key: cord-0967421-154z7abo
authors: Behl, Tapan; Kumar, Sachin; Singh, Sukhbir; Bhatia, Saurabh; Albarrati, Ali; Albratty, Mohammed; Meraya, Abdulkarim M.; Najmi, Asim; Bungau, Simona
title: REVIVING THE MUTUAL IMPACT OF SARS-COV-2 AND OBESITY ON PATIENTS: FROM MORBIDITY TO MORTALITY
date: 2022-05-24
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2022.113178
sha: f0ac21539fb889dc9a200bf7f136c3b2edf6affa
doc_id: 967421
cord_uid: 154z7abo

Obesity-related metabolic dysfunction, endothelium imbalance, chronic inflammation, immune dysregulation, and its comorbidities may all have a role in systemic inflammation, leading to the pulmonary fibrosis and cytokine storm, which leads to failure of lung function, which is a hallmark of severe SARS-CoV-2 infection. Obesity may also disrupt the function of mucociliary escalators and cooperation of epithelial cell’s motile cilia in the airway, limiting the clearance of the coronavirus that causes severe acute respiratory syndrome (SARS-CoV-2). Adipose tissues in obese patients have a greater number of proteases and receptors for SARS-CoV-2 admittance, proposing that they could serve as an accelerator and reservoir for this virus, boosting immunological response and systemic inflammation. Lastly, anti-inflammatory cytokines such as anti-IL-6 and the infusion of mesenchymal stem cells could be used as a modulation therapy of immunity to help COVID-19 patients. Obesity, on the other hand, is linked to the progress of COVID-19 through a variety of molecular pathways, and obese people are part of the SARS-CoV-2 susceptible individuals, necessitating more protective measures.

The pandemic of COVID-19 has collided squarely with the obesity pandemic. Being overweight increases the risk of symptomatic infection, hospitalisation, and even mortality from the SARS-CoV-2 virus, according to news reports from around the world [1] . Obesity has previously been associated with a greater risk of disease severity in viral infections.

Obesity leads to a reduction in total respiratory system compliance. This is due in part to a reduction in lung compliance, which may be linked to the higher pulmonary blood volume seen in obese people. COVID-19 pneumonia has the L phenotype, which is characterised by low elastance, a low ventilation/perfusion (VA/Q) ratio, and hypoxemia, according to the study [2] . Given the COVID-19 outbreak, the fact that viral diseases have a substantial impact on obese patients points to a potential factor which deserves more attention extensively. Many countries have experienced serious socioeconomic difficulties as a result of the efforts required to battle COVID-19 [1, 2] . According to the financial crisis during 2007-2008, in nations with abundant market-financial prudence and a deficiency of welfare programs on harmony, socioeconomic complications habitually worsen the situation for the poor persons in the world, thereby exacerbating socioeconomic dissimilarity and divergence of population sections [3] . COVID-19's connection to the 2007-2008 financial crisis could not be grasped. During the COVID-19 epidemic, however, time-varying conditional correlations between markets were higher. The COVID-19 pandemic has had a significant impact on the intraday volatility gap between oil, gold, and stock markets from 2019 to 2022 [111] .

One of the first studies to report BMI data was a descriptive study of a small sample of 24 severely ill subjects identified with SARS-CoV-2 in the Seattle area [63% of whom were men) (13 -obese, 7 -overweight, 3 -normal BMI and 1 omitted data) [4] . Despite the fact J o u r n a l P r e -p r o o f that the records are too lesser for statistical analysis, a ventilation support system was used on 85% of obese patients, and 62% of them died [4] . These proportions are higher than in patients without obesity, who required a ventilation support system (64%), and 36% of individuals died [4] . Due to its negative impact on drug pharmacokinetics and pharmacodynamic activity, as well as safety and efficacy, obesity is frequently abandoned as a cause of poor treatment in infectious diseases [2] . Obesity also alters cellular immunity, impairing the protective immune response to virus infection and immunisation, as shown with influenza. Obesity surges the risk of diabetes mellitus, high blood pressure, cardiovascular disease, and respiratory disease [1, 2] . Furthermore, aberrant cytokine profiles are linked to lymphoid and myeloid responses inside the RAAS receptor signalling [5] . In relevant patients, adipose tissue can operate as a pool for larger viral dissemination, with enhanced shedding, immunological stimulation, and cytokine increment [4, 5] . Obesity was also linked to a number of respiratory problems, including higher ventilation demand, increased labour of breathing, respiratory muscle inadequacy, and decreased respiratory compliance. The link between obesity and SARS-CoV-2 could be explained by a variety of processes [6] . People with obesity had higher levels of the transmembrane enzyme angiotensin-converting enzyme-2 (ACE-2) that SARS-CoV-2 exploits for cell entrance. It's unclear whether this is due to greater ACE-2 appearance in the adipocytes of obese patients or to the fact that they have more adipose tissues in common (and hence a bigger number of cells expressing ACE-2) [6] . As it has been shown with other viruses, the adipose tissue of obese patients could be a viral reservoir and possible target for SARS-CoV-2 before it blowouts to other organs [7] . Obesity has been linked to a condition of severe inflammation and a weakened immune system, making a person more susceptible to infections [2] . As a result, being overweight may be an independent risk factor for COVID-19 disease development.

Given that ARDS is one of COVID-19's most serious clinical symptoms, these opposing viewpoints cast doubt on the role of obesity in the disease's prognosis and severity [8] .

Obesity has been linked to SARS-CoV-2 severity and/or fatality in a growing number of studies [1, 4, 7] . US Centers for Disease Control and Prevention released preliminary epidemiological data which revealed that 69% of SARS-CoV-2 infected obese patients had a BMI of 30 to 40 kg/m 2 , with 30.1% having severe obesity (BMI ≥ 40 kg/m 2 ) [9] . In addition, after correcting for sex and age, the obesity rate among 340 critical SARS-CoV-2 patients was considerably greater than the overall adult population of France [10] . Severe obesity (BMI ≥ 40 kg/m 2 ) has been identified by the Centers for Disease Control and Prevention as a prevalent clinical risk factor for greater mortality and poorer prognosis in patients with Patients with -ARDS‖ in Germany were more likely to be obese (83%) as compared to an ordinary BMI (42%) [18] . Waist circumference and BMI were autonomously related to COVID-19 (lab-confirmed) in a dose-dependent manner in a huge prospective cohort study in the United Kingdom on 502,543 middle-aged people [19] . The results were unaffected by adjusting for possible confounders. In comparison to individuals of normal weight, the corrected odds ratios for severely obese, obese, and overweight patients were 1.57 (95 % CI:

1.14-2.17), 1.55(1.19-2.02), and 1.31 (1.05-1.62), respectively [19] . The number of patients requiring IMV rose with BMI groups in retrospective French cohort report (chi-square test for trend, p<0.01), and it was highest in subjects (85.7%) with BMI greater than 35 kg/m 2 [20] . Liberated from hypertension, diabetes, and age, the requirement for IMV was strongly linked with BMI (p<0.05) and male sex (p<0.05) in multivariate logistic regression. IMV in subjects odds ratio with BMI < 25 kg/m 2 vs. subjects with BMI > 35 kg/m 2 was 7.36 (p=0.02, 11.63-33.14) [20] . In Mexico, obesity is the biggest predictor of COVID-19 as per the case-J o u r n a l P r e -p r o o f control report, followed by chronic renal failure in females exclusively and hypertension & diabetes in both sexes [21] . Obesity with BMI greater than 40 had a risk ratio of 1.92 (95% CI 1.72-2.13) in a study of 10,926 fatalities linked to COVID-19 in England [22] .

Comorbidity with obesity was 11 %, type 2 diabetes was 30%, and hypertension was 67% who died (80 years' median age) with COVID-19 in Italy [23] . COVID-19 severe illness was independently linked with a BMI ≥ 28 kg/m 2 in 221 patients-Chinese case series (95% CI, 1.595 to 21.621; p = 0.008; OR, 5.872) [24] . Overweight/obese patients in China were hospitalised for a longer duration as compared to an ordinary BMI patient. Obesity was found to be strongly linked with illness severity in a study of children and adolescents hospitalised with COVID-19 in the US [25] . Being overweight is evolving as a risk for SARS-CoV-2 consequences irrespective of age or comorbidities, implying that even young persons who have a greater BMI are at risk of catastrophic disease. Obesity, thus, might be linked to SARS-CoV-2 sickness and death, irrespective of age or the existence of comorbidities [10, 15, 16] . Being overweight was the record essential factor leading to the death of young Chinese patients due to COVID-19, according to a retrospective case-control study [26] .

Obesity would cause hyperinsulinism first, followed by insulin resistance and type 2 diabetes mellitus [27] . Increases in blood pressure are one of the major medium-term repercussions of being overweight, which is regarded as the major risk that predisposes to cardiovascular problems in middle age [28] . The role of diabetes, hypertension and cardiovascular disease cannot be reduced when taking the prospective role of being overweight as a risk factor for sickness and mortality due to SARS-CoV-2 infection [27, 28] . Specified that overweight is an intimate link to the sickness, and all together are linked to COVID-19 severe cases.

Obesity is a condition marked by the buildup of body fat, which increases the risk of cardiovascular disease, depression, airway disease, fatty liver, respiratory problems, type 2 diabetes, hypertension, and some cancers [2, 27, 28] . Furthermore, to their quality-of-life and psychosocial effects, these comorbidities are linked to a shorter life expectancy and premature death (WHO 2016) [29] . Adipokine production, anatomical changes in the kidneys, hyperinsulinemia, renin-angiotensin system (RAS) activation, and an increased sympathetic tone are all thought to have a role in blood pressure changes in obesity [30] . In classic inflammation, the inflammatory response attempts to cure the damage at the site of infection or injury [31] . When the overall mortality rate of ordinary individuals was J o u r n a l P r e -p r o o f compared, then results reported 200% increase in the sickness of obese patients and 20% increase in the mortality of obese patients [24, 26, 32] .

Extreme nutrient feeding, combined with insufficient energy expense, reduces the size and number of metabolic cells like adipocytes, triggering the inflammatory reaction [33] . A chronic inflammatory state is observed in obesity, which is tempted by the metabolic surplus (different mechanism) [33] . Inflammation resolution is hampered by the metabolically excess induced inflammatory state, resulting in the formation of enduring inflammation [33, 34] . As a result, low-grade inflammation in overweight people is influenced in part by dietary factors.

In a high-fat diet (HFD) induced obesity model, increased infiltration of immune cellinflammatory macrophages (type M1) -in adipose tissues, which is linked to an increase in inflammatory cytokines [35] . After the three weeks of HFD treatment onwards, an increase in macrophage-related genes was detected, and after the sixteen weeks ahead, the increase became more pronounced, culminating in the commencement of insulin resistance [35, 36] .

The clinical impact of obesity and obesity-related co-morbidities on SARS-CoV-2 infection has been illustrated in figure 2. COVID-19 can cause serious respiratory infections, septic shock, respiratory dysfunction, and, in the most severe condition, ARDS in individuals with comorbidities [34, 37] . Being overweight can also raise the risk factors for various illnesses, which might have negative repercussions. Obesity, which is the most common underlying illness in SARS-CoV-2 patients below the age of 64, may cause COVID-19 risk to be shifted to younger ages [38] . COVID-19 has a broad clinical range, and most COVID-19 patients experience non-specific symptoms such as myalgia or fatigue (44%), cough (76%), and fever (98%) [39] . With around 70% of COVID-19 hospitalised cases being over 45 years old, older age is one of the supreme critical determinants in the hospitalisation rate [40] . Obesity, like renal disease, has been linked to endothelial dysfunction, which could lead to an increased risk of endothelial cell infection, as detailed below. Endothelial dysfunction induced by obesity is caused by a variety of processes, including the vasculature itself or the perivascular adipose tissue produced low-grade inflammation [41] . Inequity in the production of vasoconstricting and vasodilatory substances causes endothelial dysfunction. SARS-CoV-2 developed in December 2019 and quickly spread over the world, putting human health at risk. COVID-19 causes a wide range of symptoms that can progress to more serious manifestations such as pneumonia and non-respiratory consequences. Diabetes, hypertension, cardiovascular disorders, and, more recently, obesity have all been connected to increased vulnerability to COVID-19 hospitalisation and mortality [41, 42] . Diabetes, hypertension, and obesity were the utmost allied problems with critical infection cases in a meta-analysis assessing dengue infection among 47 studies when compared to other viruses in the West Nile virus, the Flaviviridae family, where the prevalence of cardiovascular problems, diabetes, and hypertension was greater, with overweight, not actuality comorbidity linked with the severity of the disease [41, 43] . Obesity is becoming progressively common as a risk factor in developed nations like the US, owing to amplified consumption of the traditional western diet, which is heavy in carbohydrates, sweets, antioxidants, essential fats J o u r n a l P r e -p r o o f (unsaturated), and low fibre saturated fat [42, 44] . Through increased oxidative stress, this type of diet activates the innate immunity while inhibiting the adaptive immunity (inhibition of B and T lymphocytes action) [44, 45] . Thrombosis, vasoconstriction, peroxidation, atherosclerosis, impaired hemostasis, vascular inflammation, mitogenesis, increased leukocyte adhesiveness, and platelet hyperactivation are all signs that the vascular endothelium is headed for a proatherogenic and prothrombotic state, with increased CVD as a result [46, 47] . These factors contribute to the onset and progression of vascular endothelial dysfunction, which can lead to damage to a key organ.

According to the Centers for Disease Control and Prevention, obesity is associated to a majority of the high-risk factors for infection of SARS-CoV-2, either directly or indirectly [9] . According to an observational study, extremely unwell subjects had a greater BMI (mean: 24.78) than non-severely ill subjects (mean: 23.20) [48] . This meant that a greater BMI meant a higher risk of COVID-19 severity. Obesity is prevalent in 21.9% of developing South-East Asian countries, according to WHO data [49] . Being overweight has been acknowledged as a self-governing risk reason for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), with MERS-CoV (50%) and SARS-CoV & SARS-CoV-2 (80% genetic similarity) [50] . A Brazilian study looked at the risk variables related with the infection of SARS-CoV-2 in the general adult population. In a survey of 51,770 people based on the domestic population, it was discovered that 22% of people, regardless of age, were fatty and at risk of infection [51] . A prospective report in New York found that among patients with COVID-19, a rise in BMI (greater than 40 with 2.6 odds) was highly related with hospital admission [48] . The investigator looked at biobank data of the UK and discovered that patients who were obese or overweight had a greater risk of contracting COVID-19 in a dose-response fashion [52] . Extremely obese (BMI⩾35), obese, and overweight participants showed a 1.57, 1.55, or 1.31 times greater risk of COVID-19 positive than healthy weight subjects [52] . According to a Chinese study, no patients who were underweight had severe COVID-19, but obese individuals advanced to critical cases (19.2% within the healthy weight group, 29.3% within the overweight group and 39% within the obese group) [53] . A meta-analysis involving 18506 participants looked into the link between COVID-19 and diabetes, and discovered that diabetic condition was linked to 65% more chance of death [54] . Obesity appears to be a risk reason for the severity of COVID-19, as per the findings. Furthermore, Yang et al. in their review, found a linear link among BMI J o u r n a l P r e -p r o o f and the requirement for IMV, with the risks being 3.06 times greater in individuals with a BMI of less than 40 [48] . A retrospective review of 112 SARS-CoV-2 subjects found that 88.2% of causalities had a BMI of 25 or less, in comparison to 18.8% survivors [55] .

The moniker "MicroCLOTS" (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) has also gained traction to characterise microvascular thrombosis with an enlightened pulmonary endothelial syndrome, explaining the coagulation factors activation (D-Dimer increment) [56, 57] . The machinery after the observation that being obese or overweight can make SARS-CoV-2 worse has yet to be discovered. Previous studies have suggested possible mechanisms. ACE2 enhances SARS-CoV-2 cellular entrance; according to Ziegler et al., obesity and SARS-CoV-2 illness appear to share some metabolic and inflammatory response mechanisms [58] .

The majority of COVID-19 patients have respiratory illness symptoms. Obese people had greater hospitalisation rates and a larger frequency of respiratory infections than normalweight patients [59] . Obesity is linked to a number of respiratory dysfunctions and poor respiratory processes; all of them can worsen the progression of COVID-19 [59, 60] . To begin with, obese people have poor gas exchange and amplified airway exchange [59] . Hindrance of ventilation of the base of the lung and restriction of diaphragmatic excursion can be due to the larger quantity of adipose tissue in the abdomen area, resulting in lower blood oxygen saturation [61] . In addition, persons with obesity have lesser lung volume and muscle strength. Jones and colleagues found that when BMI grew, ERV and FRC in obese subjects dropped exponentially, reaching 75% and 47% of the standards for lean persons, correspondingly [62] . Patients with excessive obesity may have lower total lung capacity and vital capacity [62] . Second, obesity has been associated to asthma, OSA (obstructive sleep apnea), pulmonary hypertension, OHS (obesity hypoventilation syndrome), and COPD [63] .

Furthermore, being overweight affects the progression of COPD & ARDS and pulmonary functioning in the course of acute episodes [63] . When ARDS is present, obesity raises the likelihood of hypoventilation conditions in ICU patients, which can progress to the failure of respiration [63, 64] . The mechanisms underlying these consequences are unknown; however, it is thought that adipokine disproportions induced by obesity can compromise the functioning of pulmonary vascular endothelial and lead to lung injury [65] . Additionally, leptin has been linked to both physiological and pathological diseases of the lungs, including J o u r n a l P r e -p r o o f asthma, OSA, and COPD [66] . In fact, overexpression of SOCS-3, which also depressingly controls antiviral INFs (interferons) signalling, might cause leptin resistance in people with obesity due to elevated leptin levels [67] . Furthermore, IFN deficiency may be a relationship between risk factors for pulmonary illnesses, such as the severity of disorders and obesity [65, 67] .

Cytokine, such as IL-6, has several natural functions. It's a liver severe stage reactant which aids in the control of effector and regulatory T cells and the control of B cell activation [69] .

It is involved in the control of metabolic, regenerative, and numerous brain functions, in addition to inflammatory and infectious responses. It works through dual signalling mechanisms: the classic signalling mechanism, which is accountable for IL-6's antiinflammatory effects, and the trans-signalling mechanism, which is responsible for proinflammatory activity [69] . The complex of a type I signal transducer protein (gp130) and an IL-6 binding type I glycosylated transmembrane protein (IL-6 receptor) is responsible for IL-6's biological function [70] . Contrasting IL-6R that is only articulated on a small number of cells, while the gp130 is found on every cell surface [70] . Cells which are shown to have both complex constituents are directly receptive to IL-6, which is known as the traditional signalling mechanism, while the cells lacking IL-6R react to IL-6 coupled to sIL-6R (solvable form of IL-6R), which is known as the trans signalling mechanism [69, 70] . By the assistance of metalloproteinase and disintegrin enzyme, sIL-6R is produced by proteolytic breakdown of IL-6R bounded to the membrane [71] . An underlying mechanism of the clinical pathophysiology of obesity is low-grade systemic inflammation [33] . Adipocytes are only one type of cell found in adipose tissue, which also contains pre-adipocytes, fibroblasts, macrophages, and vascular components [28] . As a result, macrophages are essential contributors to inflammation, and adipocytes have also been shown to have strong inherent inflammatory capabilities. Adipocytes, like macrophages, have several receptors which are stimulated by infective illness mediators [68] . When these receptors are stimulated, transduction cascades of inflammatory signals are activated and mediated by cytokines, resulting in the secretion of various powerful, provocative cytokines and severe stage reactants [33] . The JAK/STAT (Janus Kinase) signal transduction mechanism is further activated when cells are activated by IL-6 through either of the complexes [72] . Based on their molecular weight, a unique adipokine (adiponectin) produced by fat tissues appears in plasma in three primary oligomeric states (low, medium, high) [73] . Adiponectin levels are J o u r n a l P r e -p r o o f known to be adversely correlated with the quantity of adipose tissue. COVID-19 pneumonia patients showed increased IL-6 expression, a lower adiponectin/leptin ratio, and higher leptin levels. With a threshold of 7852 pg/mL, leptin had acceptable discriminatory accuracy for COVID-19 pneumonia in individuals with a BMI >30 and was linked with maximum respiratory support. In individuals with a BMI of 25 or below, adiponectin/leptin demonstrated high discriminatory accuracy for COVID-19 pneumonia with a threshold of 2.23 [74] . It's an anti-inflammatory hormone that has a negative relationship with the levels of IL-6 and CRP in overweight people (lesser adiponectin with raised inflammatory intermediaries) [70] . The results were supplementarily supported by the fact that obese people who lost weight saw their IL-6, CRP, and adiponectin levels reverse [75] . Obesityrelated metabolic and cardiovascular problems are exacerbated by the reciprocal and inequality connection of pro-and anti-inflammatory adipokines [76] .

Adipose tissue serves as an active endocrine tissue or cells as well as an energy storage site [77] . Adipose tissue can produce a variety of chemicals that impact the immune response, including adipokines and leptin [77] . Insulin and leptin play important roles in the relationship between nutrition and immunity. These two hormones are crucial in the development of severe COVID-19 in people with inflammation because they are disrupted in obesity and metabolic syndrome. Leptin and insulin resistance affect T-cell function by modifying the metabolic setpoint, resulting in a reduced T-cell response to infection [78] . As a result, a lower adiponectin/leptin ratio indicates adipose tissue malfunction [112] . Age, obesity, type 2 diabetes, and impaired renal function are all major risk factors for COVID-19 mortality, but leptin and insulin resistance are common denominators. In individuals with type 2 diabetes and severe COVID-19, the major role of leptin on the immune system is cytokine storm, lymphopenia, and the particular loss of cytotoxic CD 8+ cells and classical monocytes. Immunity alterations and the changes in the respiratory tract can be mediated by obesity, particularly essential at this time when there is a pressing need to figure out which problems or illness and circumstances can impact and promote COVID-19 infection. While BMI data from individuals hospitalised with SARS-CoV-2 were not initially used to characterise risk sets, few recent studies have shown the link between COVID-19 pandemic and obesity [79] . One hundred and twenty-four BMI reports of hospitalised individuals were studied in a recent study in France; all of them were in ICU with COVID-19 and found a link between the need for aggressive mechanical ventilation, demonstrating the great prevalence of hospitalised obese and severely obese individuals, as well as the worst condition of the J o u r n a l P r e -p r o o f diseased patients [80] . In another study, Obesity was found to be an extrapolative aspect for the requirement for hospitalisation of SARS-CoV-2 infected individuals in New York City, and obese COVID-19 patients in Shenzhen, China, had a significantly higher risk of severe pneumonia, especially in men [81, 82] . Overweight ARDS individuals have a lesser or same death risk than non-obese ARDS individuals; on the other hand, there was no variance in the necessity for an ICU stay or hospitalisation among the two groups [83] . The discharge of free radicals of oxygen like hydrogen peroxide and superoxide anion by polymorphonuclear cells and neutrophils is influenced by an increase in leptin. Leptin can also influence neutrophil migration by activating p38 MAPK and Src kinases and increasing TNF-a production by monocytes while decreasing the chemotaxis process by blocking IL-8 [84] . This is critical for SARS-CoV-2 mediated lung damage because an increased amount of leptin causes an increase in neutrophilic lung inflammation, which increases the severity of lung injury [84] .

SARS-CoV-2 can cause critical ARDS type pulmonary inflammation [83] .

An immunocompromised person's 1 st line of protection (nasal mucosa and skin) and 2 nd line of protection (phagocytes and bactericidal compounds) are unable to stop and eliminate the virus from entering the lungs via the airway territory. Because COVID-19 is communicated through droplets or touch, obesity would certainly exacerbate the severity of COVID-19 [85] .

A massive discharge of cytokines can cause cytokine storms, and an overactive immunity can cause ARDS, viremia, respiratory failure, fast deterioration of lung activity, and potentially MODS (multiple organ dysfunction syndrome) [86] . In lung cells, the ACE2 receptor is an attachment site for the viral spike protein, allowing the virus to move inside the cell, followed by the assembly, duplication, and discharge of a huge number of virus [87] . The target cells are destroyed and slaughtered by immunological T cells via the cellular immune system when the virus is phagocytised by macrophages in alveolar epithelia, and a high number of complements and cytokines are produced [88] . This autoinflammatory reaction causes lung cell death, which prevents the lung alveoli from transporting regular blood oxygen, resulting in a variety of clinical indications in subjects [87, 88] .

Adipocytes might have a significant function in the synthesis of circulating angiotensinogen, converting to Ang II (angiotensin II) by renin and ACE [89] . Obesity can cause changes in the RAAS, which can lead to additional COVID-19 infection abnormalities. Obesity may J o u r n a l P r e -p r o o f thus result in an overactive RAAS [90] . Ang II, elevated levels in the lungs, can cause pulmonary vasoconstriction, which can lead to a perfusion/ventilation discrepancy and hypoxemia, as well as oxidative damage and inflammation, all of which can contribute to acute lung injury [89] . Ang II levels were seen to be favourably connected to body weight in obese T2DM subjects. As a result, obese people's higher starting point of levels of Ang II might worsen SARS-CoV-2 encouraged Ang II increment, resulting in extra critical lung damage [91] . Subjects with SARS-CoV-2 were revealed to have higher Ang II intensities, which were linked to the rigorousness of lung damage as determined by the PaO 2 to a fraction of inhaled oxygen ratio in small study by Liu and colleagues [92] . Levels of Ang II dropped in rejoinder to nutritional weight loss, which was surprising. As a result, dietary changes and physical activity may help to reduce this putative mechanism of increased SARS-CoV-2 infection in obese people [92] . In COVID-19 subjects, cytokine storm is a leading cause of mortality. A higher amount of cytokines, interferon (IFN), and IL-6 characterise this immune hyperactivation phenomenon, which results in immunological activation-related consequences and symptoms [70] . Obesity has a negative impact on the anatomy and physiology of upper respiratory activity, respiratory drive and mechanics, all of which have a direct impact on the respiratory function of obese patients [80] . Obesity causes individuals to have a poor gas exchange, less lung volume, less respiratory muscle activity, and higher airway resistance. Though, because COVID-19 is mostly a respiratory viral infection, patients' obesity will exacerbate their respiratory function during the SARS-CoV-2 infection and might even set them to threat for pulmonary problems, resulting in a bad prognosis [93] .

While few studies have shown that a greater amount of proinflammatory cytokines in critical SARS-CoV-2 reproduce an augmented viral load moderately than an unsuitable host rejoinder which necessities to be amended, inflammatory cytokines (TNF-α and IL-1/1Ra/6/8/18) connected to cytokine storm are similar to those connected with critical sepsis or ARDS [80, 93] . The deleterious consequence of obesity on respiratory activities could explain why patients with concomitant obesity and COVID-19 have a higher risk of lung failure and the need for powered ventilation. On the other hand, obese individuals might be unprotected to even higher quantities of circulating inflammatory chemicals owing to their pro-inflammatory milieu. Obesity patients' unregulated inflammation and other immunological-related responses might worsen the cytokine storm, permitting for sophisticated viral dissemination and lengthier infection time, accelerating the severity of SARS-Co-2 in these individuals [31, 34] . Obesity is strongly linked to OSA, that can give rise J o u r n a l P r e -p r o o f to recurring airway impediments in COVID-19 subjects, aggravating pro-inflammatory pulmonary processes [94] .

Obese individuals have frequently increased leptin and decreased adiponectin levels [67] .

This unbalanced hormonal stage can too result in a faulty immunological reaction.

Overweight people are further vulnerable to a virus-related problems like COVID-19, increasing viral disclosure and the risk of enduring infection in obese people [61] . In a retrospective cohort study on 504 selected COVID-19 patients, there was a high risk of mortality in the overweight patients. Patients with COVID-19 who are overweight or obese have a higher risk of death and intubation than those with a normal BMI, according to the study. Obesity is a risk factor for COVID-19 problems, according to these data, and should be considered in COVID-19 care [95] . Obesity has also been linked to disruptions in phenotypes, and activity, lymphoid tissue reliability and changes in leukocyte formation, all of which have been linked to immunology and pathogen defence [96] . Obese adults and children have a reduced immune-induced response, and adults with obesity have decreased and impaired vaccine-specific T cell responses, which are required for viral infection prevention and recovery. Although the origins of variance in the inflammatory action in COVID-19 are unidentified, adipose tissue may play a role [7] . In a clinical trial involving 248 healthcare workers, There was a considerable association between BMI classes and antibody titres: the humoral response was more efficient in the under-and normal-weight groups compared to the pre-and obese groups (p0.0001 at T1) [97] . Immunity dysfunction, inflammation related to obesity, and adipocytes may all play a role in SARS-CoV-2 infection.

Because adipose tissue has the maximum ACE2 receptors' expression, which attaches to the virus and environs the heart and related veins, it's possible that adipocyte cells work as a virus pool [30, 31] . ACE2 is a new coronavirus attachment site or receptor in the COVID-19

infection [58] . Yet, more studies have to be done to determine the connection among adipose tissue and SARS-CoV-2 or the occurrence of obesity and COVID-19, that necessities to be confirmed by clinical trials. Overweight individuals have a lot of -epicardial adipose tissue‖ (EAT) that can impact the cardiac role in SARS-CoV-2 subjects at a primary stage [28] .

Furthermore, adipokines, together with different proinflammatory intermediaries that subsidise inflammatory cytokine storms, are abundant in EAT [98] . Host cells are penetrated by SARS-CoV-2 via ACE2 receptors when the host cell protease activates the spike protein;

hence tissues and cells that express ACE2 could be SARS-CoV-2 targets [87] . According to tissue study, the expression of ACE2 is lesser in the lungs than in the adipose tissue, implying J o u r n a l P r e -p r o o f that obese individuals are more susceptible to the new COVID-19 strains [7, 58] .

Furthermore, prolonged stimulation of the RAAS in obese patients promotes high ACE-2 appearance and lesser angiotensin 1-7 availability, lowering antiviral resistance and increasing vulnerability to COVID-19 [99] . Obesity complicates the subject's diagnosis and therapy by reducing the superiority of investigative imaging, making airway supervision difficult, and making the patient resistant to prone placement.

Nutritional guidelines and tips for quarantine have been issued by organisations such as the Because obesity is supposed to be linked to the SARS-Cov-2 severity, it is evident that a diet with low calories should be used to lose weight. Throughout the SARS-Cov-2 epidemic, both affected people and the wider community experienced greater psychological suffering [101] .

Furthermore, community separation was discovered to be a forecaster of greater mortality and a potential reason of sadness and nervousness in children and adolescents. It's worth noting that people who are obese are more likely to be distressed, and the psychological effects of the COVID-19 isolation can affect good obesity treatment [101] . Furthermore, losing weight has been made known to recover lung functioning [102] . Several behavioural and nutritional factors may be critical in obese individuals, and they should be taken into account when developing future guidelines. Obesity has been linked to psychosocial costs, such as stress or depression, and psychological care is an important part of obesity management. Psychological discomfort can too give rise to rampage and emotional eating in bariatric surgery subjects (pre-or post-surgical), which has been linked to inferior enduring outcomes [101] . Nevertheless, the link of obesity with mental factors in the recent epidemiological condition necessities to be researched further; emotional care should undoubtedly be included in the correct supervision of obesity during the COVID-19 pandemic [103] .

Patients with SARS-Cov-2 who are over 60 years old and obese must be hospitalised as quickly as feasible. Further chronic or basic disorders (heart disease, hypertension, diabetes)

should be treated as soon as possible [104] . They should maintain rigorous control of blood pressure, blood glucose, and blood lipids during the treatment; adequate lipid-lowering, hypotensive, and hypoglycemic regimes must be maintained throughout the treatment.

Obesity raises the likelihood of severe COVID-19 progression; hence specialist care and medical therapy in SARS-Cov-2 obese subjects should be prioritised. Obese subjects who have been unprotected to SARS-Cov-2 infected zones or SARS-Cov-2 subjects, particularly individuals who have established so-called COVID-19 indications (fever, runny nose, coughing, cold), should see a doctor as soon as possible for virus testing; those with slight indications can be checked at their residence via telemedicine and must be under 14 days of isolation prior to indications vanish [105] . To avoid "cytokine storms," immunological response pointers (CD8+, CD4+, immunoglobulin) and inflammatory response markers (CRP, TNF, IL-6) should be monitored throughout treatment [106] . To reduce treatment delays, the possibility of surgeries and suitable instruments must be examined in advance when treating obese people. It is unknown that vitamin D intake must be improved during the SARS-Cov-2 period, and it is currently not suggested [107] . Indeed, further randomisedcontrolled trials must be conducted to back up these claims. Higher intake of SFAs (saturated fatty acids) has been demonstrated to produce lipotoxicity, inflammation of adipose tissue, and enhance the innate immunity activity via TRL-4 activation (toll-like receptor-4) [66] .

Increased production of TNF and interleukin-1 generated by lipopolysaccharide, and enhanced MCP-1 for macrophage permeation into lung tissue, are induced by a high-fat diet in the animal model [108] . Maintaining good immune function requires a satisfactory consumption of omega-3 fatty acids (polyunsaturated), iron, selenium, copper, zinc, folate, and vitamins (A, B 3/6/12 , D, E). However, micronutrient deficiency and nutritious grade enhance the likelihood of SARS-Cov-2 infection and may impair its result; it is not yet suggested to utilise supraphysiologic levels to improve COVID-19's course [109] . Though, studies have shown that the consumption of various micronutrients (iron, calcium, magnesium, or potassium) and vitamins like vit-A/B 1 /C are frequently insufficient in obese people and should be considered [109] . Greater intensities of plasma interleukin-6 and TNF may be linked to a high protein and fat intake [110] . However, because the relationship among immunology and nutrition is vast and compound, further randomised-controlled experiments in this area are needed.

Obesity is common among SARS-CoV-2 individuals stayed in ICUs, and the rigorousness of 

There is no conflict of interest in the submission of the manuscript.

Fundings for publication of this paper are provided by University of Oradea, Oradea, Romania, by an Internal project.

SARS-CoV-2-host dynamics: Increased risk of adverse outcomes of COVID-19 in obesity

The potential impacts of obesity on COVID-19

Economies of contagion: financial crisis and pandemic

Covid-19 in critically ill patients in the J o u r n a l P r e -p r o o f Seattle region-case series

Pharmacoimmunomodulatory therapy in COVID-19

Obesity augments the disease burden in COVID-19: Updated data from an umbrella review

Obesity & COVID-19: mechanistic insights from adipose tissue

Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey

Groups at higher risk for severe illness

Prevalence of obesity among adult inpatients with COVID-19 in France

Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and death-United States

Obesity is associated with increased severity of disease in COVID-19 pneumonia: a systematic review and meta-analysis

The 1918 influenza and COVID-19 pandemics: The effect of age on outcomes

Clinical presentation and initial management critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brescia, Italy

Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization

Association of obesity with disease severity among patients with coronavirus disease 2019

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

The characteristics of 50 hospitalized COVID-19 patients with and without ARDS

Association of red and processed meat consumption with cardiovascular morbidity and mortality in participants with and without obesity: A prospective cohort study

General study: the effect of corpulence and persistent Sicknesses on the seriousness of the diseases with Covid-19

Obesity is the comorbidity more strongly associated for Covid-19 in Mexico. A case-control study

Factors associated with COVID-19-related death using OpenSAFELY

Gruppo della Sorveglianza COVID-19. Epicentro ISS Coronavirus

Clinical findings of patients with coronavirus disease 2019 in Jiangsu province, China: A retrospective, multi-center study

Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19

Analysis of the clinical characteristics of 77 COVID-19 deaths

Obesity, diabetes, hypertension and severe outcomes among inpatients with coronavirus disease 2019: a nationwide study

Premature death among people with severe mental disorders

The physiologic and physiopathologic roles of perivascular adipose tissue and its J o u r n a l P r e -p r o o f interactions with blood vessels and the renin-angiotensin system

Obesity-associated inflammation: does curcumin exert a beneficial role?

The Association between Nutritional Status and In-Hospital Mortality among Patients with Heart Failure-A Result of the Retrospective Nutritional Status Heart Study 2 (NSHS2)

The complex role of adipokines in obesity, inflammation, and autoimmunity

Diet-derived antioxidants and their role in inflammation, obesity and gut microbiota modulation

Targeting of adipose tissue macrophages by bee venom phospholipase A2 attenuates high-fat diet-induced obesity

CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype

The centrality of obesity in the course of severe COVID-19

Obesity and COVID-19 in Latin America: A tragedy of two pandemics-Official document of the Latin American Federation of Obesity Societies

The association between the level of serum 25 (OH) vitamin D, obesity, and underlying diseases with the risk of developing COVID-19 infection: A case-control study of hospitalized patients in Tehran, Iran

Impact of obesity on COVID-19 patients

The role of obesity-induced perivascular adipose tissue (PVAT) dysfunction in vascular homeostasis

The weight of obesity in immunity from influenza to COVID-19

Obesity as a risk factor for COVID-19: an overview

Obesity, nutrients and the immune system in the era of COVID-19

Ultra-processed diet, systemic oxidative stress, and breach of immunologic tolerance

Risk Factors in Children with Obesity, Preventive Diagnostics and Possible Interventions

COVID-19: Are non-communicable diseases risk factors for its severity?

A meta-analysis of the association between obesity and COVID-19

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): an update

Adults at high-risk of severe coronavirus disease-2019 (Covid-19) in Brazil

Prevalence of obesity and its impact on outcome in patients with COVID-19: a systematic review and meta-analysis

Obesity and COVID-19 severity in a designated hospital in Shenzhen

Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis comprising 18,506 patients

Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV

COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis

Increased severity of COVID-19 in people with obesity: are we overlooking plausible biological mechanisms

SARS-CoV-2 receptor ACE2 is an interferonstimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues

Metabolic healthy obesity, vitamin D status, and risk of COVID-19

Linking COVID-19 and Parkinson's disease: Targeting the role of Vitamin-D

Obesity in COVID-19 era, implications for mechanisms, comorbidities, and prognosis: a review and meta-analysis

The effects of body mass index on lung volumes

Effect of ventilation therapy on mortality rate among obesity hypoventilation syndrome and obstructive sleep apnoea patients

Managing acute respiratory decompensation in the morbidly obese

Obesity and diabetes as high-risk factors for severe coronavirus disease 2019 (Covid-19)

Krela-Kaźmierczak I. Should patients with obesity be more afraid of COVID-19?

Role of leptin and SOCS3 in inhibiting the type I interferon response during obesity

Immunological Mechanisms of Sickness Behavior in Viral Infection

Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance

Endosomes as signaling platforms for IL-6 family cytokine receptors

Implications of ADAM17 activation for hyperglycaemia, obesity and type 2 diabetes

22-trien-3β-ol Attenuates Inflammatory Responses via Inhibiting MAPK/AP-1 Induced IL-6/JAK/STAT Pathways and Activating Nrf2/HO-1 Signaling in LPS-Stimulated Macrophage-like Cells

Adiponectin, leptin and cardiovascular disorders

Discriminatory value of adiponectin to leptin ratio for covid-19 pneumonia

Association of obesity-related inflammatory pathways with lung function and exercise capacity

Epigenetic remodeling in obesity-related vascular disease

The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage

Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19

Obesity, ethnicity, and risk of critical care, mechanical ventilation, and mortality in patients admitted to hospital with COVID-19: analysis of the ISARIC CCP-UK Cohort

LICORN and the Lille COVID-19 and Obesity Study Group. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

Body mass index and risk for intubation or death in SARS-CoV-2 infection: a retrospective cohort study

Shenzhen'experience on containing 2019 novel coronavirus-infected pneumonia transmission

Association of body mass index with morbidity in patients hospitalised with COVID-19

Obesity and COVID-19: a detrimental intersection

Impact of COVID-19 Pandemic on Obese and Asthma Patients: A Systematic Review

The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options

Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry

Modulation of host immune response is an alternative strategy to combat SARS-CoV-2 pathogenesis

Perivascular adipose tissue in vascular function: does locally synthesized angiotensinogen play a role

Therapeutic potential of metformin in COVID-19: reasoning for its protective role

Body Mass Index and Risk for Intubation or Death in SARS-CoV-2 Infection

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Two important controversial risk factors in SARS-CoV-2 infection: obesity and smoking

Obesity as a risk factor for poor outcome in COVID-19-induced lung injury: the potential role of undiagnosed obstructive sleep apnoea

The impact of obesity on COVID-19 complications: a retrospective cohort study

Impact of obesity and metabolic syndrome on immunity

Obesity may hamper SARS-CoV-2 vaccine immunogenicity

The cytokine storm and COVID-19

Hypercoagulopathy and adipose tissue exacerbated inflammation may explain higher mortality in COVID-19 patients with obesity

The SARS-CoV-2 and mental health: From biological mechanisms to social consequences

Guidelines for enhanced recovery after lung surgery: recommendations of the Enhanced Recovery After Surgery (ERAS®) Society and the European Society of Thoracic Surgeons (ESTS)

Mental Health and Obesity During the COVID-19 Pandemic

Obesity prolongs the hospital stay in patients affected by COVID-19, and may impact on SARS-COV-2 shedding

Evidence from two cases of asymptomatic infection with SARS-CoV-2: Are 14 days of isolation sufficient?

Adjunct immunotherapies for the management of severely ill COVID-19 patients

Changes in 25-(OH) Vitamin D Levels during the SARS-CoV-2 Outbreak: Lockdown-Related Effects and First-to-Second Wave Difference-An Observational Study from Northern Italy

Effect of Advanced Glycation End-Products and Excessive Calorie Intake on Diet-Induced Chronic Low-Grade Inflammation Biomarkers in Murine Models

The role of nutrition in strengthening immune system against newly emerging viral diseases: case of SARS-CoV-2

COVID-19 severity in obesity: leptin and inflammatory cytokine interplay in the link between high morbidity and mortality

COVID-19 pandemic's impact on intraday volatility spillover between oil, gold, and stock markets

Adiponectin-leptin ratio is a functional biomarker of adipose tissue inflammation

 Special care should be given to obese patients infected with covid-19 to overcome from the condition.