Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

E-cigarettes increase the risk of adenoma formation in murine colorectal cancer model.

Background: E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development. Methods: A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APCMin/+, leads to the development of colon adenomas within 16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2-hour exposures per day (1 hour of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA. Results: CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67). The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone. Conclusion: E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.

Dual Use of Cannabis with Tobacco Is Associated with Increased Sugary Food and Drink Intake in Young People.

Rates of cannabis initiation among teenagers and young adults are increasing. Further, the use of various forms of cannabis (smoked or vaped) with nicotine (dual use) is increasingly common among young people. The health effects of dual use are lesser known, particularly in the context of high-potency cannabis products and across different routes of administration, which is ominous in terms of predicting future health outcomes. There is a long history of cannabis use being associated with decreased activity and increased snacking, both of which could portend an increased risk of metabolic and cardiovascular disease, particularly when these habits begin during formative years. However, modern forms of cannabis may not have these same effects. Here, we assess whether cannabis use alone and dual use of cannabis with nicotine impact dietary and exercise habits in young people. An anonymous, social media-based survey was designed based on the UC San Diego Inhalant Questionnaire and published diet and exercise questionnaires. A total of 457 surveys were completed. Young sole cannabis users represented 29% of responders, 16% were dual users of cannabis and nicotine, and 55% were non-users of either drug. Although the sole use of cannabis was not associated with dietary or activity differences relative to non-users, dual users of cannabis and nicotine reported higher consumption of unhealthy sugars. This novel finding of dual use being associated with increased sugar intake in young people raises concerns for an increased risk of metabolic syndrome and cardiovascular disease in this population.

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.

Dual use of e-cigarettes with conventional tobacco is associated with increased sleep latency in cross-sectional Study.

The health effects of e-cigarettes remain relatively unknown, including their impact on sleep quality. We previously showed in a pilot study that females who smoke both conventional tobacco and vape e-cigarettes (dual users) had decreased sleep quality (measurement of how well an individual is sleeping) and increased sleep latency (amount of time to fall asleep), suggesting an influence by gender. Cough is also known to adversely impact sleep quality and may be caused by inhalant use. As a result, we undertook this study to assess the impact of e-cigarette, conventional tobacco, and dual use on sleep quality, sleep latency, cough, and drug use. Participants (n = 1198) were recruited through online surveys posted to social media sites with a monetary incentive. Participants were grouped by inhalant use, with 8% e-cigarette users, 12% conventional tobacco users, 30% dual users, and 51% non-smokers/non-vapers. Dual use of e-cigarettes and conventional tobacco was associated with increased sleep latency relative to non-smokers/non-vapers by multivariable linear regression (mean difference of 4.08; 95% CI: 1.12 to 7.05, raw p = 0.007, adjusted p = 0.042); however, dual usage was not significantly associated with sleep quality relative to non-smokers/non-vapers (mean difference 0.22, 95%CI: (-0.36, 0.80), raw p = 0.452, adjust p = 0.542). Dual use was also associated with a higher reporting of cough (p = 0.038), as well as increased marijuana (p < 0.001) and cocaine (p < 0.001) usage. This study demonstrates that  dual use is associated with longer sleep latency, and suggests that the shared component of nicotine may be a driver. Because sleep broadly impacts multiple aspects of human health, defining the associations of e-cigarettes and vaping devices on sleep is critical to furthering our understanding of their influence on the body.

Effects of mango and mint pod-based e-cigarette aerosol inhalation on inflammatory states of the brain, lung, heart, and colon in mice.

While health effects of conventional tobacco are well defined, data on vaping devices, including one of the most popular e-cigarettes which have high nicotine levels, are less established. Prior acute e-cigarette studies have demonstrated inflammatory and cardiopulmonary physiology changes while chronic studies have demonstrated extra-pulmonary effects, including neurotransmitter alterations in reward pathways. In this study we investigated the impact of inhalation of aerosols produced from pod-based, flavored e-cigarettes (JUUL) aerosols three times daily for 3 months on inflammatory markers in the brain, lung, heart, and colon. JUUL aerosol exposure induced upregulation of cytokine and chemokine gene expression and increased HMGB1 and RAGE in the nucleus accumbens in the central nervous system. Inflammatory gene expression increased in the colon, while gene expression was more broadly altered by e-cigarette aerosol inhalation in the lung. Cardiopulmonary inflammatory responses to acute lung injury with lipopolysaccharide were exacerbated in the heart. Flavor-specific findings were detected across these studies. Our findings suggest that daily e-cigarette use may cause neuroinflammation, which may contribute to behavioral changes and mood disorders. In addition, e-cigarette use may cause gut inflammation, which has been tied to poor systemic health, and cardiac inflammation, which leads to cardiovascular disease.

The use of e-cigarettes or 'vaping' has become widespread, particularly among young people and smokers trying to quit. One of the most popular e-cigarette brands is JUUL, which offers appealing flavors and a discrete design. Many e-cigarette users believe these products are healthier than traditional tobacco products. And while the harms of conventional tobacco products have been extensively researched, the short- and long-term health effects of e-cigarettes have not been well studied. There is even less information about the health impacts of newer products like JUUL. E-cigarettes made by JUUL are different relative to prior generations of e-cigarettes. The JUUL device uses disposable pods filled with nicotinic salts instead of nicotine. One JUUL pod contains as much nicotine as an entire pack of cigarettes (41.3 mg). These differences make studying the health effects of this product particularly important. Moshensky, Brand, Alhaddad et al. show that daily exposure to JUUL aerosols increases the expression of genes encoding inflammatory molecules in the brain, lung, heart and colon of mice. In the experiments, mice were exposed to JUUL mint and JUUL mango flavored aerosols for 20 minutes, 3 times a day, and for 4 and 12 weeks. The changes in inflammatory gene expression varied depending on the flavor. This suggests that the flavorings themselves contribute to the observed changes. The findings suggest that daily use of pod-based e-cigarettes or e-cigarettes containing high levels of nicotinic salts over months to years, may cause inflammation in various organs, increasing the risk of disease and poor health. This information may help individuals, clinicians and policymakers make more informed decisions about e-cigarettes. Further studies assessing the impact of these changes on long-term physical and mental health in humans are desperately needed. These should assess health effects across different e-cigarette types, flavors and duration of use.

Assessing the potential impact of age and inhalant use on sleep in adolescents.

STUDY OBJECTIVES: Targeted marketing has caused a recent surge in teen electronic cigarette usage. In all-age surveys, we isolated adolescent data (13-20 years) to assess age alongside electronic cigarettes, traditional tobacco, and dual usage of both with sleep quality and cough. Based on existing adult literature, we hypothesized an association between dual usage and increased sleep latency. METHODS: Participants were recruited to complete surveys via social media sites. We performed 3 surveys: Survey 1 (n = 347) in 2018, Survey 2 (n = 1198) in 2019, Survey 3 (n = 554) in 2020. Surveys 1 and 2 had 3 sections: UCSD Inhalant Use Survey, Pittsburgh Sleep Quality Index, and Leicester Cough Questionnaire. Survey 3 did not include the Leicester Cough Questionnaire, instead the Hospital Anxiety and Depression Scale and Patient Health Questionnaire were used. The adolescent data were isolated (n = 609). RESULTS: Adolescents reported longer sleep duration with increasing age by one-way analysis of variance. By Tukey's multiple comparisons test, females slept more at ages 19 and 20 years than at age 14 years (P < .01). Female dual users slept more than nonsmokers, (P = .01; mean difference 43.8 minutes; confidence interval = 0.11 to 1.36). We observed an association between dual use and sleep latency vs nonsmokers (P = .0008; mean difference 6.27 minutes; confidence interval = 1.40 to 11.13). We saw no correlation between inhalant use and cough. CONCLUSIONS: In females, we observed a peak in sleep hours at age 19 years. College-aged females may wake later than younger adolescent females. The data also raised concern for sleep disruption and nicotine-induced wakefulness. Further data are required to guide public health strategies. CITATION: Malhotra CK, Gunge D, Advani I, Boddu S, Nilaad S, Crotty Alexander LE. Assessing the potential impact of age and inhalant use on sleep in adolescents. J Clin Sleep Med. 2021;17(11):2233-2239.