The Association of Tobacco Smoking, Second-hand Smoke, and Novel Tobacco Products With COVID-19 Severity and Mortality in Italy: Results From the COSMO-IT Study.

BACKGROUND: Despite the robust evidence of an excess risk of coronavirus disease 2019 (COVID-19) severity and mortality in ever smokers, the debate on the role of current and ex-smokers on COVID-19 progression remains open. Limited or no data are available on the link between electronic cigarette (e-cigarette), heated tobacco product (HTP) and second-hand smoke (SHS) exposure and COVID-19 progression. To fill this knowledge gap, we undertook the COvid19 and SMOking in ITaly (COSMO-IT) study. METHODS: A multi-centre longitudinal study was conducted in 2020-2021 in 24 Italian hospitals on a total of 1,820 laboratory-confirmed COVID-19 patients. We estimated multivariable odds ratios (OR) and 95% confidence intervals (CI) to quantify the association between smoking-related behaviours (ie, smoking status, e-cigarette and HTP use, and SHS exposure) and COVID-19 severity (composite outcome: intubation, intensive care unit admission and death) and mortality. RESULTS: Compared to never smokers, current smokers had an increased risk of COVID-19 mortality (OR 2.17; 95% CI, 1.06-4.41). E-cigarette use was non-significantly associated to an increased risk of COVID-19 severity (OR 1.60; 95% CI, 0.96-2.67). An increased risk of mortality was observed for exposure to SHS among non-smokers (OR 1.67; 95% CI, 1.04-2.68), the risk being particularly evident for exposures of ≥6 hours/day (OR 1.99; 95% CI, 1.15-3.44). CONCLUSION: This multicentric study from Italy shows a dismal COVID-19 progression in current smokers and, for the first time, in SHS exposed non-smokers. These data represent an additional reason to strengthen and enforce effective tobacco control measures and to support smokers in quitting.

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.

Preventive Measures against Pandemics from the Beginning of Civilization to Nowadays-How Everything Has Remained the Same over the Millennia.

As of 27 March 2022, the ß-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 487 million individuals worldwide, causing more than 6.14 million deaths. SARS-CoV-2 spreads through close contact, causing the coronavirus disease 2019 (COVID-19); thus, emergency lockdowns have been implemented worldwide to avoid its spread. COVID-19 is not the first infectious disease that humankind has had to face during its history. Indeed, humans have recurrently been threatened by several emerging pathogens that killed a substantial fraction of the population. Historical sources document that as early as between the 10th and the 6th centuries BCE, the authorities prescribed physical-social isolation, physical distancing, and quarantine of the infected subjects until the end of the disease, measures that strongly resemble containment measures taken nowadays. In this review, we show a historical and literary overview of different epidemic diseases and how the recommendations in the pre-vaccine era were, and still are, effective in containing the contagion.

Long Lasting Cellular Immune Response Induced by mRNA Vaccination: Implication for Prevention Strategies.

As the COVID19 pandemic continues to spread and vaccinations are administered throughout the world at different rates and with different strategies, understanding the multiple aspects of the immune response to vaccinations is required to define more efficient vaccination strategies. To date, the duration of protection induced by COVID19 vaccines is still matter of debate. To assess whether 2-doses vaccination with BNT162b2 mRNA COVID-19 vaccine was sufficient to induce a persistent specific cellular immune response, we evaluated the presence of SARS-COV2 Spike-specific B and T lymphocytes in 28 healthcare workers 1 and 7 months after completing the vaccination cycle. The results showed that at 7 months after second dose a population of Spike-specific B lymphocytes was still present in 86% of the immunized subjects, with a higher frequency when compared to not-immunized controls (0.38% ± 0.07 vs 0.13% ± 0.03, p<0.001). Similarly, specific CD4+ and CD8+ T lymphocytes, able to respond in vitro to stimulation with Spike derived peptides, were found at 7 months. These results confirm that vaccination with BNT162b2 is able to induce a specific immune response, potentially long lasting, and could be helpful in defining future vaccination strategies.

Nicotine upregulates ACE2 expression and increases competence for SARS-CoV-2 in human pneumocytes.

The coronavirus disease 2019 (COVID-19) pandemic has a variable degree of severity according to underlying comorbidities and life-style. Several research groups have reported an association between cigarette smoking and increased severity of COVID-19. The exact mechanism of action is largely unclear. We exposed low angiotensin-converting enzyme 2 (ACE2)-expressing human pulmonary adenocarcinoma A549 epithelial cells to nicotine and assessed ACE2 expression at different times. We further used the nicotine-exposed cells in a virus neutralisation assay. Nicotine exposure induces rapid and long-lasting increases in gene and protein expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2, which in turn translates into increased competence for SARS-CoV-2 replication and cytopathic effect. These findings show that nicotine worsens SARS-CoV-2 pulmonary infection and have implications for public health policies.

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.

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-β-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 and the role of smoking: the protocol of the multicentric prospective study COSMO-IT (COvid19 and SMOking in ITaly).

The emergency caused by Covid-19 pandemic raised interest in studying lifestyles and comorbidities as important determinants of poor Covid-19 prognosis. Data on tobacco smoking, alcohol consumption and obesity are still limited, while no data are available on the role of e-cigarettes and heated tobacco products (HTP). To clarify the role of tobacco smoking and other lifestyle habits on COVID-19 severity and progression, we designed a longitudinal observational study titled COvid19 and SMOking in ITaly (COSMO-IT). About 30 Italian hospitals in North, Centre and South of Italy joined the study. Its main aims are: 1) to quantify the role of tobacco smoking and smoking cessation on the severity and progression of COVID-19 in hospitalized patients; 2) to compare smoking prevalence and severity of the disease in relation to smoking in hospitalized COVID-19 patients versus patients treated at home; 3) to quantify the association between other lifestyle factors, such as e-cigarette and HTP use, alcohol and obesity and the risk of unfavourable COVID-19 outcomes. Socio-demographic, lifestyle and medical history information will be gathered for around 3000 hospitalized and 700-1000 home-isolated, laboratory-confirmed, COVID-19 patients. Given the current absence of a vaccine against SARS-COV-2 and the lack of a specific treatment for -COVID-19, prevention strategies are of extreme importance. This project, designed to highly contribute to the international scientific debate on the role of avoidable lifestyle habits on COVID-19 severity, will provide valuable epidemiological data in order to support important recommendations to prevent COVID-19 incidence, progression and mortality.