COVID-19: How Could Vaping Affect Infection Risk and Symptom Severity?


The use of e-cigarettes, or vaping, causes serious damage to the lungs. After the novel coronavirus responsible for the respiratory disease COVID-19 emerged last year, there have been ongoing concerns about how vaping might impact risk of infection and severity of symptoms.

Some evidence shows an increased risk of COVID-19 among those who vape. Research also shows a higher COVID-19 mortality rate in men compared to women, and men are more likely to vape than women. However, there is no evidence to link these two observations.

New research from Jefferson sheds light on this by showing that exposure to e-cigarette vapor increases levels of the coronavirus receptor in the lungs of male mice, particularly when nicotine is present in the vapor. This could make it easier for the virus to infect. The findings were published in Journal of Investigative Medicine on April 29.

Using the spike-like protein on its surface like a key, the novel coronavirus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor found in the lining of our airways, and unlocks its path into our lung cells.

It’s been shown that cigarette smokers have higher levels of ACE-2 in their lungs and that smoking is a known risk factor for developing lung disease and infection,” says Pawan Sharma, Ph.D. and co-senior author of the study. “We wanted to see if a similar effect is seen with e-cigarettes or vaping, and whether any effects observed are different between male and females.”

The researchers housed female or male mice in a box attached to an automated system that delivered precisely controlled amounts of e-cigarette vapor, with or without nicotine, for 30 min, twice a day for 21 days. Compared to control mice that breathed room air, mice exposed to e-cigarette vapor had inflammation of their lung tissue and reduced lung function, confirming the dangers of vaping.

These effects were observed whether or not nicotine was added to the vapor, pointing to the inherently harmful nature of the chemicals found in e-cigarette vapor.

There was also an increase in the levels of the ACE-2 receptor in the lungs of vapor-exposed mice, male and female. Though this was not tested in the current study, higher levels of ACE-2 receptor could make it easier for the virus to enter the airways, increasing susceptibility to infection.

Interestingly, the presence of nicotine in the vapor further enhanced the increase in ACE-2 specifically in male mice.

The researchers are the first to demonstrate this potential sex-difference in the effect of vaping and nicotine exposure on ACE-2 levels in vivo. Though further research is needed to understand the complexity of risk factors for COVID-19, this result sheds light on important physiological differences that make one sex potentially more vulnerable.

“Our findings provide rationale for looking at the effect of vaping on ACE-2 levels in the lungs of humans,” says Dr. Sharma. “If a similar induction of ACE-2 is seen, it provides further evidence for vaping being a risk factor for COVID-19 and can help us understand how to prevent and mitigate infection in this population.”

COVID-19 and smoking/vaping

Though there is no direct evidence suggesting the increased susceptibility of smokers/vapers towards COVID-19 infection, various indirect studies prove that this population is at a higher risk to show severe symptoms and need mechanical ventilation as compared to non-smokers.

While analyzing the factors associated with severe disease outcomes in patients admitted to three tertiary hospitals in the Wuhan district, Liu et al (2020), showed that patients with a history of smoking were significantly higher in the progression group (with severe symptoms) than improvement (patients showing recovery) group (27.3% vs 3%) [4].

Again, in Wuhan, the epicenter of the disease in China, the case fatality rates amongst males (2.8%) has been reported to be higher than females (1.7%). Similar trends have been reported in other hard-hit regions like Italy and Spain, where out of several cases of COVID-19 infection, 58% were men.

Furthermore, men are more prone to succumb to the disease with fatalities (72%) [7]. One of the prime reasons for this has been speculated to be higher rate of smoking amongst men (52.1%) than women (2.7%) [8, 9]. Further, smokers are more prone to contract respiratory infections with higher rates of influenza, tuberculosis and pneumonia than non-smokers [9]; which supports the rationale of considering this population group to be at high risk.

Role of epithelial cells and inflammatory response: ACE2 and TMPSSR2

The study of the pathogenesis of COVID-19 points towards the dangers of contracting a disease and eventual complications amongst smokers/vapers due to delayed clearance of virus.

SARS-CoV2 belongs to the family of Coronavirus that obtains its name from the crown-like appearance on imaging. This feature is attributed to a glycosylated cell surface spike (S) protein with two functional domains-S1 and S2. ACE2 has been shown to be the site of host-cell entry for the SARS-CoV2 virus.

The S2 domain of the viral spiked envelope has a high affinity to the ACE2 receptor on the lung epithelium. Interestingly, ACE2 expression has been found to be high amongst smokers (possibly including e-cigarette vapers) and individuals on ACE blockers (patients with hypertension and diabetes), thus rendering them susceptible to the disease [9].

Furthermore, there are more circulating ACE2 in men which provides evidence for gender-based variations in disease severity [10]. ACE2 may be highly expressed in germ cells i.e. more in men vs women. It is likely that ACE2 is related to nicotinic acetylcholine receptors (nAChRs), particularly alpha7nAChR receptor further supporting that smoking/vaping (nicotine) status might be crucial in the pathophysiology of COVID-19 [11].

The ACE2 receptors (developmentally regulated) are abundant on the lung epithelium, specifically the type II pneumocytes, goblet, nasal epithelial/ciliated and oral mucosal cells [12–14]. A recent study has suggested a role of interferon-stimulated response of SARS-CoV-2 entry via ACE2 and TMPSSR2 protease [15].

Studies suggest that ACE2 expression is upregulated in the small airway epithelia of smokers and patients with smoking-associated pathologies like COPD and IPF [15, 16]. Though not tested, vaping (nicotine) may have similar effects, thus making this group more prone to be affected by the disease.

While ACE2 is important for host entry, the host cellular proteases function to activate the viral particle thus facilitating the viral engulfment. In this respect, TMPRSS2 protease is of importance in that ACE2 employs the cellular serine protease TMPRSS2 for S protein priming and host-cell entry [17].

Studies show that the SARS-CoV-2 entry-associated protease, TMPRSS2, is highly expressed in the nasal ciliated and goblet cells. Single cell RNA sequencing analyses of multiple tissues has shown that only a small subset of ACE2+ cells express TMPRSS2, thus suggesting that other proteases might play similar role. In this respect, Cathepsin B/L has also been shown to be of importance [14].

Interestingly, in vivo and clinical data show that cigarette smoke results in increased expression of Cathepsin B, which raises the possibility of increased susceptibility towards COVID-19 infection amongst smokers [16]. Another cellular protease, furin, cleaves the S1/S2 site of the spike protein of SARS-CoV-2 which is essential for the cell-cell transmission of the virus [18]. Smoking can decrease the effectiveness of serine protease inhibitors (serpins) that control the “furin” activity [19, 20]. Also, evidence suggests that serpin-deficiency attributes to increased viral (Influenza A) susceptibility in C57BL/6 mice [21]. Taken together, these findings point toward increased possibility of COVID-19 contraction amongst smokers/vapers.

Smoking and vaping also affect the tight barrier junction leading to increased epithelial permeability (lung leakiness). In fact, the structural changes due to cigarette smoking including; increased mucosal permeability, impaired muco-ciliary clearance, peribronchiolar inflammation and fibrosis (airway remodeling); could pose little to no resistance towards viral entry amongst smokers as shown in Fig. 1 [22].

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Fig. 1
Factors responsible for higher susceptibility of smokers/vapers against COVID-19. In normal individuals, the muco-ciliary epithelium and the mucous layers act as the first line of defence against the foreign pathogen (in this case SARS-CoV2). On smoking, this layer is damaged and so is the flow of the peri-ciliary fluid (mucous; indicated by arrows) which makes them more prone to infections. Smokers are also shown to have higher surface expression of ACE2 receptors (binding sites for SARS-CoV2) which allows the entry of pathogens into the host cell and protects the virus against the host surveillance. In normal individuals, the viral infection could be checked by the, (a) cytokine release from the type II pneumocytes, goblet, nasal epithelial/ciliated and oral mucosal cells and (b) immune cell (macrophages, neutrophils and lymphocytes) infiltration at the site of infection, to contain further spread. Smoking weakens the immune system enabling easy entry into the host cell, rapid multiplication of the virus followed by hyperinflammatory response triggered by ‘cytokine storm’ in the host body eventually leading to damaged lung tissue

Smoking/vaping causes oxidative stress and inflammatory responses in the lung which make smokers/vapers more susceptible to bacterial/viral infections [23–25]. Oxidative stress has adverse effects on the epithelial permeability and ACE2 expression, which may have serious implications in smokers/vapers [26, 27]. ACE2 exists in multiple isoforms with predominance of 90 kDa in the lungs and 120 kDa in kidneys [26].

It can be post-translationally modified by oxidants/carbonyls. Hence ROS generation due to smoking or vaping could adversely affect the ACE2/Angiotensin (1-7) /Mas axis [28]. Likewise, the oxidative stress due to cigarette smoke or e-cig aerosols results in epithelial barrier dysfunction which increases the membrane permeability and susceptibility towards viral/bacterial infections [28–30] (Fig. ​(Fig.1).1).

Covid-19 related genes, such as ACE2 and TMPRSS2 are affected in patients with asthma and are linked with inhaled corticosteroids [31]. This suggests that steroid-resistance seen by smoking in patients with COPD may have ramifications in COVID-19 susceptibility via ACE2 and TMPRSS2.

The most common complication due to SARS-CoV2 infection -Acute respiratory Distress syndrome (ARDS) – is a result of the ‘cytokine storm’ caused due to uncontrolled release of proinflammatory cytokines/chemokines by effector immune cells [32]. These pro-inflammatory mediators include IP-10, MCP-3, HGF, MIG, MIP-1α, IL-6, TNF-α, IFN-γ, IL-2, IL-7 and GM-CSF. In fact, while studying the transcriptional response towards infection using in vitro model, Blanco-Melo et al. found that SARS-CoV-2 infection in normal human bronchial epithelial cells results in reduced IFN-mediated responses along with heightened production of cytokines/chemokines that enables sustained viral replication [33].

Of interest, the expression of IL-6, TNF-α and other pro-inflammatory cytokines is upregulated in chronic smoking condition and so is the low expression levels of perforin and granzyme B- the two major effector proteins of natural killer (NK) and CD8 T cells [34]. Furthermore, lung autopsy of COVID-19 patients demonstrated neutrophil infiltration in pulmonary capillaries with fibrin deposition and extravasation of neutrophils into the alveolar space [35].

These observations point towards formation of Neutrophil Extracellular Traps (NETs) that may contribute to organ damage, lung remodelling, and mortality in COVID-19 patients. Evidence suggests that smoking affects neutrophil trafficking, NET formation, humoral and cell-mediated immune responses as shown in Fig. ​Fig.1.1. This could eventually lead to susceptibility towards ARDS development further augmenting the disease pathogenesis [35].

In this respect, it is important to mention about the susceptibilities of old smokers/vapers with comorbidities like COPD or IPF. It is known that older patients are more likely to develop pneumonia and respiratory failure due to SARS-CoV-2 infection, which suggests that cellular senescence might play an important role in the disease pathogenesis for COVID-19 [35].

It has been shown that a lowered expression of regulatory proteins like TRIB3 (negative regulator of NF-kappaB signaling) and SIRT1 (anti-aging and anti-inflammatory) amongst aged/older individuals, rendering them more prone to infection [36, 37]. Interestingly, our group showed that the SIRT1 expression is lowered in the lungs of smokers and COPD patients [37].

This highlights the possible involvement of SIRT1 and senescence-associated pathways in modulating SARS-CoV-2 pathogenesis in humans, thereby putting smokers/vapers at a higher risk of contracting an infection. Further, gene tribbles homolog 3 (TRIB3) is decreased during aging in male, and its protein interacts with nucleocapsid protein and RNA dependent polymerase of the virus [36].

The same could be the case with vapers who use e-cigarettes. Considering the rapidly increasing cases of vaping-induced lung pathologies, CDC has coined the term ‘e-cigarette or vaping product use associated lung injury (EVALI)’ to characterize conditions like acute lung injury, acute fibrinous pneumonitis, diffuse alveolar damage, or pneumonia accompanied by bronchiolitis.

Such insults increase the possible risk amongst vapers. In contrast, e-liquid constituents interact with the pulmonary surfactants, i.e. dipalmitoylphosphatidylcholine (DPPC), which could lead to induction of innate immune responses in ENDS users. The lipid dysregulation in the airways of ENDS user could render them more prone to the COVID-19 infection [38]. Furthermore, it is possible that EVALI and COVID-19 have similarities as both develop interstitial pneumonia leading to ARDS [38].

In fact, both EVALI and COVID-19 are characterized by decreased arterial oxygen saturation and bilateral pneumonia, thus making it difficult in detecting the two conditions [39, 40] Also, considering that many people with COVID-19 infection do not show any symptom of the disease, there is a likelihood of the vapers with EVALI being the asymptomatic carriers of COVID-19 [41]. Further, research is required to test the hypothesis that COVID-19 and vaping are associated with severe EVALI. Similar to EVALI, patients with COVID-19 showed elevated levels of several cytokines (CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B) in BALF and peripheral blood mononuclear cells [42].

It is also possible that exosomes/extracellular vesicles released by lung epithelial cells may trap SARS-CoV2 and their respective miRNA/RNA, which would trigger a cytokine storm to other neighboring cells in response to smoking [43]. ACE2 positive cells may play a role in viral entry [44]. Exosomes may be pro-inflammatory or can be exploited pharmacologically in lung diseases [45, 46].

reference link :

More information: Vegi Naidu et al, Sex differences in the induction of angiotensin converting enzyme 2 (ACE-2) in mouse lungs after e-cigarette vapor exposure and its relevance to COVID-19, Journal of Investigative Medicine (2021). DOI: 10.1136/jim-2020-001768


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