E-Cigarette Use: Device Market, Study Design, and Emerging Evidence of Biological Consequences.

Electronic cigarettes are frequently viewed as a safer alternative to conventional cigarettes; however, evidence to support this perspective has not materialized. Indeed, the current literature reports that electronic cigarette use is associated with both acute lung injury and subclinical dysfunction to the lung and vasculature that may result in pathology following chronic use. E-cigarettes can alter vascular dynamics, polarize innate immune populations towards a proinflammatory state, compromise barrier function in the pulmonary endothelium and epithelium, and promote pre-oncogenic phenomena. This review will summarize the variety of e-cigarette products available to users, discuss current challenges in e-cigarette study design, outline the range of pathologies occurring in cases of e-cigarette associated acute lung injury, highlight disease supporting tissue- and cellular-level changes resulting from e-cigarette exposure, and briefly examine how these changes may promote tumorigenesis. Continued research of the mechanisms by which e-cigarettes induce pathology benefit users and clinicians by resulting in increased regulation of vaping devices, informing treatments for emerging diseases e-cigarettes produce, and increasing public awareness to reduce e-cigarette use and the onset of preventable disease.

COVID-19: a pandemic converged with global tobacco epidemic and widespread vaping-state of the evidence.

This review highlights the convergence of three global health challenges at a crossroad where the pandemic of coronavirus disease 2019 (COVID-19) meets the tobacco epidemic and vaping. It begins with an overview of the current knowledge on the biology, pathophysiology and epidemiology of COVID-19. It then presents the state of smoking and vaping during the pandemic by summarizing the published data on prevalence, use patterns, product availability/accessibility, sales records and motivation to quit before and after the start of the pandemic. It highlights the state of evidence on the association of tobacco product use with COVID-19 infection and transmission rates, symptom severity and clinical outcomes. Also discussed are proposed biological mechanisms and behavioral factors that may modulate COVID-19 risk in tobacco product users. Furthermore, competing hypotheses on the protective effect of nicotine against COVID-19 as well as the claimed 'smokers' paradox' are discussed. Considerations and challenges of COVID-19 vaccination in tobacco product users are underscored. Collectively, the present data show an 'incomplete' but rapidly shaping picture on the association of tobacco product use and COVID-19 infection, disease course and clinical outcomes. Evidence is also growing on the mechanisms by which tobacco product use may contribute to COVID-19 pathophysiology. Although we await definitive conclusions on the relative risk of COVID-19 infection in tobacco product users, compelling data confirm that many comorbidities associated with/caused by smoking predispose to COVID-19 infection, severe disease and poor prognosis. Additionally, it is becoming increasing clear that should smokers get the disease, they are more likely to have serious health consequences.

Understanding potential mechanisms of harm: the drivers of electronic cigarette-induced changes in alveolar macrophages, neutrophils, and lung epithelial cells.

Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and initiation of chronic lung disease took decades to unpick so in vitro studies mimicking e-cigarette exposure aim to detect early indicators of harm. In response to e-cigarette exposure, alveolar macrophages adopt a proinflammatory phenotype of increased secretion of proinflammatory cytokines, reduction in phagocytosis, and efferocytosis and reactive oxygen species generation. These effects are largely driven by free radical exposure, changes in PI3K/Akt signaling pathways, nicotine-induced reduction in phagocytosis receptors, and impaired lipid homeostasis leading to a foam-like lipid-laden phenotype. Neutrophils exhibit disrupted chemotaxis and transmigration to chemokines, reduced phagocytosis and bacterial killing, and an increase in protease secretion without corresponding antiproteases in response to e-cigarette exposure. This is driven by an altered ability to respond and to polarize toward chemoattractants, an activation of the p38 MAPK signaling pathway and inability to assemble NADPH oxidase. E-cigarettes induce lung epithelial cells to display decreased ciliary beat frequency and ion channel conductance as well as changes in chemokine secretion and surface protein expression. Changes in gene expression, mitochondrial function, and signaling pathways have been demonstrated in lung epithelial cells to explain these changes. Many functional outputs of alveolar macrophages, neutrophils, and lung epithelial cells have not been fully explored in the context of e-cigarette exposure and the underlying driving mechanisms are poorly understood. This review discusses current evidence surrounding the effects of e-cigarettes on alveolar macrophages, neutrophils, and lung epithelial cells with particular focus on the cellular mechanisms of change.

Risk Factors and Medical Symptoms Associated With Electronic Vapor Product Use Among Adolescents and Young Adults.

The use of electronic vapor products (EVPs) has increased dramatically in the past decade. The objectives of our study were to examine the frequency of EVP use; to identify demographic characteristics, risk-taking behaviors, and beliefs about vaping; and to determine symptoms associated with EVPs among adolescents. A questionnaire addressing these objectives was administered to a convenience sample of subjects aged 12 to 23 years. Among 494 completed questionnaires, 80% of responders were considered experimenters/nonusers (never tried or tried one time) and 20% were considered frequent users (at least once a month). We identified demographic features and risk-taking behaviors associated with EVP use. In the previous 6 months, frequent users were more likely to report headache, cough, sleep disturbances, dehydration, weakness, racing heart, chest pain, and tremors. Our findings provide evidence to support efforts to decrease EVP use through screening, education, and preventative strategies.

A 16-Year-Old Boy With Cough and Fever in the Era of COVID-19.

A 16-year-old white boy with a history of chronic lung disease of prematurity, cough-variant asthma, and incidental lung nodules presented to the emergency center in spring 2020 with acute onset dry cough, shortness of breath, and fever. An initial history, gathered from his mother because of the patient's respiratory distress, revealed no recent travel. However, his mother is a health care worker at a hospital, and sick contacts included ongoing contact with a friend with cold-like symptoms. He had a variety of animals at home, including a dog, cats, fish, rodents, and reptiles. He had a history of vaping tobacco products >6 months ago. Fever and respiratory symptoms were associated with fatigue, chest tightness, abdominal pain, and myalgias. On examination, he was ill appearing and had tachycardia, tachypnea, borderline hypoxia with an oxygen saturation of 91% on room air, diminished breath sounds at the lung bases, and unremarkable abdominal examination results. A chest radiograph was consistent with the lung examination, revealing bilateral lower lobe hazy infiltrates. He showed initial improvement for 48 hours with antibiotics, intravenous fluid resuscitation, oxygen via nasal cannula, albuterol, and prednisone. Subsequently, he worsened with persistent high fever, increasing respiratory distress with pulmonary findings, and severe persistent epigastric pain, which added a layer of diagnostic complexity. As this patient's clinical course evolved and further history became available, pulmonary medicine and infectious diseases services were consulted to guide diagnostic evaluation and treatment of this patient early in the era of coronavirus disease 2019.

Cigarette smoke preparations, not electronic nicotine delivery system preparations, induce features of lung disease in a 3D lung repeat-dose model.

Cigarette smoking is a risk factor for several lung diseases, including chronic obstructive pulmonary disease, cardiovascular disease, and lung cancer. The potential health effects of chronic use of electronic nicotine delivery systems (ENDS) is unclear. This study utilized fully differentiated primary normal human bronchial epithelial (NHBE) cultures in a repeat-dose exposure to evaluate and compare the effect of combustible cigarette and ENDS preparations. We show that 1-h daily exposure of NHBE cultures over a 10-day period to combustible cigarette whole smoke-conditioned media (WS-CM) increased expression of oxidative stress markers, cell proliferation, airway remodeling, and cellular transformation markers and decreased mucociliary function including ion channel function and airway surface liquid. Conversely, aerosol conditioned media (ACM) from ENDS with similar nicotine concentration (equivalent-nicotine units) as WS-CM and nicotine alone had no effect on those parameters. In conclusion, primary NHBE cultures in a repeat-dose exposure system represent a good model to assess the features of lung disease. This study also reveals that cigarette and ENDS preparations differentially elicit several key endpoints, some of which are potential biomarkers for lung cancer or chronic obstructive pulmonary disease (COPD).

Early Cardiovascular Risk in E-cigarette Users: the Potential Role of Metals.

PURPOSE OF REVIEW: Electronic cigarettes (e-cigs) are a source of metals. Epidemiologic and experimental evidence support that metals are toxic to the cardiovascular system. Little is known, however, about the role that e-cig metals may play as toxicants for the possible cardiovascular effects of e-cig use. The goal of this narrative review is to summarize the evidence on e-cig use and metal exposure and on e-cig use and cardiovascular toxicity and discuss the research needs. RECENT FINDINGS: In vitro studies show cytotoxicity and increased oxidative stress in myocardial cells and vascular endothelial cells exposed to e-liquids and e-cig aerosols, with effects partially reversed with antioxidant treatment. There is some evidence that the heating coil plays a role in cell toxicity. Mice exposed to e-cigs for several weeks showed higher levels of oxidative stress, inflammation, platelet activation, and thrombogenesis. Cross-over clinical experiments show e-cig use alters nitric oxide-mediated flow-mediated dilation, endothelial progenitor cells, and arterial stiffness. Cross-sectional evidence from large nationally representative samples in the USA support that e-cig use is associated with self-reported myocardial infarction. Smaller studies found associations of e-cig use with higher oxidized low-density protein and heart variability compared to healthy controls. Numerous studies have measured elevated levels of toxic metals in e-cig aerosols including lead, nickel, chromium, and manganese. Arsenic has been measured in some e-liquids. Several of these metals are well known to be cardiotoxic. Numerous studies show that e-cigs are a source of cardiotoxic metals. Experimental studies (in vitro, in vivo, and clinical studies) show acute toxicity of e-cigs to the vascular system. Studies of long-term toxicity in animals and humans are missing. Longitudinal studies with repeated measures of metal exposure and subclinical cardiovascular outcomes (e.g., coronary artery calcification) could contribute to determine the long-term cardiovascular effects of e-cigs and the potential role of metals in those effects.

Could E-cigarette vaping contribute to heart disease?

INTRODUCTION: E-cigarettes have become a controversial topic. While their benefits are questioned by the scientific community, a part of the medical profession is still supporting them as an effective harm reduction tool for smoking cessation. The impact of E-cigarettes on the cardiovascular system is still elusive. AREAS COVERED: We assessed results from animal, pre(clinical), and epidemiological studies to critically evaluate and synthesize evidence relevant to the cardiovascular effects of E-cigarettes. Animal studies have demonstrated that E-cigarette vapor exposure can cause endothelial and cardiac dysfunction. However, there have also been reports on the less harmful effects of E-cigarette vapor exposure in comparison to classical tobacco cigarettes. Measurements of flow-mediated dilation in acute human exposure settings have mostly demonstrated that E-cigarettes cause vascular endothelial dysfunction. Epidemiological studies have shown that E-cigarette use is associated with an increased risk for cardiovascular disease, although switching from classical tobacco cigarettes to E-cigarettes can have beneficial cardiovascular effects. Misinterpretation of scientific data by activists on either side is another problem. EXPERT OPINION: In conclusion, we need more and better (pre)clinical data comparing the health effects of E-cigarette vaping as compared with tobacco cigarette smoking, in order to counsel the legislation for better health policies.

Pathological findings in suspected cases of e-cigarette, or vaping, product use-associated lung injury (EVALI): a case series.

BACKGROUND: Since August, 2019, US public health officials have been investigating a national outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). A spectrum of histological patterns consistent with acute to subacute lung injury has been seen in biopsies; however, autopsy findings have not been systematically characterised. We describe the pathological findings in autopsy and biopsy tissues submitted to the US Centers for Disease Control and Prevention (CDC) for the evaluation of suspected EVALI. METHODS: Between Aug 1, 2019, and Nov 30, 2019, we examined lung biopsy (n=10 individuals) and autopsy (n=13 individuals) tissue samples received by the CDC, submitted by 16 US states, from individuals with: a history of e-cigarette, or vaping, product use; respiratory, gastrointestinal, or constitutional symptoms; and either pulmonary infiltrates or opacities on chest imaging, or sudden death from an undetermined cause. We also reviewed medical records, evaluated histopathology, and performed infectious disease testing when indicated by histopathology and clinical history. FINDINGS: 21 cases met surveillance case definitions for EVALI, with a further two cases of clinically suspected EVALI evaluated. All ten lung biopsies showed histological evidence of acute to subacute lung injury, including diffuse alveolar damage or organising pneumonia. These patterns were also seen in nine of 13 (69%) autopsy cases, most frequently diffuse alveolar damage (eight autopsies), but also acute and organising fibrinous pneumonia (one autopsy). Additional pulmonary pathology not necessarily consistent with EVALI was seen in the remaining autopsies, including bronchopneumonia, bronchoaspiration, and chronic interstitial lung disease. Three of the five autopsy cases with no evidence of, or a plausible alternative cause for acute lung injury, had been classified as confirmed or probable EVALI according to surveillance case definitions. INTERPRETATION: Acute to subacute lung injury patterns were seen in all ten biopsies and most autopsy lung tissues from individuals with suspected EVALI. Acute to subacute lung injury can have numerous causes; however, if it is identified in an individual with a history of e-cigarette, or vaping, product use, and no alternative cause is apparent, a diagnosis of EVALI should be strongly considered. A review of autopsy tissue pathology in suspected EVALI deaths can also identify alternative diagnoses, which can enhance the specificity of public health surveillance efforts. FUNDING: US Centers for Disease Control and Prevention.

Cytologic features of vaping-induced lung injury: A case report.

Vaping-induced lung injury is a recently recognized phenomenon owing to the rising popularity of e-cigarette use. A cluster of cases of varying severity, including six deaths, was recently reported in the United States by the Centers for Disease Control. The objective of this report is to highlight the cytologic features suggestive of vaping-induced lung injury. A 20-year-old previously healthy man presented with a 7-day history of progressively worsening respiratory symptoms including dyspnea on exertion, cough, and fever, with no improvement after initiating a course of antibiotics. No relevant travel or occupational history was reported, but patient endorsed daily use of e-cigarette with a fluid containing both tetrahydrocannabinol and nicotine. Radiographic studies demonstrated scattered areas of interlobular septal thickening and diffuse ground-glass opacities in both lungs. Laboratory tests for HIV and influenza were negative. Bronchoscopy and bronchoalveolar lavage were performed, with cytologic study showing clusters of benign bronchial cells and an increase in lipid-laden macrophages by Oil Red O stain. Patient was placed on steroid and steadily improved for the next 2 days. He was discharged on a steroid taper and follow-up with respiratory clinic. Case reports and series have shown a variety of lung injury patterns in previously healthy patients who are frequent users of e-cigarettes and among them features suggestive of lipoid pneumonia with increased lipid-laden macrophages. The clinical utility of this finding is still unclear.

Fourth generation e-cigarette vaping induces transient lung inflammation and gas exchange disturbances: results from two randomized clinical trials.

When heated by an electronic cigarette, propylene glycol and glycerol produce a nicotine-carrying-aerosol. This hygroscopic/hyperosmolar aerosol can deposit deep within the lung. Whether these deposits trigger local inflammation and disturb pulmonary gas exchanges is not known. The aim of this study was to assess the acute effects of high-wattage electronic cigarette vaping with or without nicotine on lung inflammation biomarkers, transcutaneous gas tensions, and pulmonary function tests in young and healthy tobacco smokers. Acute effects of vaping without nicotine on arterial blood gas tensions were also assessed in heavy smokers suspected of coronary artery disease. Using a single-blind within-subjects study design, 25 young tobacco smokers underwent three experimental sessions in random order: sham-vaping and vaping with and without nicotine at 60 W. Twenty heavy smokers were also exposed to sham-vaping (n = 10) or vaping without nicotine (n = 10) in an open-label, randomized parallel study. In the young tobacco smokers, compared with sham-vaping: 1) serum club cell protein-16 increased after vaping without nicotine (mean ± SE, -0.5 ± 0.2 vs. +1.1 ± 0.3 µg/l, P = 0.013) and vaping with nicotine (+1.2 ± 0.3 µg/l, P = 0.009); 2) transcutaneous oxygen tension decreased for 60 min after vaping without nicotine (nadir, -0.3 ± 1 vs. -15.3 ± 2.3 mmHg, P < 0.001) and for 80-min after vaping with nicotine (nadir, -19.6 ± 2.8 mmHg, P < 0.001). Compared with sham vaping, vaping without nicotine decreased arterial oxygen tension for 5 min in heavy-smoking patients (+5.4 ± 3.3 vs. -5.4 ± 1.9 mmHg, P = 0.012). Acute vaping of propylene glycol/glycerol aerosol at high wattage with or without nicotine induces airway epithelial injury and sustained decrement in transcutaneous oxygen tension in young tobacco smokers. Intense vaping conditions also transiently impair arterial oxygen tension in heavy smokers.

Acute pulmonary effects of aerosolized nicotine.

Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that is readily absorbed in blood. Nicotine-containing electronic cigarettes are promoted as a safe alternative to cigarette smoking. However, the isolated effects of inhaled nicotine are largely unknown. Here we report a novel rat model of aerosolized nicotine with a particle size (~1 µm) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid protein, IgM, lung wet-to-dry weight ratio, and high-mobility group box 1 (HMGB1) protein and decreased lung E-cadherin protein. Immunohistochemical analysis revealed congested blood vessels and increased neutrophil infiltration. Lung myeloperoxidase mRNA and protein increased in the nicotine-exposed rats. Complete blood counts also showed an increase in neutrophils, white blood cells, eosinophils, and basophils. Arterial blood gas measurements showed an increase in lactate. Lungs of nicotine-inhaling animals revealed increased mRNA levels of IL-1A and CXCL1. There was also an increase in IL-1α protein. In in vitro air-liquid interface cultures of airway epithelial cells, there was a dose dependent increase in HMGB1 release with nicotine treatment. Air-liquid cultures exposed to nicotine also resulted in a dose-dependent loss of barrier as measured by transepithelial electrical resistance and a decrease in E-cadherin expression. Nicotine also caused a dose-dependent increase in epithelial cell death and an increase in caspase-3/7 activities. These results show that the nicotine content of electronic cigarettes may have adverse pulmonary and systemic effects.

Changes in resting state functional brain connectivity and withdrawal symptoms are associated with acute electronic cigarette use.

Resting state functional brain connectivity (rsFC) may be an important neuromarker of smoking behavior. Prior research has shown, among cigarette smokers, that nicotine administration alters rsFC within frontal and parietal cortices involved in executive control, as well as striatal regions that drive reward processing. These changes in rsFC have been associated with reductions in withdrawal symptom severity. We currently have a limited understanding of how rsFC is affected by the use of electronic cigarettes (ecigs), an increasingly popular class of products, the members of which deliver nicotine with varying effectiveness. The current study used fMRI to determine the effects of ecig use on rsFC and withdrawal symptoms. Independent component, dual regression, and permutation analyses were conducted on rsFC collected from ecig users before and after an ecig use episode (n=9) that occurred after 14h of nicotine abstinence. Similar to the known effects of nicotine administration, ecig use decreased rsFC of two clusters in the right frontal pole and frontal medial cortex with an attentional control salience network, and decreased rsFC of five clusters in the left thalamus, insula, and brain stem with a reward network encompassing the striatum. Ecig use increased inverse coupling between the prefrontal reward network and the right frontoparietal executive control network. Reductions in craving and difficulty with concentration were correlated with decreases in coupling strength between reward and executive control networks. These preliminary results suggest that the effects of ecig use on rsFC are similar to those seen with nicotine administration in other forms. In order to gain insight into the addictive potential of ecigs, further research is needed to understand the neural influence of ecigs across the range of nicotine delivery within this class of products.