Possible role of caffeine in nicotine use onset among early adolescents: Evidence from the Young Mountaineer Health Study Cohort.

BACKGROUND: Preventing nicotine use onset among children and youth is an important public health goal. One possible contributor that has received little empirical investigation is caffeine use. The goal of this study was to examine the possible contribution of caffeine to nicotine onset during early adolescence. METHODS: We used data from the Young Mountaineer Health Study Cohort. Survey data were collected from 1,349 (response rate: 80.7%) 6th grade students (mean age at baseline 11.5 years) in 20 middle schools in West Virginia during the fall of 2020 and spring of 2021. We limited our analyses to students reporting never having used any form of nicotine at baseline. Logistic regression was employed in analyses. RESULTS: Approximately 8% of participants reported having used nicotine at least once between baseline and the follow-up, and 4.7% reported solely using electronic nicotine delivery systems (ENDS) and no other forms of nicotine. In multivariable analyses, we controlled for many environmental, social, and behavioral variables known to influence nicotine use such as alcohol use, peer substance use, and perceived access to nicotine. We formulated our main independent variable, caffeine consumption, as continuous deciles. Any nicotine use, as well as ENDS use only at follow-up, were modeled as dependent variables. Caffeine was significantly associated with nicotine use in both models with ORs of 1.15 (1.04-1.27) and 1.13 (1.00-1.28). CONCLUSIONS: Caffeine consumption among 6th grade non-nicotine users was associated with nicotine use at approximately 6-months follow-up.

The association between risk perceptions, anxiety, and self-reported changes in tobacco and nicotine product use due to COVID-19 in May-June 2020 in Israel.

BACKGROUND: Early in the COVID-19 pandemic, reports about a possible protective effect of nicotine on COVID-19 conflicted with messaging by public health organizations about increased risks of COVID-19 due to smoking. The ambiguous information the public received, combined with COVID-19-induced anxiety, may have led to changes in tobacco or other nicotine product use. This study examined changes in use of combustible cigarettes (CCs), nargila (hookah/waterpipe), e-cigarettes, and IQOS and home-smoking behaviors. We also assessed COVID-19 related anxiety and perceptions regarding changes in risk of COVID-19 severity due to smoking. METHODS: We used cross-sectional data from a population telephone survey that was conducted in Israel in the early phase of the COVID-19 pandemic (May-June 2020) and included 420 adult (age 18+) individuals who reported having ever used CCs (n = 391), nargila (n = 193), and/or electronic cigarettes (e-cigarettes)/heated tobacco products (e.g., IQOS) (n = 52). Respondents were asked about the effect that COVID-19 had on their nicotine product use (quit/reduced use, no change, increased use). We assessed changes in product use, risk perceptions, and anxiety using adjusted multinomial logistic regression analyses. RESULTS: Most respondents did not change their frequency of product use (CCs: 81.0%, nargila: 88.2%, e-cigarettes/IQOS: 96.8%). A small percentage either decreased use (CCs: 7.2%, nargila: 3.2%, e-cigarettes/IQOS:2.4%) or increased use (CCs:11.8%, nargila:8.6%, e-cigarettes/IQOS:+ 0.9%). 55.6% of respondents used a product in the home prior to COVID-19; but during the first lockdown COVID-19 period, a greater percentage increased (12.6%) than decreased (4.0%) their home use. Higher levels of anxiety due to COVID-19 were associated with increased home smoking (aOR = 1.59, 95% CI:1.04-2.42, p = 0.02). Many respondents believed that increased severity of COVID-19 illness was associated with CCs (62.0%) and e-cigarettes/vaping (45.3%), with uncertainty about the association being lower for CCs (20.5%) than for vaping (41.3%). CONCLUSIONS: While many respondents believed that nicotine product use (particularly CCs and e-cigarettes) was associated with increased risk of COVID-19 disease severity, the majority of users did not change their tobacco/nicotine use. The confusion about the relationship between tobacco use and COVID-19 calls for clear evidence-based messaging from governments. The association between home smoking and increased COVID-19-related stress suggests the need for campaigns and resources to prevent smoking in the home, particularly during times of stress.

Nicotine in Combination with SARS-CoV-2 Affects Cells Viability, Inflammatory Response and Ultrastructural Integrity.

The aims of our study are to: (i) investigate the ability of nicotine to modulate the expression level of inflammatory cytokines in A549 cells infected with SARS-CoV-2; (ii) elucidate the ultrastructural features caused by the combination nicotine+SARS-CoV-2; and (iii) demonstrate the mechanism of action. In this study, A549 cells pretreated with nicotine were either exposed to LPS or poly(I:C), or infected with SARS-CoV-2. Treated and untreated cells were analyzed for cytokine production, cytotoxicity, and ultrastructural modifications. Vero E6 cells were used as a positive reference. Cells pretreated with nicotine showed a decrease of IL6 and TNFα in A549 cells induced by LPS or poly(I:C). In contrast, cells exposed to SARS-CoV-2 showed a high increase of IL6, IL8, IL10 and TNFα, high cytopathic effects that were dose- and time-dependent, and profound ultrastructural modifications. These modifications were characterized by membrane ruptures and fragmentation, the swelling of cytosol and mitochondria, the release of cytoplasmic content in extracellular spaces (including osmiophilic granules), the fragmentation of endoplasmic reticulum, and chromatin disorganization. Nicotine increased SARS-CoV-2 cytopathic effects, elevating the levels of inflammatory cytokines, and inducing severe cellular damage, with features resembling pyroptosis and necroptosis. The protective role of nicotine in COVID-19 is definitively ruled out.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Electronic cigarette use and perceptions during COVID-19.

This study was designed to examine how the COVID-19 pandemic changed e-cigarette user habits and risk perceptions. A nationally distributed 52-item questionnaire assessed nicotine e-cigarette use, perceptions, COVID-19 diagnosis, demographic data, and vaping habits among respondents aged 16-96 years (n = 565). Questions were developed in-house to assess vaping habits of users and risk perceptions of nicotine containing e-cigarette users and non-users both before and during the COVID-19 pandemic. Seventy-six percent of non-users believed that e-cigarette use would lead to worse COVID-19 symptoms, compared to 40% of e-cigarette users (P < 0.001). Twenty-eight percent of non-users also believed that e-cigarette users were more likely to be infected with SARS-CoV-2, versus 11% of e-cigarette users (P < 0.001). Fifty-eight percent of e-cigarette users described themselves as making no change in their e-cigarette usage, 10% decreased e-cigarette use, and 32% increased e-cigarette use during the pandemic. Twenty-five percent of users switched to vaping non-socially during the pandemic (P < 0.001). Sixty-seven percent of e-cigarette users replied that they would decrease or stop vaping if diagnosed with COVID and 31% said they would continue (P < 0.001). These findings reveal there are large differences in risk perception of e-cigarette use between users and non-users. Additionally, our findings characterize the habits of e-cigarette users during the COVID-19 pandemic, revealing users report steady to increased use, more caution in social settings, and would reduce usage if diagnosed with COVID-19.

Increased nicotine vaping due to the COVID-19 pandemic among US young adults: Associations with nicotine dependence, vaping frequency, and reasons for use.

Previous research has not examined increased vaping because of the pandemic using a national sample of young adults (YAs), which is a critical gap because pandemic-related increases in vaping among YAs could have important implications for nicotine dependence, prolonged regular use, and using substances to cope with stress. We examined self-reported increased vaping attributed to the COVID-19 pandemic among YAs, and its associations with outcomes that have important implications for future nicotine use. Data came from the Monitoring the Future (MTF) Vaping Supplement. Participants were selected from a nationally representative sample of US 12th-graders who were surveyed at age 19 in fall 2020 (N = 1244). Cross-sectional analyses of the 2020 survey included YAs who vaped nicotine in the past year (35%; N = 440). Weighted descriptive analyses and logistic regression models examined self-reported pandemic-related increased vaping (vs. decreased vaping, or no change), and its associations with current nicotine dependence, vaping behavior, and reasons for vaping. Among YAs who vaped nicotine in the past year, 16.8% reported increased and 44.4% reported decreased vaping due to the pandemic, while 38.9% reported no change. Increased vaping (vs. decreased and/or no change) was significantly associated with nicotine dependence symptoms, current regular nicotine vaping, and vaping to relax, get high, and because of boredom. Self-reported increased vaping because of the pandemic was associated with increased risk for current nicotine dependence and frequent use. Increased vaping may have been a form of coping with pandemic-related stressors, which increases risk for future substance use problems.

Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects.

As an anti-inflammatory alkaloid, nicotine plays dual roles in treating diseases. Here we reviewed the anti-inflammatory and pro-inflammatory effects of nicotine on inflammatory diseases, including inflammatory bowel disease, arthritis, multiple sclerosis, sepsis, endotoxemia, myocarditis, oral/skin/muscle inflammation, etc., mainly concerning the administration methods, different models, therapeutic concentration and duration, and relevant organs and tissues. According to the data analysis from recent studies in the past 20 years, nicotine exerts much more anti-inflammatory effects than pro-inflammatory ones, especially in ulcerative colitis, arthritis, sepsis, and endotoxemia. On the other hand, in oral inflammation, nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity. We also carefully analyzed the nicotine dosage to determine its safe and effective range. Furthermore, we summarized the molecular mechanism of nicotine in these inflammatory diseases through regulating immune cells, immune factors, and the vagus and acetylcholinergic anti-inflammatory pathways. By balancing the "beneficial" and "harmful" effects of nicotine, it is meaningful to explore the effective medical value of nicotine and open up new horizons for remedying acute and chronic inflammation in humans.

Association of Health Status and Nicotine Consumption with SARS-CoV-2 positivity rates.

BACKGROUND: Much of what is known about COVID-19 risk factors comes from patients with serious symptoms who test positive. While risk factors for hospitalization or death include chronic conditions and smoking; less is known about how health status or nicotine consumption is associated with risk of SARS-CoV-2 infection among individuals who do not present clinically. METHODS: Two community-based population samples (including individuals randomly and nonrandomly selected for statewide testing, n = 8214) underwent SARS-CoV-2 testing in nonclinical settings. Each participant was tested for current (viral PCR) and past (antibody) infection in either April or June of 2020. Before testing, participants provided demographic information and self-reported health status and nicotine and tobacco behaviors (smoking, chewing, vaping/e-cigarettes). Using descriptive statistics and a bivariate logistic regression model, we examined the association between health status and use of tobacco or nicotine with SARS-CoV-2 positivity on either PCR or antibody tests. RESULTS: Compared to people with self-identified "excellent" or very good health status, those reporting "good" or "fair" health status had a higher risk of past or current infections. Positive smoking status was inversely associated with SARS-CoV-2 infection. Chewing tobacco was associated with infection and the use of vaping/e-cigarettes was not associated with infection. CONCLUSIONS: In a statewide, community-based population drawn for SARS-CoV-2 testing, we find that overall health status was associated with infection rates. Unlike in studies of COVID-19 patients, smoking status was inversely associated with SARS-CoV-2 positivity. More research is needed to further understand the nature of this relationship.

SARS-Co-V2 infection in never, former, and current tobacco/nicotine users: a cohort study of 4040 Egyptian healthcare workers.

BACKGROUND: Smoking negatively impacts COVID-19 severity and adverse outcomes. Evidence on whether smoking is associated with SARS-Co-V2 infection and having a positive test is scarce, particularly from low-and middle-income countries, where most of the world's billion smokers live. The inconsistency in relevant findings calls for study designs and analyses to account for possible confounders including background characteristics and pre-existing co-morbidities, to disentangle the specific effect of smoking. In healthcare workers (HCWs) the frequency of exposure to COVID-19 cases adds another layer of risk that was not factored in previous studies. We examined the association of HCWs' tobacco/nicotine use (never, former, and current use) with having a positive SARS-Co-V2 test result and symptoms suggestive of infection, accounting for demographics, exposures, and co-morbidities. METHODS: A prospective cohort study of 4040 healthcare workers with baseline and follow-up screening took place during April-June 2020 in 12 healthcare facilities in Cairo, Egypt. Data on demographics, tobacco/nicotine use (manufactured or roll-your-own cigarettes, waterpipe tobacco, and electronic devices), co-morbidities, symptoms, exposures, and SARS-Co-V2 investigations were analyzed. Multinomial and multivariable logistic regression analyses were performed. RESULTS: Overall, 270/4040 (6.7, 95%CI: 5.9-7.5) had positive SARS-CoV-2 tests, 479 (11.9%) were current and 79 (2.0%) were former tobacco/nicotine users. The proportion of positive tests was 7.0% (243/3482, 95%CI: 6.1-7.8) among never, 5.1% (4/79, 95%CI: 0.1-10.0) among former, and 4.8% (23/479, 95%CI: 2.9-6.7) among current users. HCWs' SARS-CoV-2 test results did not vary significantly by single/multiple or daily/non-daily tobacco/nicotine use. Compared to never users, former users were more likely to self-report a pre-existing medical condition (ORadjusted1.87, 95%CI: 1.05-3.33, p = 0.033), and to experience symptoms suggestive of COVID-19 (ORadjusted1.76, 95%CI: 1.07-2.90, p = 0.027). After adjustment, former (ORadjusted0.45, 95%CI: 0.11-1.89, p = 0.273) and current (ORadjusted0.65, 95%CI: 0.38-1.09, p = 0.101) tobacco/nicotine use was not associated with HCWs' SARS-CoV-2 positive test results. CONCLUSIONS: This is the first report on this association from low- and middle-income countries with high tobacco/nicotine use prevalence. In this HCW cohort, having a positive SARS-CoV-2 test was not associated with tobacco/nicotine use after accounting for demographics, exposures, and co-morbidities. Additional population-based studies could use such preliminary evidence to investigate this controversial association.

Transdermal nicotine in non-smokers: A systematic review to design COVID-19 clinical trials.

Recent data show an interaction between COVID-19 and nicotine and indicate the need for an assessment of transdermal nicotine use in non-smokers. Assessments have been conducted into the short-term cognitive effects of nicotine and into diseases such as Parkinson's, Tourette syndrome, ADHD or ulcerative colitis. METHODS: Analyses of nicotine administration protocols and safety were conducted after reviewing Medline and Science Direct databases performing a search using the words [transdermal nicotine] AND [non-smoker] AND selected diseases. RESULTS: Among 298 articles identified, there were 35 reviewed publications reporting on 33 studies of non-smokers receiving transdermal nicotine for >48hours. In the 16 randomized trials, 7 crossover, 1 case/control and 9 open studies patients received an initial nicotine dose of between 2.5mg and 15mg/day. In 22 studies, daily doses increased by 2 to 7 steps in 3 to 96 days until the dose was between 5mg and 105mg/day. The target nicotine dose was 19.06±20.89mg/day. The 987 non-smokers (534 never-smokers, 326 ex-smokers and 127 classified as "non-smokers") received or did not receive nicotine. The most common side-effects were nausea and skin itching. Forty-three (7.1%) non-smokers stopped treatment because of an adverse event of nicotine. No hospitalization related to nicotine side-effects were reported. CONCLUSION: Despite a relatively safe tolerance profile, transdermal nicotine therapy in non-smokers can only be used in clinical trials. There is a lack of formal assessment of the potential risk of developing a tobacco addiction. This review offers baseline data to set a transdermal nicotine protocol for non-smokers with a new purpose.

Nicotine Changes Airway Epithelial Phenotype and May Increase the SARS-COV-2 Infection Severity.

(1) Background: Nicotine is implicated in the SARS-COV-2 infection through activation of the α7-nAChR and over-expression of ACE2. Our objective was to clarify the role of nicotine in SARS-CoV-2 infection exploring its molecular and cellular activity. (2) Methods: HBEpC or si-mRNA-α7-HBEpC were treated for 1 h, 48 h or continuously with 10-7 M nicotine, a concentration mimicking human exposure to a cigarette. Cell viability and proliferation were evaluated by trypan blue dye exclusion and cell counting, migration by cell migration assay, senescence by SA-ß-Gal activity, and anchorage-independent growth by cloning in soft agar. Expression of Ki67, p53/phospho-p53, VEGF, EGFR/pEGFR, phospho-p38, intracellular Ca2+, ATP and EMT were evaluated by ELISA and/or Western blotting. (3) Results: nicotine induced through α7-nAChR (i) increase in cell viability, (ii) cell proliferation, (iii) Ki67 over-expression, (iv) phospho-p38 up-regulation, (v) EGFR/pEGFR over-expression, (vi) increase in basal Ca2+ concentration, (vii) reduction of ATP production, (viii) decreased level of p53/phospho-p53, (ix) delayed senescence, (x) VEGF increase, (xi) EMT and consequent (xii) enhanced migration, and (xiii) ability to grow independently of the substrate. (4) Conclusions: Based on our results and on evidence showing that nicotine potentiates viral infection, it is likely that nicotine is involved in SARS-CoV-2 infection and severity.

COVID-19 breakthroughs: separating fact from fiction.

The newly recognised coronavirus SARS-CoV-2, causative agent of coronavirus disease (COVID-19), has caused a pandemic with huge ramifications for human interactions around the globe. As expected, research efforts to understand the virus and curtail the disease are moving at a frantic pace alongside the spread of rumours, speculations and falsehoods. In this article, we aim to clarify the current scientific view behind several claims or controversies related to COVID-19. Starting with the origin of the virus, we then discuss the effect of ibuprofen and nicotine on the severity of the disease. We highlight the knowledge on fomites and SARS-CoV-2 and discuss the evidence and explications for a disproportionately stronger impact of COVID-19 on ethnic minorities, including a potential protective role for vitamin D. We further review what is known about the effects of SARS-CoV-2 infection in children, including their role in transmission of the disease, and conclude with the science on different mortality rates between different countries and whether this hints at the existence of more pathogenic cohorts of SARS-CoV-2.

Clinical implications of nicotine as an antimicrobial agent and immune modulator.

Nicotine is perhaps the most important and potent, pharmacologically active substance in tobacco products. This commentary examines the possible effects that nicotine has on microbial viability and also on the host's immune system as it responds to the indigenous microflora (the microbiome) due to nicotine-induced changes to the indigenous microbial environment and any associated antigenic stimulation / immunization that may occur. To our knowledge, the analysis of such profound microbiologic changes attributable to a tobacco-related product, such as nicotine, has not been fully explored in the context of its consequences on the viability of the microbiome/microbiota and on some of the host's basic physiologic processes, such as the immune response, and its possible association on the induction and persistence of certain immunologically related diseases. Future studies should be aimed at uncovering the molecular mechanisms involved in such interactions, especially in the context of manipulating them for therapeutic purposes.

Is nicotine exposure linked to cardiopulmonary vulnerability to COVID-19 in the general population?

The recent emergence of COVID-19 has resulted in a worldwide crisis, with large populations locked down and transportation links severed. While approximately 80% of infected individuals have minimal symptoms, around 15-20% need to be hospitalized, greatly stressing global healthcare systems. As of March 10, the death rate appears to be about 3.4%, although this number is highly stratified among different populations. Here, we focus on those individuals who have been exposed to nicotine prior to their exposure to the virus. We predict that these individuals are 'primed' to be at higher risk because nicotine can directly impact the putative receptor for the virus (ACE2) and lead to deleterious signaling in lung epithelial cells.