Methodology
Search strategy
A systematic literature search was conducted in online database PubMed using search
string “(((((Lung injury*[Title/Abstract]) AND Vaping[Title/Abstract]) OR electronic
nicotine delivery device[Title/Abstract]) OR electronic cigarette*[Title/Abstract])
AND e-cigarettes liquid) AND electronic cigars and search filter used were “published
in the last 5 years” and “Human Studies.” Similar search terms were used to search
EMBASE, Web of Science, Google Scholar, and the CENTRAL database of the Cochrane Library
with the help of Boolean terms [Flowchart 1].[INLINE:1]
Flowchart 1: Flowchart for selection of articles
Selection criteria
Data extraction was performed by authors (HS and SV) from the full-text reads of the
selected for articles inclusion. All written papers related to vaping by electronic
devices, E-cigarettes or electronic nicotine delivery systems (ENDS), and lung injury
have been included due to limited literature on the topic of interest. Moreover, those
papers who failed to meet the inclusion criteria were excluded.
What is vaping?
According to the Merriam-Webster Dictionary, vape or vaping is to inhale vapor through
the mouth from an electronic device that is normally powered by batteries (such as
an electronic cigarette) that heats up and vaporizes a liquid or solid.[9]
According to the Bill passed by the Ministry of Health and Family Welfare, “The Prohibition
of Electronic Cigarettes (Production, Manufacture, Import, Export, Transport, Purchase,
Distribution, Storage and Advertising) Act, 2019,” electronic cigarettes (E-cigarettes)
are classified as electronic devices that heat a substance that may contain nicotine
and other chemicals to produce inhalation vapor. Such E-cigarettes may also contain
various types, including all forms of ENDS, heat-not-burn products, E-hookahs, and
similar devices.[10]
What makes vaping more appealing to youth and young adults?
Most E-cigarettes at the end are fitted with a light-emitting diode to mimic the appearance
of a normal burning cigarette. Traditional devices through heating elements produce
a vapor of nicotine that is suspended in a propylene glycol and glycerin mixture.
Using different cigarette-looking devices and tempting E-cigarette blends, vaping
looks fun and fashionable, and when the vapor is inhaled, it gives the user a sensation
in their mouth and throat identical to smoking regular filtered cigarettes. However,
the related physical activity of vaping, such as raising the tool to the mouth, inhaling
and exhaling smoke, is similar to smoking and may lead to new addicts.[11]
Along with these, nowadays, most of the brands provide the option to smoke a variety
of materials promoting customizable devices to meet user demands. Such customizable
vaping devices can be replenished with liquids of a variety of flavors and nicotine
brands from local markets and online stores and can be conveniently replenished by
watching videos on most online pages. This helps them to vape a variety of flavor
and nicotine concentration via altering the vaporizing power of the device by variable
voltage, current, and temperature. Alternatively, consumers can purchase readymade
or base formulations that can be blended with flavors to match individual preferences
for taste, density of vapor, visibility and amount, and sensation and concentration
of nicotine.[12]
Currently, kid-friendly flavored E-cigarettes and cigars are aggressively marketed
by manufacturers in enticing flavors such as gummy bear, cherry crush, and banana
smash, which may lure children and young adults to this vaping habit. Such flavors
are advertised primarily in the name of products generally recognized as safe (GRAS)
and mean that the product or material added to the E-cigarette liquid for flavoring
is considered safe by experts and is therefore excluded from the normal provisions
of the Federal Food, Drugs and Cosmetic Act.[13]
A research conducted by Zhu et al. revealed the ugly side of the E-cigarette industry and reported that, by January
2014, there were approximately 7764 different flavors of 466 E-liquid brands each
with their own website. Moreover, there had been net surge of 10.5 brands and 242
new flavors per month in 17 months between their searches.[14],[15]
According to a report published by Times of India on May 26, 2019, about 6.25 lakh
children have been reported to smoke. A recent surprise inspection at a popular school
in East Delhi has resulted in the discovery of a large number of vaping devices from
the students. The trend of vaporizing equipment used by school students is steadily
increasing as students are tempted by a variety of vaporizing flavors such as lemon,
strawberry, fruit medley, banana, and cucumber. Even after a large number of students
are involved in the act, it is difficult to catch errant students as there is limited
or no odor emitted from such devices.[16]
Does particle size of the inhaled aerosol matter?
Although vapor inhaled by E-cigarette is believed to contain fewer particles of larger
size, it still poses a threat to the respiratory tract by exposing individuals to
ultrafine particles. Some researchers have shown that vaping by E-cigarettes creates
ultrafine particles with a diameter of <100 nm; the concentration of which in the
inhaled aerosol depends on puffing times and nicotine content.[17]
The ultrafine particles generated by cartomizer fluid comprise particles of more than
1 μm consisting of gold, silver, iron, nickel, aluminum, silicate, and nanoparticles
and <100 nm of tin, chromium, and nickel.[7]
Such highly concentrated ultrafine particles can pose a high toxicological risk to
the respiratory tract and lungs as their deposition is significantly higher than particles
of regular smoked cigarettes.[18]
What makes vaping more dangerous?
Vaping cannabis-related products (VCRPs) such as tetrahydrocannabinol (THC) in the
form of cannabinoid oils are considered safe and much more pleasurable compared to
cannabis-related products as inhaling smoke from a dried cannabis plant is thought
to pose a higher risk of adverse effects. The VCRPs show perceived advantages over
smoking as it provides better taste, more extreme effect, and flexibility of being
able to use at any place.[19]
In addition, THC vapers tend to inhale deeply and hold their breath together with
the smoke for long periods of time to get maximum pleasure, executing a Valsalva maneuver
(forced attempted exhalation against a closed airway) at optimum breath-hold.[20]
A report published in the Morbidity and Mortality Weekly Report (MMWR) reports that
many of these product companies use potentially hazardous additives such as Vitamin
E acetate, medium-chain triglyceride oil, and other lipids to manufacture liquids
for these vaping products. In particular, Vitamin E acetate has indeed been added
to E-cigarette liquid or vaping products to serve as a thickener in THC products.
Vitamin E acetate inhalation can impair the function of the lung.[21]
Another report published in the MMWR describes features of uglier side of E-cigarette
product use by patients in Illinois and Wisconsin. The reports state that out of all
the comprehensive interviews conducted on the patients, 96% of individuals used THC-containing
products that were packed, prefilled cartridges. Of these consumers, 89% purchased
prefilled cartridges from informal sources (e.g., friends, family members, andunauthorized
or off-street dealers) whose chain for production and distribution is unclear. In
view of the high number of patients suffering from lung injury involved in vaping
these THC-related products, the Centers for Disease Control and Prevention (CDC) had
advised that all persons should consider refraining from using E-cigarette or vaping
products, particularly those containing THC, until the investigation is in progress.[22]
However, most of the individuals remain unaware of the fact that science of vaping
is still at its infancy with very less known about the benefits and adverse effects.
In addition, many of the nicotine-based vaping products contain specially formulated
nicotine and higher amounts of benzoic acid, thus increasing nicotine potency, rendering
the vapor less harmful, and creating a “spiking” effect that makes it easier for consumers
to inhale more nicotine for longer periods. Regular use of these nicotine-based vaping
products with high concentration of nicotine may lead to nicotine dependence and may
lead to combined use of vaping devices along with combustible forms of tobacco.[23],[24]
Many of current vaping products come with options of certain flavoring agent. Tobacco
companies perceive their products to be safe, claiming that the flavoring agents are
not harmful as they are all “food grade” and “GRAS.” However, the option to purchase
base formulations that can be blended with flavors to adjust to subjective desires
and commercially available readymade cartridges with potentially toxic levels of flavoring
agents found by Farsalinos et al. 2015 and existing evidence of irritation and inflammation of the respiratory and
cardiovascular systems to such high levels of flavoring agents makes it a public health
concern.[25]
It is evident from the literature that individual exposure depends on a number of
variables, such as product voltage, temperature, taste of different e-liquids, nicotine
content/density of vapours emitted, air flow rate, vapour pressure drop and individual
smoking behavior, making it difficult to scientifically assess the threshold for such
exposures and toxicological outcomes in humans. Many of the companies now market customizable
devices that can be used to vape varieties of products through these devices. These
customizable products allow the user to change the resistance and voltage of atomizer
through replaceable parts and adjustable dials. Hence, such self-adjustable vaping
devices pose a threat by altering the composition of aerosols generated by inhaling
the same E-liquid through different devices.[26]
It is also of concern that these vaping devices with adjustable heating temperature
can be used to vape recreational drugs and new psychoactive substances, information
for which is easily available on social media, and several internet drug forums. Hence,
it makes it much appealing to the youth for vaping cannabis and creates the negative
image of these vaping devices that E-cigarettes are not just for nicotine use.[27]
Health consequences of vaping
The habit of vaping and smoking among adolescents and young adults has grown steadily.
Vaping nicotine, THC, or simply vaping with flavoring liquids for fun are very effective
ways to inhale dangerous quantities of fine and ultrafine particulate matter. Long-term
use may have a detrimental effect on brain health due to cerebral oxidative stress,
which is very similar to smoking-related oxidative stress.[28]
Even in small quantities, inhalation of nicotine results in local and systemic release
of catecholamine, which leads to increased heart rate, blood pressure, and heart contraction.
In addition, there is a marked decrease in cutaneous and coronary blood flow along
with increased skeleton muscle blood flow leading to reduced myocardial oxygen delivery,
contributing to myocardial ischemia and cardiovascular disease.[29]
Long-term nicotine inhalation promotes the release of basic fibroblast growth factor
while inhibiting indigenous production of transforming growth factor-β1 resulting
in increased endothelial cell proliferation due to increased mitogenic activity that
ultimately leads to atherosclerotic plaque formation that is further aggravated by
neovascularization stimulated by nicotine.[29],[30]
In addition, many of these vaping products are loaded with a solution containing known
carcinogenic effects when inhaled such as carbonyl compounds (formaldehyde, acetaldehyde,
acrolein, and o-methylbenzaldehyde), volatile organic compounds (toluene and p, m-xylene),
tobacco-specific nitrosamines, and metals (cadmium, nickel, and lead).[6],[8],[31],[32]
Although it is known that various potential carcinogens may already be present in
unregulated e-liquids, they are often equipped with uncontrolled and user-adjustable
heating elements that may further contribute to the development of other carcinogens,
such as formaldehyde-containing hemiacetals, due to high-temperature heating solutions.
It was shown in one of thein vitro studies that vapor produced by these vapor devices
causes DNA strand breaks and cell death independent of nicotine content.[33]
The MMWR released on November 8, 2019, reported that, when testing THC-containing
product samples collected by the Food and Drug Administration (FDA) and state public
health labs were analyzed, a number of additives were identified. They reported finding
potentially hazardous Vitamin E acetate from bronchoscopy and bronchoalveolar lavage
(BAL) of all patients suffering from E-cigarette, or vaping, product use-associated
lung injury (EVALI), which may be a potential additive related to the injury. Researchers
also suggested that although more than one compound or component could be a source
of lung injury, there is still insufficient evidence to rule out the association of
other toxicants with EVALI.[21]
Many of these EVALI patients reported having respiratory symptoms such as cough, chest
pain, and shortness of breath, while some reported gastrointestinal symptoms such
as abdominal pain, nausea, vomiting, and diarrhea with constitutional symptoms such
as fever chills and weight loss. Therefore, as suggested by a report published by
CDC on November 19, 2019, since EVALI patients may have symptoms similar to those
associated with influenza or other respiratory infections, it may be difficult to
distinguish EVALI from influenza or community-acquired pneumonia upon initial assessment,
and EVALI may co-occur with respiratory infections, thus making it difficult to identify
and treat.[34]
Diacetyl (2,3-butanedione), a very popular flavoring agent providing a buttery or
creamy flavor, has been shown to trigger an acute onset of bronchiolitis obliterans,
an irreversible pulmonary obstructive disease often referred to as “popcorn lung”
when used daily.[35],[36]
Eugenol (phenylpropene) and cinnamaldehyde (α, β-unsaturated aldehyde) are the main
components of clove oil, cinnamon-favored additives applied to the E-cigarette liquid
to obtain such blends of flavors, both of which are classified as asthma sensitizers.
Likewise, benzaldehyde is a recognized irritant to the mucous membranes of the respiratory
passages that are widely used to make cherry or fruit flavored and liquids.[36]
Some of the other flavoring agents that are known as Airway Irritants and Chemical
Sensitizers are diacetyl, acetoin, 2,3-pentanedione (buttery flavors), camphor and
cyclohexanone (minty flavors), benzaldehyde (cherry or almond flavors), cinnamaldehyde
(cinnamon flavors), cresol (leathery or medicinal flavors), butyraldehyde (chocolate
flavors), and isoamyl acetate that provides (banana flavor).
In a correspondence published by Butt et al. in 2019, histopathological findings showed patterns of acute lung injury, including
acute fibrinous pneumonitis, diffuse alveolar damage, or pneumonia, typically bronchiolocentric,
and accompanied by bronchiolitis. In the two cases where BAL fluid was available for
analysis, it was seen that it contained abundant foamy macrophages. Two patients with
diffuse alveolar damage suffered death despite the effective treatment.[37]
Steps taken to curb the practice in globally
On May 21, 2003, an appreciative step was taken by the WHO by formulating a treaty,
i.e., Framework Convention on Tobacco Control (FCTC) and had urged all its signatories
to adopt treaty and consider banning or restricting E-cigarettes to reduce the potential
health risks associated with them which came into force on February 27, 2005.[38]
Thereafter, several researchers advocated that there is insufficient scientific evidence
to prove the safe use of ENDS and vaporizing devices and their beneficial contribution
to the cessation of tobacco smoking habit, so it is pointless to mark it as safe and
legal. Currently, more than 30 countries, including Argentina, Brazil, Brunei, Cambodia,
Egypt, Indonesia, Jordan, Lebanon, the Philippines, Malaysia, Mexico, Oman, Qatar,
Singapore, Taiwan, Thailand, Turkey, the United Arab Emirates, Uruguay, and Vietnam,
have imposed a ban on the manufacturing, import or sales of E-cigarettes or vaping
devices in some or the other ways, while the countries which had placed restrictions
on manufacturing, import or sales of E-cigarettes or vaping devices are Australia,
Canada, Norway, Japan, United States, and Hong Kong.[10],[39]
The U.S. FDA via FDA voice on September 10, 2019, states that ENDS such as E-cigarettes,
cigars, pipe tobacco, and hookah tobacco already on the market as of August 8, 2016,
must submit a premarket authorization application to FDA by May 12, 2020, at the latest.
However, on the other hand, any E-cigarettes or other ENDS products that have not
been marketed as of August 8, 2016, need to receive marketing authorization from the
FDA before the product can enter the market or are subject to enforcement. FDA is
actively monitoring ENDS and vaping products that use any flavored cartridge or refills,
products whose manufacturer failed or failing to take adequate measures to prevent
minors' access, and products that are targeted to minors or that may be unlawfully
on the market and has released letters to about 90 companies seeking information on
more than 110 brands to assess whether those items are being inappropriately sold.
Moreover, as of now, the FDA had issued warning letters to six companies notifying
them of the need to remove from the market a combined 71 products.[40],[41]
As part of WHO, FCTC India was not behind, and Punjab and Haryana were India's first
states to ban E-cigarettes or ENDS under the Poisons Act, 1919, which not only promoted
the significant decrease of practice across the country, but also helped raise awareness
of ill effects.[42] Indians have taken a very appreciative measure by formulating an ordinance on the
use of these vaping tools, known as the “Prohibition of Electronic Cigarettes (Production,
Manufacture, Import, Export, Transport, Purchase, Distribution, Storage and Advertising)
Regulation, 2019.” This Act prohibits the manufacture, trade, and advertising of e-cigarettes
in India, and any person found to be in violation of this Act shall be punished by
imprisonment of up to one year or a fine of up to one lakh rupee or both. This also
states that no person is permitted to use any place to store any stock of E-cigarettes
or vaping products, and if someone is found to be in violation, he will be punished
with up to 6 months' imprisonment or a fine of up to Rs. 50,000 or both.[42]
