrocannabinol (THC) or hashish oil (so-called "dabs") can only be mixed with the carrier substances mentioned by using emulsifiers. The use of lipophilic carriers is forbidden due to the obvious lung-damaging properties known for a long time; there has been general consensus within the industry for years. So there is a significant difference between these products, both technically and legally. Products containing THC are not e-cigarettes and are only officially approved in a few US states.

In the USA there are regulations for consumer protection. Obviously, however, there are deficits in the official monitoring of the market. There are a large number of products, some of them from domestic production, about whose quality and safety no information is available due to a lack of effective market surveillance. The use of e-cigarettes has skyrocketed in recent years and since 2014 e-cigarettes have been the nicotine-containing product most frequently used by high school students in the USA (“youth vaping epidemics”). However, this statement does not allow any conclusions to be drawn as to the extent to which e-cigarette users also consume products with THC.

Another physical peculiarity of the THC-containing products led to the observed increased occurrence of health problems up to and including death (see section Epidemiology). Products with a very high THC content show a relatively high viscosity and a noticeable color. Due to the different legal situation in the individual states and the high achievable sales price, this was counterfeited en masse and marketed through illegal channels. In official products, concentrate with the PEG and MCT (medium chain terpenes) approved for this is adjusted by mixing. However, counterfeit products were manipulated to simulate a high THC content while maintaining viscosity and color by adding vitamin E acetate up to well over 85% (weight percent). The product "Honey-Cut", which was mainly used for this from the beginning of 2019, promised unimagined degrees of blending. In an initial success of the investigation, the police confiscated around 100,000 cartridges from the Huffines brothers, which were sold under the fantasy label "Thanks Vape" and which they produced commercially in quantities of around 5,000–6,000 pieces per day. While no vitamin E acetate could be detected in Minnesota in 2018, this was the case for all products seized by the US regulatory authorities in September 2019.

In an analysis of samples from bronchoalveolar lavages in 51 patients who were acutely ill with EVALI, vitamin E acetate could be detected in 94% of the cases, but not in a healthy comparison group. In addition, 94% of the samples had detectable traces of THC or metabolites of THC. Nicotine or nicotine metabolites were found in 64%. Apart from coconut oil and limonene in one sample each, no other toxic additives were found in the lava samples, thus establishing a connection between the EVALI epidemic and the addition of vitamin E acetate.

Vitamin E and its oxidation-protected form, acetate, have strong antioxidant and thus protective effects, especially on phospholipids of cell membranes, as they also occur as surfactants in the lungs. This depends crucially on the isoform of the molecule - the α-tocopherol has a protective effect, the γ-tocopherol an inflammation-promoting and hypersensitivity triggering effect. From this point of view, α-tocopherol as a low-dose additive would even have a positive benefit. In 2003, the tobacco industry also pursued the approach of using vitamin E acetate as an additive for cigarettes in order to reduce the negative effects of smoking through its protective effect on the lung epithelium. The BfR (Federal Institute for Risk Assessment) involved in this refused, as neither the benefit nor the harmlessness could be proven. In contrast, further studies have shown that γ-tocopherol has a promoter effect for lung carcinomas. Due to its insolubility in water and its high boiling point , it can be assumed that vitamin E acetate which has reached the lungs in high doses remains there for a relatively long time and accumulates in the lungs when the manipulated products are consumed. The relatively viscous liquid in the lungs hinders the gas exchange and can ultimately lead to damage to the lung tissue. Two possible mechanisms are discussed:

  1. Vitamin E acetate has an aliphatic chain that aligns itself through the surfactant parallel to the phospholipids of the cell membrane of the underlying alveolar cells . As a result, the surfactant loses its ability to maintain surface tension and the alveolus collapses with subsequent damage to the alveolar cell.
  2. Another mechanism can be that heating the vitamin E acetate in the vaporizer produces ethenones , which are reactive and, depending on the concentration, are considered to be irritating to the lungs.

A study in which mice were exposed to vitamin E acetate showed acute lung damage with pathological changes that were very similar to those seen with EVALI.

Epidemiology

In August 2019, the US Centers for Disease Control and Prevention (CDC) reported for the first time an epidemic increase in cases of severe lung damage related to e-cigarette use and vaping, after a first cluster on August 1, 2019 in Wisconsin was reported. In the United States, the epidemic peaked at the beginning of September 2019, with numbers falling since then.

In view of the rapidly increasing cases of toxic lung damage, it was initially suspected at the beginning of the epidemic that contamination in the form of pesticide or heavy metal residues in the products used caused these acute pulmonary insufficiencies. Analyzes confirmed high levels of pesticide contamination, especially with myclobutanil, the thermal decomposition of which results in HCN , which in low concentrations causes lung damage. The substance is banned in official cannabis cultivation in many states, but can often be found in illegally produced marijuana, as it is used there because of its fungicidal effect. Residues can hardly be removed and are almost completely transferred to the product during oil extraction.

As of February 18, 2020, a total of 2,807 patients from all states had been registered in the United States to be hospitalized, and 68 of them died as a result of lung damage. A cumulative report from Germany reported on cases of three patients whose clinical picture corresponds to that of EVALI lung disease caused by e-cigarettes, but according to the authors "there is no evidence of the connection between the diseases and e-cigarette consumption".

The vast majority of patients are young and healthy and apart from asthma (22% in a case study) have no previous medical conditions. Affective and anxiety disorders were reported in 40%. The mean age of onset was 24 years, 16% of the patients were under 18 years old.

Most patients confirmed regular e-cigarette or vaping use, and only 11% reported using only nicotine in a case study, but 89% also used or only used THC or CBD.

However, the first cases of lung damage associated with e-cigarettes or other "vaping" devices were published as early as 2012, and also after the US epidemic, and with the numbers falling significantly after the predominant connection with the addition of vitamin E-acetate, numerous cases have also been reported that could not be associated with tetrahydrocannabinol or vitamin E-acetate. In addition, there were many different pathological manifestations from congestive pneumonia to acute alveolar damage to interstitial lung disease , so that in April 2020 the hypothesis was made that several different forms of lung damage are grouped under EVALI and that a large number of components are responsible for the toxic effects. In general, an acute, severe form, as in the past US epidemic, can be distinguished from lighter, chronic, long-term forms.

Symptoms

The first signs are usually unspecific shortness of breath and chest pain. In a case study of 98 US patients found themselves at hospital admission

Often tachycardia (63%) and tachypnea (43%) were present on admission . Without additional oxygen, the oxygen saturation in room air was 33% between 89% and 94%, with 25% below 89%.

The blood analysis mostly revealed leukocytosis (83%, over 11,000 / mm³), primarily with neutrophils (91% with> 80%), but in no one with an increased proportion of eosinophils . In about half of the cases the aminotransferases were slightly increased, in almost a third the sodium and potassium in the serum were decreased.

Radiological examinations

In addition to an x-ray of the chest one is often CT examination performed. Upon clinical admission, both examinations may still be normal or show infiltrates in the lungs. In computed tomography, these are often “ground-glass opacity” and often found in the lower (“basilar”) lung areas on both sides, as is known from other lung damage caused by inhalation of toxic gases. Occasionally the subpleural areas are spared. A pneumomediastinum , a pleural effusion or a pneumothorax are less common .

Histopathology

For further diagnosis, a bronchoscopy can be performed and the bronchoalveolar lavage can be cytologically evaluated. Occasionally, fat-laden granulocytes are found.

If a transbronchial lung biopsy is performed, acute diffuse pulmonary alveoli damage with few foam cells and interstitial and peribronchiolar granulomatous pneumonitis are typical. An inflammatory reaction is at best mild and unspecific. A secondary infection can also result in pneumonia or acute bronchiolitis , possibly due to a secondary bacterial infection.

The pathological picture fits most closely to a toxic pneumonitis with predominantly interstitial lung changes, but can also be a sarcoidosis are similar.

Diagnosis

Acute lung damage can be classified as an EVALI if three conditions come together (diagnostic criteria of the CDC 2019):

  • e-cigarettes or another "vaping" method were used in the 90 days prior to the onset of symptoms
  • Lung infiltrates can be seen in the X-ray or CT images,
  • other, especially viral (including flu and COVID-19 ), bacterial, but also cardiological, rheumatological and oncological causes have been excluded.

The diagnosis is often made belatedly after initial treatment for alleged pneumonia . In one case study, patients were admitted to hospital a median of six days after onset of symptoms, and 71% within the first seven days of onset of symptoms. But 66% had already consulted a doctor on an outpatient basis before admission to hospital and 45% had been prescribed an antibiotic .

treatment

In the case of increasing dyspnoea and hypoxemia , oxygen is first necessary, and if the oxygen saturation deteriorates, intubation and mechanical ventilation are also necessary .

In one case series, 56% of the patients admitted to the hospital had to be monitored by intensive care and 27% ventilated. A quarter developed acute lung failure (ARDS), which in some cases requires extracorporeal membrane oxygenation (ECMO) and can lead to death.

In addition to general intensive medical care, glucocorticoid is used very often, which was able to improve respiratory performance in about two thirds of the cases.

The mortality or probability of dying increases with pre-existing chronic obstructive pulmonary disease (COPD) (nine times more often in the deceased), in asthma and cigarette smokers (twice as often in the deceased), but also with pre-existing cardiovascular diseases (five times more often in the deceased) ), especially high blood pressure . With a mean age of 51, the deceased were significantly older than the survivors (24 years).

Regulatory measures

As part of the epidemic, bans on some additives, especially vitamin E acetate, and discussions on better regulating the additives took place in numerous states in the USA in autumn 2019.

The causative products with THC or CBD must, if they are allowed to be legally placed on the market at all, be generally safe as consumer products within the scope of the intended use, unless there are privileged regulations that define more precise requirements. For this, however, the supervisory authorities usually have very effective options for immediately withdrawing products that have been identified as unsafe, even without costly changes to the law. In Germany this is regulated in Section 26 (II) ProdSG.

In the European Union only e-cigarettes and other nicotine-containing products covered by Directive 2014/40 / EU, which in April 2016, the tobacco product law was implemented in Germany. A general clause (Art. 20 (3)) prohibits the use of ingredients that " pose a risk to human health " in " heated or unheated form ". Accordingly, every EU member state can very easily implement corresponding substance bans, should this be necessary. Vitamins are already explicitly forbidden as additives, whereby the protective purpose here is not in health protection, but in the prohibition of the pretense of a health-promoting effect.

Individual evidence

  1. a b c d e f g Jennifer E. Layden, Isaac Ghinai, Ian Pray, Anne Kimball, Mark Layer, Mark W. Tenforde, Livia Navon, Brooke Hoots, Phillip P. Salvatore, Megan Elderbrook, Thomas Haupt, Jeffrey Kanne, Megan T. Patel, Lori Saathoff-Huber, Brian A. King, Ph.D., Josh G. Schier, Christina A. Mikosz, Jonathan Meiman et al .: Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report New England Journal of Medicine 2020, Volume 382, ​​Issue 10, March 5, 2020, pages 903-916, DOI: 10.1056 / NEJMoa1911614
  2. Welt Video: "Dutch company develops electrical joint" Welt Nachrichten of August 10, 2015; accessed on July 12, 2020
  3. Christopher M. Jones, Grant T. Baldwin, Peter A. Briss: The EVALI and Youth Vaping Epidemics - Implications for Public Health . New England Journal of Medicine 2020, Volume 382, ​​Issue 8 February 20, 2020, pages 689-691, DOI: 10.1056 / NEJMp1916171
  4. Cannabidiol as a common cannabinoid dissolves very well in propylene glycol but also in lipophilic solvents.
  5. a b c Hendrik Suhling, Tobias Welte, Thomas Fuehner: Case reports from three patients with acute lung damage after using e-cigarettes Deutsches Ärzteblatt Int 2020, Volume 117, Pages 177–182, DOI: 10.3238 / arztebl.2020.0177 (German version)
  6. David Downs, Dave Howard, Bruce Barcott: "Journey of a tainted vape cartridge: from China's labs to your lungs" Leafly, September 24, 2019; accessed on July 14, 2020
  7. a b c Benjamin C. Blount, Mateusz P. Karwowski, Peter G. Shields, Maria Morel-Espinosa, Liza Valentin-Blasini, Michael Gardner, Martha Braselton, Christina R. Brosius, Kevin T. Caron, David Chambers, Joseph Corstvet , Elizabeth Cowan, Víctor R. De Jesús, Paul Espinosa, Carolina Fernandez, Cory Holder, Zsuzsanna Kuklenyik, Jennifer D. Kusovschi, Cody Newman, Gregory B. Reis, Jon Rees, Chris Reese, Lalith Silva, Tiffany Seyler, Min-Ae Song, Connie Sosnoff, Carleen R. Spitzer, Denise Tevis, Lanqing Wang, Cliff Watson, Mark D. Wewers, Baoyun Xia, Douglas T. Heitkemper, Isaac Ghinai, Jennifer Layden, Peter Briss, Brian A. King, Lisa J. Delaney , Christopher M. Jones, Grant T. Baldwin, Anita Patel, Dana Meaney-Delman, Dale Rose, Vikram Krishnasamy, John R. Barr, Jerry Thomas, James L. Pirkle et al. for the "Lung Injury Response Laboratory Working Group": Vitamin E Acetate in Bronchoalveolar Lavage Fluid Associated with EVALI . New England Journal of Medicine 2020, Volume 382, ​​Issue 8 February 20, 2020, pages 697-705, DOI: 10.1056 / NEJMoa1916433
  8. Joan M. Cook-Mills et al .: "The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study"; BMC Respiratory Research , Springer, March 15, 2014, DOI: 10.1186 / 1465-9921-15-31
  9. BfR BUND: Vitamin E additive in cigarettes ; BfR opinion, PDF, 2013, accessed on July 15, 2020.
  10. Wu, Qi-Jun et al .: "Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women's Health Study."; International journal of cancer 2014, volume 136, issue 3, from June 19, 2014, pages 610-7, DOI: 10.1002 / ijc.29016
  11. Tariq A. Bhat, Suresh G. Kalathil, Paul N. Bogner, Benjamin C. Blount, Maciej L. Goniewicz, Yasmin M. Thanavala: An Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury New England Journal of Medicine 2020, Volume 382, ​​Issue 12 of March 19, 2020, pages 1175–1177, DOI: 10.1056 / NEJMc2000231
  12. Jill Daly: "CDC, FDA say e-cigarette investigation calls for caution" post-gazette.com of August 29, 2019
  13. C. Ferguson, C. McFadden, S. Dong, R. Schapiro: Tests show bootleg marijuana vapes tainted with hydrogen cyanide , NBC News, September 27, 2019, (included table as PDF )
  14. ^ Frank Conrad: Eagle 20 and Myclobutanil in the Context of Cannabis Cultivation and Consumption Colorado Green Lab, May 14, 2015
  15. ^ A b Matthew B. Stanbrook, Jeffrey M. Drazen: Vaping-Induced Lung Disease - A Look Forward by Looking Back . New England Journal of Medicine 2020, Volume 382, ​​Issue 17 April 23, 2020, pages 1649-1650, DOI: 10.1056 / NEJMe2004876
  16. Travis S. Henry, Jeffrey P. Kanne, Seth J. Kligerman: Imaging of vaping-associated lung disease . The New England Journal of Medicine. 381 (15): 1486-1487. doi: 10.1056 / NEJMc1911995. ISSN 0028-4793. PMID 31491070 .
  17. Joshua G. Schier, Jonathan G. Meiman, Jennifer Layden, Christina A. Mikosz, Brenna VanFrank, Brian A King, Phillip P. Salvatore, David N. Weissman, Jerry Thomas, Paul C. Melstrom, Grant T. Baldwin, Erin M. Parker, Elizabeth A. Courtney-Long, Vikram P. Krishnasamy, Cassandra M. Pickens, Mary E. Evans, Sharon V. Tsay, Krista M. Powell, Emily A. Kiernan, Kristy L. Marynak, Jennifer Adjemian, Kelly Holton, Brian S. Armor, Lucinda J. England, Peter A. Briss, Debra Houry, Karen A. Hacker, Sarah Reagan-Steiner, Sherif Zaki, Dana Meaney-Delman for the "CDC 2019 Lung Injury Response Group": Severe Pulmonary Disease Associated with Electronic-Cigarette – Product Use - Interim Guidance Morbidity and Mortality Weekly Report 2019, Volume 68, Issue 36 of September 13, 2019, pages 787–790, doi: 10.15585 / mmwr.mm6836e2
  18. Matthew B. Stanbrook, Jeffrey M. Drazen: Vaping-Induced Lung Disease - A Look Forward by Looking Back New England Journal of Medicine 2020, Volume 382, ​​Issue 17 of April 23, 2020, pages 1649–1650, DOI: 10.1056 / NEJMe2004876
  19. Angela K. Werner, Emilia H. Koumans, Kevin Chatham-Stephens, Phillip P. Salvatore, Christina Armatas, Paul Byers, Charles R. Clark, Isaac Ghinai, Stacy M. Holzbauer, Kristen A. Navarette, Melissa L. Danielson, Sascha Ellington, Erin D. Moritz, Emily E. Petersen, Grant T. Baldwin, Peter Briss, Christopher M. Jones, Brian A. King, Vikram Krishnasamy, Dale A. Rose, Sarah Reagan-Steiner for the "Lung Injury Response Mortality Working Group “: Hospitalizations and Deaths Associated with EVALI New England Journal of Medicine 2020, Volume 382, ​​Issue 17 of 23 April 2020, pages 1589–1598, DOI: 10.1056 / NEJMoa1915314
  20. Directive 2014/40 / EU of the European Parliament and of the Council of 3 April 2014 on the approximation of the laws and regulations of the member states on the manufacture, presentation and sale of tobacco products and related products and on the repeal of Directive 2001/37 / EG, Official Journal of the European Union of April 29, 2014, L127 / 1