The War Against SARS-CoV-2: The Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

We examined SARS-CoV-2 (Covid-19) available treatments and prophylactic methods that included interventions associated with inhibiting the ‘type II transmembrane serine protease’ (TMPRSS2) to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors, or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication. We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders, yet, they serve as the viral points of entry, elevating the probability of infection. Human tissues’ analysis reveals a higher ACE2 expression in adipose tissue, placing obesity-related conditions in the eye of the pandemic storm. It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues. Males manifest a relatively higher positive ACE2 correlation with certain immune cells in the lungs, thyroid, adrenals, liver and colon, while females evidence higher ACE2 correlations with immune cells in the heart. The remaining tissues’ ACE2/immunity expressions are equivalent in both sexes, indicating that despite its preference for males, the threat of Covid-19 can easily target females. Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the “cytokine storm,” the aggravated immune response that indiscriminately perseveres, rampaging the host’s vital organs. Sedentary lifestyle, age-related hormonal imbalance, and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion, spotlighting the detrimental aftermath of metabolic dysfunction, and excess food consumption, provoked by elevated cortisol and dysregulated appetite hormones. ACE2 expression is suppressed in the skeletal muscle, rendering fitness and weight management an effective Covid-19 preventive intervention, along with social distancing, hygiene, and facial coverings. Physical activity, or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein (CRP), triglycerides, visceral fat, cortisol and the orexigenic hormone ghrelin, juxtaposed by optimal increases of IGF-1, skeletal muscle mass, Free T3, HDL, and the anorexic hormone leptin.


Introduction
The severe acute respiratory syndrome coronavirus2 (SARS-Cov-2) related to the Coronavirus disease 2019 (Covid-19) is currently recognized as a global health crisis. In a way, it resembles the initially unforeseen results of the David and Goliath battle, the virus against all our medical advances, ultimately leading to devastating consequences that range from lockdowns and economic disruption to family and personal tragedies with over a million deaths worldwide. The purpose of this review was to analyse the six primary strategies currently available in the prevention and treatment of SARS-CoV-2. 1/Inhibit the 'type II transmembrane serine protease' (TMPRSS2) that primes both ACE2 receptors and the Covid's Spike (S1, S2) glycoproteins to facilitate their fusion. 2/ Increase shedding of the ACE2 receptors, induced by 'A Disintegrin And Metalloprotease 17'(ADAM17) that may potentially restrict the spread of the disease. 3/ Obstruct the action of the Nucleocaspic (N) proteins involved in the replication of the viral DNA. 4/ Prophylactic measures or techniques to harness the rampaging inflammatory response leading to the "cytokine storm" that promotes high mortality rates. 5/ Protect against infection with hygiene, face coverings and social distancing. 6/ Capitalize on wellbeing via a lifestyle that promotes optimal weight, fitness and hormonal balance to prevent and/or defend against infection.

The Dilemma of Ang II and ACE2 Receptors
The imminent fusion between Covid-19 Spike (S) proteins and angiotensin enzyme-2 (ACE2) receptors preludes the viral entry into human cells, placing the focus on the hierarchic multi-dimensional activity of the renin angiotensin system (RAS) [1]. Angiotensin enzyme (ACE) cleaves Ang II from Ang I, hence increasing Ang II, which can be then transformed into Ang III and IV. Angiotensins are vasoconstrictor hormones that increase blood pressure. ACE2 catalyses Ang II, generating Ang (1-7), a vasodilator agent that features antioxidant and anti-inflammatory effects; ACE2 metabolizes Ang I into Ang (1)(2)(3)(4)(5)(6)(7)(8)(9) which performs a protective function on the heart, the vessels, and possibly the kidneys; while ACE, which actually determines the Ang II production results in the degradation of Ang (1-7) [2][3][4][5]. Based on this simultaneous mosaic of processes, ACE inhibitors decrease the production of Ang II, and increase the Ang (1-7) in the system. With regards to Covid-19, as ACE inhibitors compromise the levels of Ang II, they reduce the concentrations of 'A Disintegrin and Metalloprotease 17' (ADAM17) which is normally promoted by Ang II. ADAM17 can cleave ACE2 from the cellular membrane, shedding it into body fluids, thus restricting the viral S proteins' fusion with ACE2 receptors, consequently, limiting infection [6,7]. The ADAM17 cleavage of ACE2 that can be potentially beneficial to suppressing the entrance and spread of the virus, is an antagonist to the 'type II transmembrane serine protease' (TMPRSS2) which cleaves both the ACE2 receptor and the viral S proteins, preparing them to fit into each other, hence facilitating the ominous proliferation of . This priming action of TMPRSS2 is necessary for the S/ACE2 fusion that commences the viral advancement into the body.
Ang II is functional in upregulating ADAM17 that is involved in the ACE2 shedding thus restricting Covid-19 access into the cell; however, Ang II increases inflammation, oxidative stress and has been associated with atherosclerosis [9]; ACE2 catalyses Ang II, acting as a protective mechanism against the blood pressure increase induced by Ang II that would otherwise be deleterious to diseases such as hypertension, diabetes, and cardiovascular illness [10]. ACE2 receptors protect the lungs from pulmonary vasoconstriction and remodelling, they prevent myocardial hypertrophy and high blood pressure; yet, by the same token, they serve as a Covid-19 gateway, exposing the body to the deleterious effects of the virus. Ang II increases pulmonary edema and vascular permeability that can result in ARDS (Acute Respiratory Distress Syndrome); it induces atherosclerosis, hypertension and possible heart failure; yet it is involved in the shedding of ACE2 receptors via ADAM17 which ultimately reduces the chances of viral entry. The lethal effects of SARS-COV-2 are more pronounced in pre-existing cardiac and pulmonary disorders, spotlighting the dualistic function of both Angiotensin II and ACE2 receptors that can be both an advantage and a disadvantage, rendering treatment insurmountable when SARS-CoV-2 is combined with dysfunctional vital organs.

The Complex Testimony of Human
Tissues SARS-CoV-2 affects the upper respiratory track with flu-like symptoms, and the lower respiratory system by symptoms including difficulty breathing that may evolve into pneumonia or the Acute Respiratory Distress Syndrome (ARDS). Counterintuitively, the lungs do not encapsulate the greatest multitude of ACE2 receptors. The analysis of 31 normal human tissues revealed that adipose tissue, heart, testes, kidneys and small intestines had the highest ACE2 expression, rendering these organs the primary Covid-19 targets, representing the most vulnerable points of viral entry. The lungs, adrenal gland, bladder, liver and colon manifest a moderate ACE2 expression, while the muscle, the brain, blood vessels, spleen and bone marrow evince the lowest ACE2 expression [11,12]. These investigators also explored male, female, young and old immune cells including a) B cells, lymphocytes that develop into plasma cells producing antibodies; b) natural killer cells (NK); c) CD8+ cells which include cytotoxic T cells that specifically target viral infections; and d) interferons, that represent proteins designed to inhibit viral replication, as well as T cells' suppressors, designed to restrain an over reactive immune system. Males' ACE2 expression in the lungs, thyroid, liver, colon, kidney, stomach, testes, and pancreas was linked with increased levels of B, NK, CD8 + T cells and interferons. On the other hand, females' ACE2 expression in the lungs and thyroid was associated with decreased levels of B, NK, CD8+ T cells. Increased ACE2 expression in the female heart tissues was accompanied by increased B, NK, CE8 + T cells and Interferons, unlike male heart tissues, where ACE2 receptors and immune cells featured a negative correlation. ACE2 receptors in the kidneys, skin, stomach, and adipose tissue were associated with increased levels of immune cells in both sexes. ACE2 receptors were positively correlated with the lung tissues of older individuals over 45 years and negatively correlated with the lung tissues of younger individuals under 45 years of age. These results reflect a male vulnerability in terms of the positive ACE2/immune cells' correlation with the lungs, testes and thyroid tissues, and a disadvantage for females regarding the positive ACE2/immune cells correlations with the heart tissues.
The remaining tissues' ACE2/immunity correlations appeared to be similar in both sexes. The positive ACE2/immunity may signify the eventual mushrooming of the overstated immune response, preluding the lethal consequences of the cytokine storm, a process during which lymphocytes, leukocytes, interferons and CD8+ T cells spin out of control in an overly aggressive attack against the virus that causes injury to the vital organs.
The positive ACE2/immunity correlations in male lungs, testes and thyroid tissues, and older individuals' lung tissues when compared to females and younger people respectively, may explain the higher SARS-COV-2 mortality rates among males and the eldest [11,12,13]. However, the higher correlation between ACE2 receptors and immune cells in female heart tissues, as well as the fact that such positive correlations are equivalent in both males' and females' kidneys, skin, stomach, and adipose tissue, warns against reaching the conclusion that women are indiscriminately less susceptible to the disease. Therefore, a thorough medical evaluation of all vital organs is necessary in evaluating female prognosis to Covid-19. More research focused on human tissues' analysis from SARS-COV-2 patients may be necessary to further elucidate the molecular interactions between ACE2 receptors and the complex network of immune activity.

The Mechanics of the Cytokine Storm
Cytokine storm reflects a persistent immune response, defensively propelled to annihilate the virus that blindly perseveres, rampaging the infected vital organs with lethal consequences [14. 15]. Cytokines are pleiotropic, multifunctional bio-communication agents composed by diverse, yet interconnected entities, including: 1. Interferons (INFs) which regulate immune activity and are classified into I, II, and II subtypes; INFs type I (IFN-αs, IFN-β, IFN-ω, IFN-κ, and IFN-τ) are crucial in eliciting immune responses against viral infections [16,17]. 2. Interleukins (IL) which are vital in stimulating the immune system; they are involved in the proliferation, differentiation and survival of leukocytes, otherwise known as white blood cells (WBCs). Interleukin-2 (IL-2) is a signalling molecule that has been used to treat cancer, while Interleukin-3 (IL-3) has a protective function regarding the survival of macrophages and mast cells, and a preventive one against cellular apoptosis [18]. Interleukins have both pro-and antiinflammatory properties. Interleukins-1a and 1b (IL-1a and IL-1b) are proinflammatory. IL-6 is both a proinflammatory cytokine and an antiinflammatory myokine. IL-8 in involved in elevating inflammation [19]. IL-10 is largely accepted as an anti-inflammatory cytokine [20]. 3. Chemokines which are mostly proinflammatory, recruit leukocytes and other immune cells, like neutrophils and monocytes/macrophages to attack viral entities; leukocytes demonstrate a positive chemotaxis -a Greek work that reflects a chemically driven movement towards a stimulus. Leukocytes shift from blood vessels towards, and into bodily tissues initiating inflammation. Chemokines are primarily classified into CXC, CC, C, and CX3C3 subtypes [21]. 4. Colony-stimulating factors (CSFs) activate the genesis of hematopoietic progenitor cells (HPCs), and are closely associated to inflammation via an intertwined network that features IL-1 and the tumour necrosis factors (TNF) [22]. 5. Tumour Necrosis Factor (TNF) stimulates cytotoxic T lymphocytes (CTL), or otherwise known as T-killer cells, or CD8+ T-cells. TNF is a protagonist in the emergence of the cytokine storm and has been associated with chronic inflammation [23,24]. IL-1b is one of the central cytokines driving the lungs' proinflammatory processes [25]. The lungs' inflammatory condition provokes renal epithelial cell apoptosis and eventual renal dysfunction [26]. This happens as inflammation overflows from the lungs into the circulation, igniting systemic sepsis where TNF, IL-1b and IL-8 are eventually accompanied by a more substantial increase of IL-6, followed by the anti-inflammatory cytokine IL-10. This sequence suggests that IL-6 is stimulated by TNF and IL-1b which are manifested during the earlier stage of the infection [27,28]. The clinical manifestations of the cytokine storm appear to resemble a sepsis syndrome, or a Systemic Inflammatory Response Syndrome (SIRS), induced by the host's dysregulated response to infection. This may be partly genetically determined [29], while a sedentary lifestyle that accumulates adiposity and instigates inflammation, may be a major contributor to immune aberration evoking the cytokine storm. Interleukins (IL-1, IL-2, IL-6, IL-8) and TNF, along with the inflammatory marker C-Reactive Protein (CRP) are prominent in both subcutaneous and visceral adipose tissue, increasing the probability of Covid-19 infection, due to the abundance of ACE2 receptors in adipose tissue, while exposing the organism to the cytokine storm, due to the pre-existing elevated inflammatory condition [30][31][32][33][34][35][36][37]. Health is based on immune homeostasis which depends on a balance between proinflammatory cytokines and their inhibitors. For example, TNFR1 is the inhibitor of TNF, and IL-1RA is the inhibitor of IL-1b [38]. The disturbance of this balance is followed by the flaring of the cytokine storm. It is unclear if the immune cells can no longer distinguish between the virus and the infected tissues, or whether immune efficiency has deteriorated. Autopsies reveal minimal lymphocytes and neutrophils, yet a relatively larger number of macrophages, whose primary function is to engulf foreign substances and cellular debris [39]. However, an autopsy depicts a biological landscape after the war against the virus is over, and may not represent the processes occurring during the battle. Possibly, the excessive effort to overcome the virus depletes energy in the form of Adenosine Triphosphate (ATP), promoting lymphocytes' and neutrophils' apoptosis [40]. Energy depletion, however, does not accurately describe the entire process of why and how the immune activity turns against itself during the cytokine storm. Initially, cytokines regulate an innate or non-specific line of immune defence. This evolves into the adaptive immune response that focuses on the specific virus, a critical switch largely controlled by cytokines and chemokines. The cytokine storm is either the result of a) A deficient initial response; b)An inadequate switch between the innate and adaptive defences, hence compromising viral identification; or c) A series of errors during the adaptive stage, obscuring immune ability to distinguish between self and non-self, attacking and rampaging the vital organs of the host. A number of investigators have postulated that insufficient production of Interferon (INF) type I can impair immune innate action [41,42,43]. A recent review suggests that coronavirus is designed to hinder the critical process of viral recognition, and suppress the production of IFN type I, ultimately inhibiting the emergence of the adaptive immune response [44]. IFN type I was reportedly lower in a patient with poor prognosis and outcome [45]. The Interferon-induced proteins 2 and 10 chemokines (CXCL2) appear to be associated with disease severity, and there is evidence that patients with elevated CXCL10 have a larger number of fatalities [46,47]. There is evidence that severely ill patients are deficient in the human leukocyte antigen (HLA) system of proteins which are recorded by the major histocompatibility complex (HMC) gene. Additionally, they present defects related to the Immunoglobulin (IG) gene that regulates antigen receptors of the B cells. B cells secrete antibodies which target both bacteria and viruses, unlike T cells that can only recognize viral antigens [48]. HMC genes that encode many proteins involved in T cells antigens that are active during the adaptive response, are upregulated in recovered patients but not in deteriorated ones. HMC genes are essential for the adaptive immune response, therefore, possibly the transition from the innate to the adaptive immune response may be flawed. As a result the immune target remains non-specific, with compromised recognition of the actual virus, resulting in an indiscriminate general attack that involves the tissues of vital organs with inevitable deleterious circumstances [49,50].

Methods to Inhibit Viral DNA Replication
As previously stated Nucleocaspic (N) proteins are instrumental in the viral RNA replication and transcription that is facilitated by the RNA-dependent RNA polymerase 12 (RdRp), or otherwise known as non-structural protein 12 (nsp12) in collaboration with the non-structural proteins nsp7 and nsp8. Nsp12 is the primary target of Remdesivir, a nucleotide analogue (NA) antiviral inhibitor that has recently gained popularity in the treatment of SARS-CoV-2 by inhibiting viral RNA replication [51,52,53,54,55,56,57]. Clinical research found a statistically significant advantage of Covid-19 patients receiving a 5-day Remdesivir course vs. standard care, but no difference between the 5-and 10-day Remdesivir courses [58]. However, a data analysis shows only a small clinical improvement between the 5day / 10-day Remdesivir groups when juxtaposed against the standard care group. From the 193 patients who received a 10day Remdesivir course, 2 died and one required invasive mechanical ventilation, while 0 needed non-invasive ventilations. From the 191 patients who received a 5-day Remdesivir course, 0 died or required invasive mechanical ventilation, while 5 needed non-invasive ventilation. From the 200 standard care patients, 4 died, 4 required invasive mechanical ventilation, and 7 required non-invasive ventilation. Subsequent evidence with 1,300 participants revealed that Remdesivir may speed up clinical improvement and reduce fatalities in severely ill patients. Overall, most current research provides low certainty, and a weak recommendation for Remdesivir in the treatment of 60,61,62].

Protective Methods
The extensive person-to-person transmission of Covid-19 by asymptomatic individuals or those at the initial stages of the disease has driven the World Health Organization (WHO) to reverse their original recommendation that did not require face coverings [63][64][65][66][67][68]. Wearing masks can protect the public from those who have already contracted the virus, while being a successful prophylactic measure in reducing the viral load when one is near infected individuals [69][70][71].
Social models emerging from Taiwan, China and Hong Kong where a large part of the population wears masks have demonstrated both a lower infection and mortality rate, unlike countries like the USA where not wearing a mask is considered as a right to personal freedom [72,73,74]. Hygiene and social distancing are globally accepted as additional protection methods against Covid-19.

Capitalize on Wellbeing
A retrospective clinical trial on 150 Covid-19 patients demonstrated that visceral adiposity (p=0.032 p<0.05), age (p=0.009 p<0.01) and inflammation measured by Creactive protein (CRP -p<0.0001), were positively correlated with poor prognosis and elevated mortality rates [75]. Another clinical study used computer tomography (CT) to determine the presence of Visceral Adipose Tissue (VAT) in Covid-19 infected patients. BMI did not distinguish between patients in the normal ward and Intensive Care Unit (ICU) with or without mechanical ventilation. In fact the ICU patients without mechanical ventilation had a slightly higher BMI. ICU patients that did not required mechanical ventilation manifested larger amounts of subcutaneous fat; however, the most severely ill ICU patients that required mechanical ventilation were distinguished by their accumulated VAT. These investigators concluded that VAT may be a possible predictor of exacerbated symptomatology and poor prognosis after contracting Covid-19 [76]. These results were confirmed by another CT study examining hepatic steatosis associated with visceral fat, as well as epicardial adipose tissue (EAT) in younger Covid-19 patients under 40 years of age that classified VAT as one of the primary risk factors of viral vulnerability and disease severity [77].
VAT has a higher expression of ACE2 receptors, which, as previously noted, represent the entry points of Covid-19, in contrast to muscle tissue that has the lowest expression of ACE2 receptors. Therefore, any method that reduces VAT, utilizing it as an energy source to increase muscle can serve as a protective and preventive measure to safeguard health during this pandemic. VAT generates more fatty acids, angiotensinogen, and interleukin-6 that can act as a proinflammatory cytokine, than subcutaneous adipose tissue (SAT) [78]. Glucose and fatty acids metabolism provide the energy both for the basal metabolic processes that sustain life during rest, and the increased demand for energy during exercise where myokines like Insulin Growth Factor-1 (IGF-1), Fibroblast Growth Factor2 (FGF2), interleukins-6 (IL-6) and IL-7 are involved in muscle hypertrophy [79,80]. Experiments where artificially elevated free fatty acids were added during sustained physical activity found that the metabolic process initially used carbohydrates in the first 15 minutes, decreasing glycogen by 50%, and increasing fat oxidation by 15% after 30 minutes [81,82]. Fat metabolism reflects a complex process that commences with the release of free fatty acids (FFA) from the adipose tissue, which are transferred across the membranes of muscle cells, where they bind with protein receptors in the cytoplasm, with the mitochondria being the final destination, where the oxidation process, i.e. burning fat via oxygen takes place; this results in the release of electrons, which in turn push protons to mobilize the energy production process by spinning the ATPace synthase anabolic enzyme clockwise, to add a phosphate to Adenosine Diphosphate (ADP), via the transmembrane proton gradient to compose Adenosine Triphosphate molecules of energy [83,84,85,86,87,88]. Growth Hormone (GH) appears to be instrumental in reducing visceral fat on the basis of a 12 month computed tomography (CT) clinical trials that administered recombinant human GH to 40 postmenopausal women, demonstrating reduced visceral fat tissue upon completion [89]. Relatively to SAT, VAT secretes less anorexic hormone leptin.
Although a clinical trial in Europe demonstrated a high correlation between leptin and VAT [90], other studies with Asian men and African American women indicated that leptin is associated with overall fat rather than VAT specifically. VAT appears to be a liable predictor of insulin sensitivity, elevated levels of triglycerides and inhibited high density lipoproteins (HDL) [91,92]. VAT is also associated with triiodothyronine (T3) and the identifier of atherosclerosis pulse wave velocity (PWV) [93]. Weight management solutions including lasers and RF primarily address subcutaneous fat reduction with no evidence of increased fitness; additionally, there are several reports of eventual escalated inflammation following some of these procedures [94][95][96][97][98][99].
Pre-existing inflammation can potentially exacerbate the deleterious immune response termed "cytokine storm" that is detected in Covid-19 severe cases; therefore, inflammation inducing procedures may be counterproductive and conceivably dangerous. Physical fitness has been deemed a health enhancing solution by a number of research projects [100,101,102,103,104,105,106,107,108]. On the other hand there is evidence that exercise may induce asthma that usually exacerbates Covid-19 symptomatology, or provoke an inverse cortisol/testosterone relationship, while supressing the anorexic hormone leptin, thus increasing food consumption [109][110][111][112][113][114].
Recent studies report an advantage with an exercise alternative method invented in London University that results in hormonal balance, and enhanced wellbeing as measured by statistically significant decreases of visceral fat, inflammation, CRP, BMI and Triglycerides, juxtaposed by optimal increases of skeletal muscle mass, Free T3, IGF-1 and HDL [115,116,117,118,119,220,221,222,223,224,225]. We combined some of the data presented in these studies and analysed the results with ANOVA for repeated measures.

Data Results Analysis
The visceral fat decrease and skeletal mass increase of 29 patients, 20 females and 9 males with an average BMI of 29.9 are shown on Table 1. Table 2 reflects the results of the same patients indicating a statistically significant increase in the anorexic hormone leptin contrasted by an optimal decrease in the orexigenic hormone ghrelin. Table 3 depicts leptin ranges in relation to body mass index. Table 4 shows the inflammation reduction as measured by CRP and the cortisol decrease of 10 females with an average BMI of 32.91 and at least one medical condition.       Table 6 reflects the results of 20 subjects, 15 females and 5 males on Free T3 and IGF-1.  Table 7 shows the significance values for all variables after the data was analysed with ANOVA for repeated measures. Results yielded highly statistically significant results.
Visceral fat decrease was accompanied with increased skeletal muscle mass. IGF-1, Free T3 and Leptin increased within the normal range, while cortisol and ghrelin decreased but without descending into abnormality. These results demonstrated a centralized tendency towards hormonal balance and optimal appetite regulation resulting by a healthy proportional interaction between the anorexic hormone leptin, juxtaposed by the relatively suppressed concentrations of the orexigenic hormone ghrelin, combined with reduced cortisol that is known to provoke stress-eating behaviours. Elevated HDL was accompanied by diminished triglycerides.

Discussion
The immune collapse during the cytokine storm following Covid-19 invasion that has infected over forty-three million individuals worldwide, resulting in over a million deaths, brings to mind the unpredictable defeat of the giant during the David and Goliath battle. The virus enters the system via ACE2 receptors which catalyze Angiotensin II (Ang II). Excess Ang II increases blood pressure that is deleterious to diseases such as hypertension, diabetes, and cardiovascular illness, which represent the pre-existing conditions with elevated Covid-19 mortality rates. On the other hand, Ang II increases concentrations of 'A Disintegrin and Metalloprotease 17' (ADAM17) that can cleave ACE2 from the cellular membrane, shedding it into body fluids, thus restricting viral access. Human tissues' research has revealed a multitude of ACE2 receptors in adipose tissue, heart, kidneys, thyroid, testes and small intestines, with relatively less ACE2 expression in the muscle, brain, spleen and blood vessels. Lungs, liver, adrenal gland, bladder and colon seem to be somewhere in between. Investigation of B, NK, CE8+ T cells and Interferons in males, females, young and old, has shown a greater susceptibility among older individuals evidenced by a multitude of immune cells in the lungs. Higher ACE2 expression in the testes in addition to other tissues increase male vulnerability that is marked by the elevated number of certain immune cells in the lungs, thyroid, adrenals, liver and colon. In contrast, females present a higher positive correlation between immune cells and the heart; all other tissues manifest equivalent levels of immune cells in both sexes. In other words, there may be a Covid-19 preference for males and older individuals, but without a safety guarantee for females that may be equally susceptible in certain cases. A literature review of the immune overreaction during the cytokine storm suggests a possible imbalance between proinflammatory cytokines and their inhibitors, a deficient innate response due to insufficient production of INF type I, or a dysregulated transition from the nonspecific / innate to the adaptive immune response that is designed to recognize and attack the particular threat, represented in this case by Covid-19. Hence, the frenzied immune overreaction aimlessly persevering, unable to distinguish self from non-self that rampages and injures the body. New pharmaceuticals designed to interfere with viral RNA replication like Remdesivir that targets the non-structural protein 12 (nsp12) in collaboration with the nonstructural proteins nsp7 and nsp8, have had modest to moderate clinical outcomes, providing a weak recommendation for Remdesivir in the treatment of Covid-19. Protective techniques including, face coverings, social distancing and thorough hygiene, as well as prevention via fitness, health enhancement and weight management are currently the most reliable methods of limiting the spread of the pandemic. Visceral adipose tissue (VAT) is strongly linked to Covid-19 severely ill patients in ICU needing mechanical ventilation, irrespective of BMI which does not distinguish between patients in normal wards and ICU. VAT has a higher expression of ACE2 receptors that represent the portals for Covid-19 entry. VAT generates more fatty acids, angiotensinogen, and the proinflammatory interleukin-6 (IL-6). Any method that reduces VAT, utilizing it as an energy source to increase muscle which features the least ACE2 receptors, therefore limiting Covid-19 entry, can serve as a protective and preventive measure in safeguarding health during this health crisis. Lasers and RF primarily address subcutaneous fat reduction with no evidence of increased fitness, and often report escalated inflammation following some of these procedures. Physical activity has universally accepted benefits, but also a downside by provoking an inverse cortisol/testosterone relationship, while supressing the anorexic hormone leptin, thus increasing food consumption. Recent research on an effortless exercise intervention presents statistically significant VAT and inflammation reduction, juxtaposed by skeletal muscle mass increase, along with reduced lipids, cortisol and the orexigenic hormone ghrelin; importantly, it also elevates Free T3, IGF-1 and the anorexic hormone leptin within the normal range, offering an optimal alternative to fast efficient fitness. These clinical trials, however, are mostly based on small samples, in the absence of imaging techniques that can substantiate their results, warranting the need for additional research.

Acknowledgement
The author would like to thank all the patients that supplied their records for the metanalysis included in this review.

Conflict of Interest
The author declares no conflict of interests. This study was conducted by independent operators that were not employed or contracted by the author.

Funding
No funding was received by a third party or institution. blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension, 75 (6) Pugin, J., Ricou, B., Steinberg, K.P., Suter, P.M. and Martin, T.R., 1996. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1.
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