Scholars Insight Publishers Journal of and Global Research Research Article Open Access From the COCCI to the COVID-19 : A Cautionary Tale Interaction of Metabolic Syndrome, , Particulate Matter (PM), SARS-CoV-2 and the inflammatory response Clearfield M*, Gayer G, Wagner A, Stevenson T, Shubrook J and Gugliucci A Touro University College of Osteopathic , California, USA

Corresponding Author: Dr. Clearfield M, Touro University Abstract College of Osteopathic Medicine, California, USA. A narrative review of the literature was conducted to determine E-mail id: [email protected] associations between cardiovascular (CV) risk factors associated with the COCCI syndemic (Cardiovascular as a result of the Received Date: March 15, 2021; interactions between obesity, and ) and Accepted Date: May 19, 2021; COVID-19. Published Date: May 21, 2021; The COCCI syndemic consists of two health conditions Publisher: Scholars Insight Online Publishers (dysmetabolic obesity and ) that interact via biologic Citation: Clearfield M*, Gayer G, Wagner A, Stevenson T, pathways admixed with social, economic and ecologic drivers Shubrook J and Gugliucci A “From the COCCI Syndemic to augmenting adverse clinical outcomes in excess of either of these the COVID-19 Pandemic: A Cautionary Tale Interaction of health conditions individually. Metabolic Syndrome, Obesity, Particulate Matter (PM), SARS- The noted with COVID-19 are in large part aligned CoV-2 and the inflammatory response”. J Epidemiol Glob Health with those traditional risk factors associated with CVD. In addition, Res. 2021; 1:102 when the traditional CV comorbidities are combined with the Copyright: ©2021 Clearfield M. This work is licensed under a emerging CV risk factors found in the COCCI syndemic there is Creative Commons Attribution 4.0 International License, which an increasing likelihood for the development of COVID-19 and for permits unre stricted se, distribution, and reproduction in any increasing the morbidity and mortality associated with COVID-19, medium, provided the original work is properly cited. especially as a result of cardiovascular complications.

Background: The severe acute respiratory syndrome -2 the world exhibiting some common trends, characteristics and (SARS-CoV-2), the causal agent of the Corona Disease-2019 comorbidities associated with both disease and severity. (COVID-19) was first identified in December 2019 in Wuhan China From the onset, COVID-19 prevalence and severity was associated and within a few months spread around the world creating a global with comorbidities and risk factors associated with Cardiovascular pandemic [1]. Disease (CVD) such as older age, male sex, hypertension, and the presence of CVD itself [4-6]. In addition to the traditional Methods: A narrative review of the literature was conducted to CV risk factors, several residual or emerging CVD risk factors determine associations between the cardiovascular (CV) risk factors including obesity, metabolic syndrome and air pollution have also associated with the COCCI syndemic (obesity with associated been investigated as potential risk factors for COVID-19 [7-10]. metabolic disorders, climate change and air pollution, and inflammation) and COVID-19 [1,2]. Conclusion: The comorbidities noted with COVID-19 are in large part the same as those traditional risk factors associated with CVD. Findings: From a global perspective, since the onset of COVID-19 In addition, the traditional CV comorbidities when combined through January 1, 2021, there have been 82,707,976 cases and with the emerging CV risk factors noted in the COCCI syndemic 1,805,002 deaths, attributed to coronavirus-2 with 19,654,998 cases consisting of obesity, metabolic syndrome and air pollution share and 340,679 deaths in the United States alone [3]. COVID-19 has an increasing likelihood for the development of COVID-19 and the created an unprecedented response in the medical literature with a associated morbidity and mortality, especially as a result of cardiac PubMed search for COVID-19 resulting in 86,000 articles published complications [11,12]. through January 1, 2021 with hundreds of new articles appearing daily. Over the first few months of the pandemic the trajectory of Keywords: Metabolic syndrome; Obesity; Particulate matter (PM); disease moved from China to Europe to the United States and to SARS-CoV-2 and the inflammatory response.

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Introduction Cardiovascular disease as a result of traditional and residual risk factors Cardiovascular disease has remained the number one cause of mortality for the past century. It has maintained its status despite the many groundbreaking advances in the treatment of the primary risk factors causing CVD, as well as advanced interventional measures treating the disease itself [9].

The Behavioral Risk Factor Surveillance System measured five traditional CV risk factors: total blood cholesterol ≥240 mg/ dL, hypertension, BMI ≥30 kg/m2, hemoglobin A1c ≥6.5% and Figure 1: PM and obesity can symbiotically augment and enhance current smoker which accounted for approximately half of CV [13]. events in 2009-2010 [13]. The other half of CV events are, in part represented by the residual risk associated with metabolic, and O3 and all-cause mortality, while cardiovascular, respiratory thrombotic, and inflammatory pathways [7-9]. Of note, as with and cerebrovascular mortality remained positively associated with traditional CV risk factors, many of the residual CV risk categories PM10 and PM2.5 [25]. Long term exposure to PM2.5 across the also augment the chances of a poor prognosis from COVID-19 [7- United States has been associated with increased CVD, especially 9,15-19]. in areas where the prevalence of obesity was greater throughout the population [26]. The residual risk for CVD has been explored previously with a particular focus on the metabolic syndrome associated, or not, Subclinical inflammation is one factor connecting obesity and with obesity and its related risk factors of elevated triglyceride, PM where both inflamed adipocytes and PM2.5 can induce an decreased HDL-C, increased blood pressure, blood glucose inflammatory response resulting in macrophage release of IL-1α, and waist circumference [20]. As an emerging residual risk, the IL-1β, Il-18 and IL-33 signaling pathways activating an immune metabolic syndrome was found to double the risk for CVD [21]. system response through the NOD-Like Receptor Family Pyrin Expanding the residual CV risk secondary to obesity and metabolic domain containing 3 (NLRP3) inflammasome [7-29]. A mechanistic syndrome to also include the projected synergistic effects from aberrant pathway activating the NLRP3 inflammasome proposes air pollution, specifically particulate matter less than 2.5 micron both central adipose tissue and PM2.5 induce oxidative and (PM2.5), introduces the possibility of augmenting risk even beyond inflammation which contributes to acute, sub-acute and chronic those ascribed to an additive affect from each of the individual responses promoting atherosclerosis and subsequent CV events residual risk factors [10]. [30-32,46].

COCCI Syndemic and CVD Three recent trials using two different anti-inflammatory The concept of a syndemic consists of two or more health medications (canakinumab, colchicine) demonstrated significant conditions or contributors to health conditions that interact via reductions in CV events which appear to be dependent on their biologic pathways admixed with social, economic and/or ecologic ability to influence the NLRP3 inflammasome [33-37]. The drivers that augment the adverse clinical outcomes in excess of CANTOS trial (Canakinumab Anti-inflammatory Thrombosis the health conditions individually [22]. The combining of obesity Outcomes Study) utilizes a monoclonal antibody that binds IL- and associated metabolic risk factors with air pollution and climate 1β, significantly reduced major CV events by 15% [34]. The change sets the foundational context for a syndemic [13,23]. The COLCOT trial (Colchicine Cardiovascular Disease Outcome unfavorable adverse outcomes previously explored by combining Trial) and the LoDoCo2 trial (Low Dose Colchicine Trial-2) obesity, specifically central obesity associated with metabolic both utilize colchicine, which interferes with the assembly of abnormalities, and air pollution/climate change, contributes to the inflammasome and the release of IL-1β. Both COLCOT and sustaining and augmenting CV morbidity and mortality [13,21,24]. LoDoCo2 also demonstrated significant reduction in CV events, 23% and 31% respectively [35,36]. The COCCI syndemic (CVD as a result of Obesity, Climate Change and Inflammation) proposes that central adiposity when Several recent trials have also reported on the efficacy associated with an underlying dysmetabolic state, is highly of Interleukin-6 receptor (IL-6) antagonists (tocilizumab and vulnerable to the pro-inflammatory effects from particulate matter sarilumab) in hospitalized patients with COVID-19 [38,39]. The less than 2.5 micron (PM2.5) [13]. (Figure 1) A systematic review results were mixed with no significant benefit noted in reducing and meta-analysis of 196 articles found evidence of a positive intubation or mortality with tocilizumab in the BACC Bay trial association between short-term exposure to PM10, PM2.5, NO2, [38]. On the other hand, the REMAP-CAP trial did demonstrate a

2 Journal of Epidemiology and Global Health Research Scholars Insight Publishers benefit in reducing organ support and death in critically ill patients with COVID-19 treated with tocilizumab or sarilumab [39]. Moreover, the EMPACTA trial found a reduction in the combined outcomes of mechanical ventilation or death in hospitalized COVID pneumonia cases that included underserved populations [40]. These trials differ from CANTOS, COLCOT and LoDoCo2 in that they intervene at a different level (downstream) in the inflammatory cascade, IL-6 versus IL-1, and they are focused on hyper-inflammatory hospitalized COVID-19 patients rather than the prior trials which focused on CVD prevention in a non- COVID population. Obviously there is still much to learned about the interactions between the COCCI syndemic, COVID-19 and Figure 2: Obesity & climate interchange [45,46]. inflammatory response, in particular the NLRP3 inflammasome. But what does seem clear is the inflammatory cascade associated Exposure to air pollution has been previously associated with with the NLRP3 inflammasome does play a role in both CVD and increased risk from viral respiratory illnesses including , COVID-19. rhinovirus and respiratory syncytial virus [48,50]. In areas with Lastly, another anti-inflammatory trial, Cardiovascular higher levels of air pollution more individuals have developed Inflammation Reduction Trial (CIRT), in which the anti- COVID-19 and once contracted there was an increased risk for inflammatory, low dose methotrexate was utilized, did not greater viral associated morbidity and mortality [49]. significantly alter CV outcomes [12,41]. Low dose methotrexate Chronic exposure to PM2.5 from urban combustion sources influences a totally different inflammatory pathway, one that does such as traffic may result in alveolar Angiotensin Converting not reduce IL-1, IL-6 or hs-CRP which may help explain the Enzyme-2 (ACE-2) receptor overexpression which can in theory lack CV benefit while attesting to the different specificities of the increase the viral load and enhance susceptibility to severe pathways involved [12,41]. COVID-19 outcomes [51]. Some regions throughout the world COCCI syndemic and COVID-19 pandemic have higher rates and up to twice the mortality rates Risk factors for COVID-19 mirror those for CVD to a great from SARS-CoV-2 and many of these regions also exhibit higher degree, such that they include age greater than 60 years, smoking, concentrations of PM2.5 [52]. A cross sectional study of county diabetes, hypertension, and CVD itself [4-6]. In addition, the data throughout the United States demonstrated long term exposure components from the COCCI syndemic which include obesity and to PM2.5 can lead to an increase susceptibility to COVID-19 and air pollution have individually been demonstrated to enhance the an increase in COVID related mortality. In this analysis an increase complications and severity from COVID-19 [42,43]. of 1µg/m3 in PM2.5 was associated with a statistically significant 8% increase in COVID-19 mortality [53,54]. Obesity, especially when it is accompanied by increased visceral fat has been demonstrated to be associated with In an attempt to coalesce these varied risks it has been COVID-19 clinical outcomes [43]. Air pollution has been cited postulated that inflammation may represent a unique mechanistic as a potential cause for obesity, as cities with a higher prevalence pathway connecting central/visceral obesity, air pollution and of obesity, especially in the elderly, have been correlated with SARS-CoV-2 [49]. It has been suggested that exposure to PM can increased air pollution.44 The converse that obesity will increase alter the immune response away from an anti-viral response toward air pollution also has supporting evidence [44-46]. People with a bacterial/allergic immune response, such that this re-direction in excess body weight tend to have elevated energy consumption, immune response predisposes those exposed to SARS-CoV-2 to utilize motorized transportation to a greater extent and burn more have an increased chance to develop COVID-19 and have a more fossil fuels increasing greenhouse gases 20% greater than those at virulent response [50]. PM exposure can increase the permeability normal weight [44,47]. From a global perspective that equates to through the tight junctions of the pulmonary epithelium to allow an estimated 700 megatons of CO2 equivalent annually, which is enhanced viral access for promoting viral spread and inflammation about 1.6% of all the global greenhouse gas emissions [47]. Thus [55]. the concern that obesity may be a consequence of air pollution The optimal activation of the NLRP3 inflammasome can result and air pollution may be a consequence of obesity is relevant in antiviral defense while aberrant activation with SARS- given both these risks may interact in a manner that predisposes CoV-2 can lead to an infectious storm of inflammatory cytokines individuals to higher , faster spread and greater mortality resulting in tissue damage [56]. A unifying theory brings forth the from coronavirus-2 [45,46] (Figure 2). ability of obesity, air pollution and SARS-CoV-2, all sharing the

3 Journal of Epidemiology and Global Health Research Scholars Insight Publishers capacity to induce and augment the aberrant NLRP3 inflammasome ● One recommendation to consider is a greater adherence to pathway activating IL-1β, IL-6, TNF and C-reactive protein a Mediterranean style diet which positively impacts some of the [51,57,58]. Activating the NLRP3 inflammasome by utilizing three metabolic abnormalities associated with central obesity noted in different stimuli at once may markedly enhance the inflammatory the COCCI syndemic [13]. The Mediterranean diet characterized response providing a hypothesis as to why some individuals who by high content of plant based foods, reduced intake of red and present with all three risks (obesity, air pollution, SARS-CoV-2) processed meat, low sugar, low to moderate consumption of present with a more severe response than others given a similar fish, dairy and poultry, olive oil as a source of fat andlowto viral exposure but without the other risks [43,51]. moderate intake of wine with meals [64]. A meta-analyses of the Mediterranean diet indicated that this diet reduced the risk of The confluence of risk factors associated with the COVID overall mortality, CVD, diabetes, cancer and neurodegenerative pandemic have been proposed to meet the criteria for a syndemic .65 The inflammatory cascade of cytokines and chemokines where the interaction of the SARS-CoV-2 with an array of non- that are released by both SARS-CoV-2 and inflammatory obesity communicable diseases such as CVD, diabetes and obesity are have been shown to improve with adherence to the Mediterranean clustered within social and economic disparate groups [59]. diet [66]. A cautionary tale ● A second possible outcome as a result from adhering Some say what we have experienced with COVID-19 was to the Mediterranean diet is a modification in the source of inevitable and a clear wakeup call for us to formulate a better carbohydrate intake from simple sugars, specifically fructose, strategy to address potential future viral pandemic outbreaks. to complex carbohydrates. A unifying factor associated with COVID-19 has invoked extensive research to identify medications, unhealthy obesity, cardiometabolic dyslipidemia and metabolic candidate compounds and other therapeutic approaches to address syndrome is hyperinsulinemia, due to Insulin Resistance (IR) this global pandemic. It is beyond the scope of this discussion to with sugar being a main factor promoting IR [67]. Hepatic insulin review the proposed antiviral , repurposed therapeutics, resistance combined with inflamed fat explains a large percent of non-medication based interventions and vaccines many of which the biochemical phenotype of the syndrome while also frequently have already had various degrees of clinical success and failure leading to overexpression of alveolar Angiotensin Converting [60,61]. Enzyme-2 (ACE-2) receptor [67-69]. Instead we will explore the cautionary tale of structural A study of 43 obese children with metabolic syndrome whose competency and how COVID-19 has been influenced by ‘upstream’ baseline percent of calories from fructose averaged 28%, consumed social determinants of health, to serve as an example of what a diet for nine days with a comparable percent of protein, fat and the future may hold should we not address these issues moving carbohydrate but had their dietary sugar, specifically fructose forward. reduced to <5% of calories while replacing those calories with In this article we have presented a hypothesis that obesity, complex carbohydrates. The isocaloric fructose restriction especially when associated with dysmetabolic parameters and air maintained the same percent of total carbohydrate albeit far less pollution, in the context of elevated PM2.5, can both contribute to fructose which resulted in improved hepatosteatosis, insulin the subclinical inflammatory pathways that predispose individuals resistance and inflammatory markers [70]. The excessive intake of to both higher prevalence rates of SARS-CoV-2 and once infected, refined sugar and high-fructose corn syrup has contributed to the to greater severity of the disease [16,19,62,63]. unhealthy dietary habits of the populace [71]. Combining the data from the Mediterranean diet with that of further fructose restriction The concept of social determinants has over the years been may be a practical means to decrease the sub-clinical inflammatory expanded to include almost any factor outside the traditional response that may predispose those exposed to SARS-CoV-2 and health care system that can impact health [64]. The impact to modify the symptoms to those infected with SARS-CoV-2. from the various social determinants often overlap and it has been recommended these risks should be viewed as poly-social ● A third consideration includes changes in lifestyle that could interactions, which allows for grouping of these determinants mitigate the adverse inflammatory changes induced by obesity, to better delineate their impact on health and wellness [64]. The air pollution and SARS-CoV-2 [72]. Lifestyle changes such as COCCI syndemic risk factors and social determinants also overlap smoking cessation, suggested weight loss, if obese, of at least 1 kg/ which may help elucidate foundational elements which allow month and an increase in physical activity to at least 135 minutes certain infectious agents such as SARS-CoV-2 to evolve into a of moderate exercise (60-65% target heart rate) per week [72- pandemic [13]. To that end, our cautionary tale may provide some 74]. The combined dietary and lifestyle recommendations may practical interventions that could reduce both the prevalence and further augment the benefits for the treatment of CVD as well as virulence of SARS-CoV-2 and possibly extend to other potential COVID-19 infectivity and symptomology. Collective actions of that may follow. , wearing masks, decreasing our congregating in

4 Journal of Epidemiology and Global Health Research Scholars Insight Publishers groups especially indoors, avoiding public gatherings, washing Table 1: Race, Ethnicity and COVID-19 [83-86]. hands have all contributed to addressing the spread of SARS- Causes higher rates Explanation CoV-2 [75]. COVID-19 ● A fourth consideration is to monitor levels of PM in the Diabetes, CVD, community. If the air quality is above the National Ambient Air Increased comorbidities hypertension, obesity risk Quality Standard for PM2.5 > 12 µg/per cubic meter there is an factor for COVID-19 associated increase in mortality, CVD and potentially the risk Housing near highways and Increase exposure to air for COVID-19 [50,76,77]. In Northern Italy in areas with higher industry or burn solid fuels pollution PM, SARS-CoV-2 RNA was found attached to PM and this (wood, coal, charcol) finding aligned with an increase in morbidity and mortality due to Increase residence in urban Crowding, less social COVID-19 [78]. areas distancing Why might the attachment of SARS-CoV-2 to PM be of More "essential" workers (public transit, health care, grocery, concern? By attaching to PM, viral particles can remain viable custodial) longer in the atmosphere, suspended for extended periods of time Increase intake processed allowing for greater traveling distances well beyond the standard 6 Increase exposure to food and pro-inflammatory foods. feet radius to as much as 23-27 feet. The increase in viral viability deserts, food scarcity and Increase confinement and combined with increase viral travel distance can allow a higher limited access to safe stresses immune percent of people exposed to viral particles for extended periods outddor areas to exercise response of time (> 15 minutes) [78-80]. Two studies from China suggest reducing PM exposure in both outdoor and indoor settings was "Weathering" effect of beneficial in reducing inflammation and possibly COVID-19 Socioeconomic status, accelerated afing due to risk [81,82]. The first study demonstrated a reduction up to 60% housing insecurity and stress external stressors, decrease in PM from pre to post-Olympic Beijing air quality resulting in a access to health care reduction in air pollution with an associated significant reduction The Lancet Commission on Pollution and Health concluded in inflammatory biomarkers [81]. The second study of college that over 90% of pollution related mortality worldwide occurred students living in nonsmoking dormitories randomized to rooms in low and middle income countries.87 However, even in higher with either air purifiers or sham purifiers for nine days each. PM2.5 income countries death rates from pollution were still primarily significantly decreased, as did inflammatory biomarkers, when noted in minority and marginalized communities [87]. housed in a room with an air purifier.82 From these studies the use of indoor air filters, high efficiency particulate arrestance (HEPA) Discussion filters, to decrease PM within the living space may seem prudent The significant increases over the past 50 years of obesity and if burning household solid fuels (wood, coal, charcoal, dung) for air pollution, the key factors contributing to the COCCI syndemic, cooking, heating, lighting or other purposes, or if the residence have been proposed as one reason why CVD remains the number is within 150-300 meters of major highways or industrial plants one cause of mortality not only in the United States but globally producing high levels of PM. [13]. The underlying rationale for the connection between the COCCI syndemic, CVD and now the COVID-19 pandemic is based ● The risks from environmental and other social determinants on the number of overlapping risk factors and co-morbidities from of health are not equally distributed across our nation nor globally. obesity, metabolic syndrome, air pollution, climate change, and When the analyses of the and severity of COVID-19 is social determinants of health which individually and collectively focused on race/ethnicity, the data indicates that African American, impact both the COCCI syndemic and the COVID-19 pandemic Latino, Native American and Immigrant communities in the United [13,44,50]. States exhibit a disproportionate amount of COVID-19 related cases and hospitalizations [83-86]. There are several reasons postulated In this discussion we put forward a unifying theory suggesting for the higher rate of COVID-19 in these populations including: a a common inflammatory state induced by dysmetabolic obesity, greater proportion with underlying comorbidities, more likely to air pollution/climate change and SARS-CoV-2 [31,51]. This live in urban areas with overcrowding, disproportionate numbers inflammatory state, at least in part, is derived from an aberrant of “essential workers”, decreased socioeconomic status, decrease activation of the NLRP3 inflammasome through caspase-1, access to health care, less healthy food options, limited safe promoting activation of IL-β and IL-18 which are critical for outdoor space and greater exposure to higher levels of air pollution anti-viral immunity, obesity related metabolic regulation, and an [83-86] (Table 1). inflammatory response [32,51].

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The SARS-CoV-2 activation of the NLRP3 inflammasome century apart. may help support an appropriate immune response, however, alternatively a maladaptive or aberrant response may be more the Conclusion Given how devastating COVID-19 was in 2020, it still came norm especially when the has been compromised in third following heart disease and cancer as the leading causes by co-morbid conditions.88,89 Therefore if the immune system has of death in the United States [102,103]. However, what also needs been compromised, SARS-CoV-2 infection may result in a very to be appreciated is COVID unlike CVD or cancer portends the aggressive immune response which has been labeled as “cytokine risk of even more deaths among those in close contact. What also storm” and can potentiate pre-existing systemic subclinical cannot be denied is the abundance of risk shared by COVID-19 and inflammatory states initiated by dysmetabolic obesity and/or air CVD. The interconnectivity of the risk factors for CVD, whether pollution that pre-date exposure to SARS-CoV-2 [88,89] (Figure 3). they be traditional or emerging, with those for COVID-19 should signify the need to address the risks from diet, activity, air quality, racial-ethnic-socioeconomic disparities and ensuing metabolic dysfunction as key elements for future interventions to ultimately benefit our collective .5,6 With newly approved vaccines being released to the public, the hope is the pandemic will soon subside substantially, if not completely. However, addressing risk factors associated with inflammation and CVD, such as dysmetabolic obesity and exposure to high levels of PM2.5, may help reduce further risk from SARS-CoV-2 today, while also helping to prevent or at least mitigate the next viral predator for Figure 3: Potential Cytokine Storm resulting from interaction with tomorrow. inflamed adipose, PM2.5 and SArS-CoV-2 Our modern lifestyles have set the stage by exploiting our planet Finally, another key factor in inflammation is the receptor for with air pollution and climate change, modifying the type and advanced glycation end products (RAGE), which binds damage- quantity of food we ingest, decreasing our physical activity and associated molecular patterns and is expressed in the , heart, increasing our dependence on motorized transportation and a and in priming organs, such as the blood vessels and adipose fossil fuel economy. The result of these actions have sustained the tissue [90]. RAGE enrichment in these priming organs, and in the public health crisis resulting in CVD remaining as the number one and heart during active COVID infection, participates in the cause of mortality, which is buoyed by co-factors such as obesity general tissue damage induced by the virus. Therefore, the RAGE and air pollution. Therefore, targeted public health actions have axis may play a co-adjuvant role colluding with PM, obesity as the additive benefits of addressing the long standing CVD crisis well as SARS-CoV-2 augmenting adverse changes associated with as well as protecting the public from COVID-19 and future viral the NLRP3 inflammasome [91-97]. that could employ the same or similar pathways for viral There is still much to be learned about these risk factors and spread and virulence. how they interact with SARS-CoV-2. For example, the presence References of dysmetabolic obesity as a risk factor for COVID-19 can occur 1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus even in individuals with BMIs <25 kg/m2, who are metabolically disease 2019 in China. NEJM. 2020; 382: 1708-1720. abnormal yet not overweight or obese by BMI standards (normal weight obesity) [98,99]. The normal weight obesity individuals 2. Wiersinga W, Rhodes A, Allen C, et al. Pathophysiology, along with those exposed to high levels of PM, may help us , diagnosis and treatment of coronavirus disease understand the subgroup of COVID-19 patients who present 2019 (COVID-19) JAMA. 2020; 324: 782-793. critically ill yet do not appear to have any obvious co-morbidities. 3. Coronavirus daily tracker (2021) Centers for Disease Control and Prevention, Johns Hopkins University, the World Health The cautionary tale traces back over a century ago when the Organization. influenza pandemic of 1918 killed over 50 million as a result of 4. Wang W, Tang J, Wei F. Updated understanding of the outbreak the meshing of virus, host and societal factors. Issues of the day of 2019 novel coronavirus (2019-nCoV) in Wuhan China. J Med that increased risk included race, flies, dirty dishes, overcrowding Virol. 2020; 92: 441-447. and weather [100,101]. At that time some of the co-morbidities for COVID-19 such as CVD and obesity, may not have been as 5. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics prevalent as they are today, but others such as race, overcrowding, and outcomes of 1591 patients infected with SARS-CoV-2 dust with associated particulate matter should give us pause to admitted to ICUs of the Lombardy region, Italy. JAMA. 2020; understand what similarities coexist within two a 323: 1574-1581.

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6. Richardson S, Hirsch J, Narasimhan M, et al. Presenting 21. Clearfield M, Pearce M, Nibbe Y, et al. The “new deadly characteristics, comorbidities, and outcomes among 5700 patients quartet” for cardiovascular disease in the 21st century: Obesity, hospitalized with COVID-19 in the New York City area. JAMA. metabolic syndrome, inflammation, and climate change: How 2020; 323: 2052-2059. does statin fit in this equation? Curr Atherocler Rep. 7. Cheng P, Zhu H, Witteles R, et al. Cardiovascular risks in 2014; 16: 380. patients with COVID-19: Potential mechanisms and areas of 22. Singer M, Bulled N, Ostrach B, et al. and the uncertainty. Current Reports. 2020; 22: 34 biosocial conception of health. Lancet. 2017; 389: 941-950. 8. Gori T, Lelieveld J, Munzel T. Perspective: cardiovascular 23. Swinburn B, Kraak V, Allender S, et al. The global syndemic disease and the COVID-19 pandemic. Basic Research in of obesity, undernutrition and climate change: The Lancet Cardilology. 2020; 115: 32 Commission report. Lancet. 2019; 393: 791-846. 9. Heart Disease facts. Centers for Disease Control and Prevention website. 24. Bray G, Fintel D, Clearfield M, et al. Overweight and obesity: 10. Patel SA, Winkel M, Ali MK, et al. Cardiovascular mortality the pathogenesis of cardiovascular risk. Clin Cornerstone. 2009; associated with 5 leading risk factors: national and state 9: 30-42. preventable fractions estimated from survey data. Ann Int Med. 25. Orellano P, Reynoso J, Quaranta N, et al. Short-term exposure 2105; 163: 245-253. to particulate matter (PM 10 and PM2.5), nitrogen dioxide (NO2), 11. Dhindsa D, Sandesara P, Shapiro M, et al. The evolving and ozone (O3) and all-cause and cause-specific mortality: understanding and approach to residual cardiovascular risk Systematic review and meta-analysis. Environ Int. 2020; Sep; management. Frontier in CV Med. 2020; 7: 88b 142: 1058796. 12. Ridker P, MacFayden J, Glynn R, et al. Comparison of 26. Mazidi M, Speakman J. Impact of obesity and ozone on the interleukin-6, C-reactive protein, LDL-C as biomarkers of association between particulate air pollution and cardiovascular residual risk in contemporary practice: secondary analysis of disease and mortality among U.S adults. J Am Heart Assoc. Cardiovascular Inflammation Reduction Trial. European Heart 2018; 7: e008006. Journal. 2020: 1-10. 27. De Falco G, Terlizzi M, Siriganano M, Commodo M, D’Anna 13. Clearfield M, Davis G, Weiss J, et al. Cardiovascular disease A, Aquino R, et al. Human peripheral blood mononuclear cells as a result of the interactions between obesity, climate change (PBMC) from smokers release higher levels of IL-1 like cytokines and inflammation: the COCCI syndemic. J Am Osteopath Assoc. after exposure to combustion-generated ultrafine particles. 2018; 118: 719-729. Scientific Reports. 2017; 7: 43016. 14. Birkenfeld S, Schulze A, Ludwig D. Obesity and impaired 28. Cavellos V, Diaz V, Sirios C. Particulate matter air pollution metabolic health in patients with COVID-19. Nat Rev Endocrinol. from the city of Quito, Ecuador, activates inflammatory signaling 2020; 16: 341-342. in vito. Innate Immun. 2017; 23: 392-400. 15. Korakas E, Ikonomidis I, Kousathana F wt al. Obesity and 29. Zheng R, Tao L, Jian H, et al. NLRP3 inflammasome COVID-19: Immune and metabolic derangements as a possible activation and lung fibrosis cause by airborne fine particulate link to adverse clinical outcomes. Am J Physiol Endocrinol matter. Ecotoxicology and Environmental safety. 2018; 163: 612- Metab. 2020; 319: A#105-E109. 619. 16. Engin A, Engin E, Engin A. Two important controversial risk 30. Shanley R, Hayes R, Cromar K, Ito K, Gordon T, Ahn J. factors in SARS-CoV-2 infection: Obesity and smoking. Environ Particulate air pollution and clinical cardiovascular risk factors. Toxicol Pharmacol. 2020; 78: 103411. Epidemiology. 2016; 27: 291-298 17. Bikdeli B, Madhaven M, Jimenez D, et al. COVID-19 31. Brook R. Particulate matter air pollution and atherosclerosis. and thrombotic or thromboembolic disease: Implications for Current Atherosclerosis Reports. 2010; 12: 291-300. prevention, anti-thrombotic therapy and follow-up. JACC State 32. Grant R. Mechanisms of disease: inflammation activation and of the art review. J Am Coll Cardiol. 2020; 75: 2950-2973. the development of . Front Immunol. 2013. 18. Connors J, Levy J. COVID-19 and its implications for 33. Ridker P. From CANTOS to CIRT to COLCOT to Clinic: thrombosis and anticoagulation. Blood. 2020; 135; 2033-2040. Will atherosclerosis patients soon be treated with combination 19. Clearfield M. Another inconvenient truth: Continuing the lipid lowering and inflammation inhibiting agents? Circulation. risks from obesity and metabolic syndrome with global warming. 2020; 141: 787-789. Curr Atheroscl Rep. 2008; 10: 273-276. 34. Ridker P, Everett B, Thuren T, et al. Anti-inflammatory 20. Mottillo S, Filion K, Genest J etal. The metabolic syndrome therapy with canakinumab for atherosclerotic disease. N Engl J and cardiovascular risk: A systematic review and meta-analysis. J Med. 2017; 377: 1119-1131. Am Coll Cardiol. 2010; 56: 1113-1132. 35. Tardif J, Kouz S, Waters D, et al. Efficacy and safety of low

7 Journal of Epidemiology and Global Health Research Scholars Insight Publishers dose colchicine after . N Engl J Med. 2019; the connection? Ann NY Acad Sci. 2020; 1-24. 381: 2497-2505. 52. Frontera A, Cianfanelli L, Vlachos K et a. Severe air pollution 36. Nidorf A, Fiolet A, Mosterd A, et al. Colchicine in patients links to higher mortality in COVID-19 patients: the “double-hit” with chronic coronary disease. N Engl J Med. 2020; 383: 1838- hypothesis. J Infect. 2020; 81: 255-259. 1847. 53. Wu X, Nethery R, Sabath, et al. Exposure to air pollution and 37. Mauro AG, Thurber CJ, Abbate A. Colchicine in acute COVID-19 mortality in the United States: A nationwide cross myocardial infarction: “Teaching new tricks to an old dog. Transl sectional study. MedRxiv. 2020; 04.05.20054502. Med (Sunnyvale). 2015; 5: 1-3. 54. Wu X, Nethery R, Sabath M, et al. Air pollution and 38. Stone J, Frigault M, Sterling-Boyd N, et al. Efficacy of COVID-19 mortality in United States: Strengths and limitations Tocilizumab in patients with hospitalized with COVID-19. N of an ecological regression analysis Sci Adv. 2020; 6: eabd4049. Engl J Med. 2020; 383: 2333-2343. 55. Liu J, Chen X, Dou M, et al. Particulate manner disrupts airway 39. Gordon A. Randomised, Embedded, Multifactorial, Adaptive epithelial barrier via oxidative stress to promote Pseudomonas Platform Community Acquired Pneumonia trial. Response to aeruginosa infection. J Thorac Dis. 2019; 11: 2617-2627. the COVID-19 pandemic. Tocilizumab und Sarilumab senken 56. da Costa L, Outlioua A, Anginot A, et al. RNA viruses promote Sterberisiko bei schwerem COVID-19 The REMAP-CAP activation of the NLRP3 inflammasome through cytopathogenic Investigators. 2021. effect induced potassium efflux. Cell Death Dis. 2019; 10: 346 40. Salama C, Han J, yau L, et al. Tocilizumab in patients 57. Hirota J, Hirota S, Warner S,, et al. The airway epithelium hospitalized with Covid-19 pneumonia. N Engl J Med. 2021; 384: nucleotide-binding domain and leucine-rich repeat protein 3 20-30. inflammasome is activated by urban particulate matter. J 41. Ridker P, Everett B, Pradhamn A, et al. Low dose methotrexate Clin Immuno. 2012; 129: 1116-1125.e1116. for the prevention of atherosclerotic events. N Engl J Med. 2019; 58. Barra N, Henriksbo B, Anhê F, et al. The NLRP3 380: 752-762. inflammasome regulates adipose tissue metabolism. Biochem J. 42. Meyerowitz E, Richterman A, Gandhi R, et al. Transmission 2020; 477: 1089-1107. of SARS-CoV-2: A review of viral, host, and environmental 59. Horton R. COVID -19 is not a pandemic. Lancet. 2020; 396: factors. Ann Int Med. 2020. 874 43. Sanchis-Gomar F, Lavie C, Mehra M, et al. Obesity and 60. Sanders J, Monogue M, Jodlowski T, et al. Pharmacologic outcomes in COVID-19 when an and pandemic collide. treatments for coronavirus disease 2019 (COVID-19) JAMA. Mayo Clinic Proceed. 2020; 95: 1445-1453. 2020; 323: 1824-1836. 44. Deschenes O, Wang H, Wang S, et al. The effect of air 61. Dong Y, Dai T, Wei Y, et al. A systematic review of SARS- pollution on body weight and obesity: Evidence from China. J CoV-2 vaccine candidates. Signal Transduct Target Ther. 2020; Develop Economids. 2020; 145. 5: 237. 45. An R, Ji M, Zhang S. Global warming and obesity: a systematic 62. Rheinheimer J, de Souza B, Cardoso n, et al. Current role of review Obesity reviews. 2017; 19. the NLRP3 inflammasome on obesity and insulin resistance: A 46. Egger G. Dousing our inflammatory environment(s): is systematic review. Metabolism. 2017; 74: 1-9. personal carbon trading an option for reducing obesity and 63. Comunian S, Dongo D, Milani C, et al. Air pollution and climate change? Obesity Review. 2008; 9: 11. COVID 19; the role of particulate matter in the spread and 47. Magkos F, Tetens I, Bugel S, et al. The environmental footprint increase of COVID-19’s morbidity and mortality. Int J Environ of obesity. Obesity. 2019. Res Public Health. 2020; 17: 4487. 48. Yang A, Song Q, Li J, et al. Air pollution as a cause of obesity: 64. Figueroa J, Frakt A, Jha A. Addressing social determinants micro-level evidence from Chinese cities. Int J Environ Res. of health: Time for a polysocial risk score. JAMA. 2020; 323: Public Health. 2019; 16: 4296. 1553-1554. 49. Lubrano C, Risi R, Masi D, et al. Is obesity the missing link 65. Dinu M, PaglialG, Casini A, et al. Mediterranean diet and between COVID-19 severity and air pollution? Environ Pollut. multiple health outcomes: an umbrella review of meta-analyses 2020; 266: 115327. of observational studies and randomized trials. Eur J Clin Nutr. 50. Oliver B, Robinson P, Peters M, et al. Viral infections and 2018; 72: 30-43. : an inflammatory interface. Eur Respir J. 2014: 44; 1666. 66. Malorino M, Bellstella G, Longo M, et al. Mediterranean diet 51. Woodby B, Arnold M, Valacchi G. SARS-CoV-2 infection, and COVID-19: Hypothesizing potential benefits in people with COVID-19 pathogenesis and exposure to air pollution: What is diabetes. Frontiers in Endocrin. 2020; 11: 574315.

8 Journal of Epidemiology and Global Health Research Scholars Insight Publishers

67. Taskinen, Packard C, Boren J. Dietary fructose and the 82. Li H, Cai J, Chen R, et al. Particulate matter exposure and metabolic syndrome. Nutrients. 2019; 11: 1987. stress hormone levels: A randomized, double-blind crossover trial 68. Dalan R, Bornstein S, El-Armouche A, et al. The ACE-2 in of air purification. Circ. 2017; 136: 618-627. COVID-19; Foe or Friend? Horm Metab Res. 2020; 52: 257-263. 83. Price-Haywood E, Burton J, Fort D, et al. Hospitalization 69. Roca-Ho H, Riera M, Palau V, et al. Characterization of ACE and mortality among black patients and white patients with and ACE-2 expression within different organs of the NOD mouse. COVID-19. N Engl J Med. 2020; 382: 2534-2543. Int J Mol Sci. 2017; 18: 563. 84. Van Dorn A, Cooney R, Sabin M. COVID-19 exacerbating 70. Lustig R, Mulligan K, Noworolski S Isocaloric fructose inequalities in the US. Lancet. 2020; 395: 1243-1244. restriction and metabolic improvement in children with obesity 85. Hooper M, Napoles A, Perez-Stable. COVID and racial/ethnic and metabolic syndrome. Obesity. 2016; 24: 453-460. disparities JAMA. 2020; 323: 2466-2467 71. Johnson R, Stenvinkel P, Andrews P, et al. Fructose metabolism 86. Chowkwanyun M, Reed A. Racial health disparities and as a common evolutionary pathway of survival associated with COVID-19- Caution and context. N Engl J Med. 2020; 3: 201- climate change, food shortage and droughts. J Intern Med. 2020; 203. 287: 252-262 87. Landrigan P, Fuller R, Acosta N, et al. Effect of particulate 72. Klooster C, Graaf Y, Ridker P, et al. The relation between matter air pollution and health. Lancet. 2018; 391: 462-512. healthy lifestyle changes and decrease in systemic inflammation 88. Lopez-Reyes A, Martinez-Armenta C, Espinosa-Valazquez R, in patients with stable cardiovascular disease. Atheroscl. 2020; et al. NLRP3 inflammasome: The stormy link between obesity 301: 37-43. and COVID-19. Front Immunol. 2020; 11: 570251 73. Bianchi V. Clin Nutrit ESPEN Weight loss is a critical factor 89. Van den Berg D, Velde A. Severe COVID-19: NLRP3 to reduce inflammation. Clin Nutrit ESPEN. 2018; 28: 21-35. inflammasome dysregulated. Front Immunol. 2020; 11: 1580 74. Ortega F, Lee D, Katzmazyk P, et al. The intriguing 90. Roy D, Ramasamy R, Schmidt A. Journey to a receptor for metabolically healthy but obese phenotype: cardiovascular Advanced Glycemic End Product connection in sever acute prognosis and role of fitness. Eur Heart J. 2013; 34: 389-397. respiratory syndrome coronavirus 2 infection. With stops along 75. Chu D, Akl E, Duda S, et al. Physical distancing, face mask, the way in the lung, heart, blood vessels and adipose tissue. eye protection to prevent person to person transmission of SARS- Published ahead of print 2020 Dec 17 Atheroscler Thrombo Vasc CoV-2 and COVID 1: a systematic review and meta-analysis. Biol. 2020. Lancet. 2020; 395: 1973-1987. 91. Yeh W, Yang H, Pai W, et al. Long term administration of 76. Di Q, Wang Y, Zanobetti A, et al. Air pollution and mortality advanced glycation end products stimulates the activation of in the Medicare population. N Engl J Med. 2017; 376: 2413-2522. NLRP3 inflammasome and sparking the development of renal 77. Lepeule J, Laden F, Dockery D, et al. Chronic exposure to fine injury. J Nutr Biochem. 2017; 39: 68-78 particles and mortality: an extended follow-up of the Harvard Six 92. Yi X, Zhang L, Lu W, et al. The effect of NLRP inflammasome Cities study from 1974 to 2009. Environ Health Perspect. 2012; on the regulation of AGEs induced inflammatory response in 120: 965-970. human periodontal ligament cells. J Periodontal Res. 2019; 54(6): 78. Setti L, Passarini F, De Gennaro G, et al. Searching for 681-689. SARS-CoV-2 on particulate matter: A possible early indicator of 93. Barton D, Betteridge B, Earley T, et al. Primary alveolar COVID-19 epidemic recurrence, Int J Environ Res Pub Health. macrophages exposed to diesel particulate matter increase RAGE 2020; 17: 2986. expression and activate RAGE signaling. Cell Tissue Res. 2014; 79. Bourouiba L. Turbulent gas clouds and respiratory : 358: 229-238. Potential implications for reducing transmission of COVID-19. 94. Haider L, Crowley G, Caraher E, et al. Synergistic effect of JAMA. 2020; 323: 1837-1838. WTC-particulate matter and lysophosphatidic acid exposure and 80. Setti L, Passarini F, De Gennaro G, et al. the role of RAGE: In vitro and translational assessment. Int J route of COVID-19: Why 2 meters/6 feet of inter-personal Environ Res Public Health. 2020; 17: 4318. distance could not be enough. Int J Environ Res Pub Health. 95. Stilhano R, Costa A, Nishino M, et al. SARS CoV-2 and 2020; 17: 2932. the possible connection to ERs, ACE2 and RAGE: Focus on 81. Rich D, Kipen H, Huang W, et al. Association between changes susceptibility factors. FASEB J. 2020; 34: 14103-14119. in air pollution during the Beijing Olympics and biomarkers of 96. Kerkeni M, Gharbi J. RAGE receptor: May be a potential inflammation and thrombosis in healthy young adults. JAMA. mediator for SARS-CoV-2 infection. Med Hypotheses. 2020; 2012; 307: 2068-2078. 144: 109950.

9 Journal of Epidemiology and Global Health Research Scholars Insight Publishers

97. Kehribar Y, Cihangiroglu M, Sehmen E wt al. The receptor 101. Short K, Kedzierska K, van de Sandt C. Back to the future: for advanced glycation end product (RAGE) pathway and Lessons learned from the 1918 influenza pandemic. Front Cell COVID-19. Biomarkers. 2021; 13: 1-5. Infect Microbiol. 2018; 8: 343. 98. Ding C, Zhiling C, Magkos F. Lean but not healthy: the 102. CDC Covid likely the third leading cause of death in US metabolically obese, normal weight phenotype. Cur Opin Clin (2021) Johns Hopkins University Resource Center. Nutr Metabol Care. 2016; 19: 408-417. 103. Woolf S, Chapman D, Lee J. COVID-19 as the leading cause 99. Sathsish T, Kapoor N. Normal weight obesity and COVID-19 of death in the United States. JAMA. 2021; 325: 123-124. severity: A poorly recognized link. Diab Res Clin Prac. 2020; 169: 108521. 100. Aligne C. Overcrowding and mortality during the influenza pandemic of 1918. AM J Public Helath. 2016; 106: 642-644.

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