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Background Several coronavirus vaccine have been fast-tracked to halt the pandemic, the usage of immune adjuvants that can boost immunological memory has come up to the surface. This is particularly of importance in view of the rates of failure of seroconversion and re-infection after COVID-19 infection, which could make the vaccine role and response debatable. Peroxisome proliferator-activated receptors (PPARs) have an established immune-modulatory role, but their effects as adjuvants to vaccination have not been explored to date. Main body of the abstract It is increasingly recognized that PPAR agonists can upregulate the levels of anti-apoptotic factors such as MCL-1. Such effect can improve the results of vaccination by enhancing the longevity of long-lived plasma cells (LLPCs). The interaction between PPAR agonists and the immune system does not halt here, as T cell memory is also stimulated through enhanced T regulatory cells, antagonizing PD-L1 and switching the metabolism of T cells to fatty acid oxidation, which has a remarkable effect on the persistence of T memory cells. What is even of a more significant value is the effect of PPAR gamma on ensuring a profound secretion of antibodies upon re-exposure to the offending antigen through upregulating lipoxin B4, therefore potentially assisting the vaccine response and deterring re-infection. Short conclusion In view of the above, we suggest the use of PPAR as adjuvants to vaccines in general especially the emerging COVID-19 vaccine due to their role in enhancing immunologic memory through DNA-dependent mechanisms.

Supplemental Digital Content is available in the text., Introduction Coronavirus disease 2019 (COVID-19) is the largest outbreak to strike the world since the Spanish flu in 1918. Visual examination of the world map shows a wide variation of death tolls between countries. The main goal of our series is to determine the best predictors of such discrepancy. Methods This is a retrospective study in which the rate of COVID-19 deaths was correlated with each of the following independent variables: total tests per 1 million population, gross domestic product (GDP), average temperatures per country, ultraviolet index, median age, average BMI per country, food supply, Bacille Calmette-Guerin compulsory status, and passenger traffic. Results BMI per country proved to be the second best predictor of death rate with an R value of 0.43, and GDP being the best predictor with R = 0.65. Conclusion This article shows a tight correlation between average BMI, food supply per country, and COVID-19-related deaths. Such predisposing factors might operate by upregulating the inflammation pathway in heavily struck countries, leading to easier triggering of the infamous cytokine storm syndrome. Obesity also increases cardiovascular and respiratory morbidities, which are coupled to increased ICU demand and deaths among infected cases. Video abstract: http://links.lww.com/CAEN/A25.

Background: With the current mass international roll out of several vaccines against SARS-Cov-2, several reports of unheeded complications have made headlines. One of which involves myocarditis with the now FDA fully approved vaccine, Pfizer, and others. We hypothesize through this study that a dysregulated micro-RNA response resulting from such type of vaccines can be involved in triggering myocarditis. Methodology: Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “mRNA COVID-19 vaccines” AND “Myocarditis” for relevant publications up to 1st of September 2021. The systematic review was performed using PRISMA protocolResults:Literature review has identified 26 cases series and reports involving the development of myocarditis from mRNA vaccines, a total of 89 patients were included. Age range was clearly identified in 66 patients. Among those 66 patients, 94% were below 50 years of age, also out of 89 patients, 94% were males. Myocarditis developed, after a median time of 72 hours of the 2nd dose. 90 of cases of myocarditis developed myocarditis after the 2nd dose, the few patients developing myocarditis after the first dose were either predisposed by a history of myocarditis or a history of previous COVID-19 infection. Conclusion:In conclusion, interpretation of the results in view of the suggested hypothesis, reveals that the micro-RNAs implicated in myocarditis in general are as well implicated in the pathogenesis of severe COVID-19, this can explain why patients having a first dose with a history of COVID-19 can develop myocarditis from mRNA vaccines, also the relatively higher likelihood of this complication in males and younger aged individuals can be explained by the upregulation of key myocarditis related miRNAs in those two strata, due to higher muscle mass and suggests performing a sarcopenia index in recipients of the vaccine to correlate it with the likelihood of this complication. This could later set a cut-off of this easy bed-side index to stratify cases a higher risk of this rare complication.

Background Several vaccines have been fast-tracked in an attempt to decrease the morbidity and mortality of COVID-19. However, post-exposure prophylaxis has been overlooked in battling COVID-19. Main text Inhaled nitric oxide is a potential tool in post-exposure prophylaxis of COVID-19. It decreases cytosolic calcium levels, which impairs the action of Furin. SARS-CoV-2 uses Furin to replicate in the respiratory tract. Short conclusion Inhaled nitric oxide could decrease the viral load in the upper respiratory tract, abort clinically symptomatic infection, and prevent subsequent complications. Nitric oxide might be a tool for post-exposure chemoprophylaxis in at-risk groups, especially medical personnel.

Background: Postexposure prophylaxis has been an overlooked strategy in the context of COVID-19. Inhaled Nitric Oxide offers itself as a potential tool in this context. The aim of this systematic review was to depict previous in vivo and in vitro studies demonstrating an antiviral role for NO Methodology:Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “Nitric oxide” AND “Antiviral activity” for relevant publications up to 1st of June 2021. The systematic review was performed using PRISMA protocolResults:Twenty-one studies were identified depicting an antiviral role for Nitric Oxide. Those studies involved sixteen viruses. Only four of the depicted studies were clinical trials, while three were performed on a murine model. The remainder of the studies involved in vitro experimentation of the role of NO in halting viral replication of several viruses including SARS-CoV-2Conclusion: While early reports of NO role in the treatment of COVID-19 suggested its use for the treatment of established ARDS, NO seems to have a much earlier and more efficient prophylactic role. It inhibits a protease needed for canonical viral replication of SARS-CoV-2, namely Furin, by decreasing calcium's cytosolic levels. This might add a significant tool for postexposure chemoprophylaxis in the at-risk group, especially medical personnel.

Ever since the uncovering of the severe discrepancy of COVID-19 manifestations, irrespective of viral load, scientists have raced to locate and manage factors contributing to the genesis of a critical state. Recent evidence delineates the role of oral dysbiosis in the development of low-grade inflammation, characterized by the increase of inflammatory cytokines common to those fundamental to the development of severe COVID. Furthermore, high periodontopathic bacteria were recorded in severe acute respiratory syndrome in COVID patients as well as its common provoking comorbidities such as diabetes and hypertension. This can be explained by the immigration and elimination of oral bacteria into the airways, which, in the context of an injured lung, allows for their preferential overgrowth familiar to that causing the progression to advanced lung diseases. This is why we indicate the promising usage of oral microbiome transplantation as a treatment of the oral microbial dysbiosis, not only associated with worst outcomes of COVID-19 but also in other disorders of low-grade inflammation., Graphical abstract Image 1

Background: Recent reports of the prothrombotic states announced in the recipients of the ChAdOx vaccine, similar to HIT sounded alarm bells internationally.The sole outcome parameter of this systematic review was to detect similar cases of Prothrombotic state in COVID-19 infected patientsMethodology: Embase, Medline and the Cochrane Central Register were used to search for specic keywords such as “COVID-19” OR “SARS-CoV-2” AND “Heparin induced thrombocytopenia” for relevant publications up to 1st of April 2021. The systematic review was performed using PRISMA protocol.Results: Nine cases reports/series have been identified including 18 cases, venous thrombosis was the commonest type of observed thrombosis accounting for 72 % of cases, the mean age of cases was 57±4.Conclusion: Similar episodes of HIT were detailed in several case reports of COVID patients. This suggests a common pathogenesis and warrants a screening of all COVID-19 patients presenting with thrombo-embolism using anti-PF4 antibodies and using non heparin based anticoagulants for their management.

Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.

The COVID-19 death toll has involved to date more than 1 million confirmed deaths. The death rate is even higher in the obese COVID-19 patients, as a result of hypoxia, due to the interplay between adipose tissue hypoxia and obstructive sleep apnea. The discrepancy of manifestations seen in COVID-19 seems to be mediated by a differential immune response rather than a differential viral load. One of the key players of the immune response is HIF. HIF-1β is a stable constitutively expressed protein in the nucleus; and under hypoxic changes, its activity is unaffected, whereas the HIF-α subunit has a short half-life and because of its degradation by an enzyme known as propyl hydroxylase; under hypoxic conditions, propyl hydroxylase gets deactivated thus leading to the stabilization of HIF-1α. As mentioned before, HIF-1α expression is triggered by hypoxic states, this crippling condition will aggravate the pro-inflammatory characteristics of HIF-1α. The vast majority of decompensated COVID19 cases manifest with drastic lung injury and severe viral pneumonia, the infection-induced hypoxia will the existing hypoxia in obesity. This will additionally augment HIF-1α levels that will provoke the already existing cytokines' storm to fulminant. Consequently, this will directly correlate the effect of a hypoxic environment with the increase of HIF-1α level. HIFɑ exists in two main isoforms HIF-1α and HIF-2α. HIF-1α and HIF-2α act in distinct ways in how they work on different target genes. For example, HIF-2α may act on hemopoietin genes (heme-regulating genes); while HIF-1α acts on EPO. HIF-1α release seems to be markedly augmented in obesity due to adipose tissue hypoxia and obstructive sleep apnea resulting in cyclic hypoxia. HIF-1α can also be secreted by direct viral proteolytic effects. Whereas, HIF-2α is stimulated by chronic hypoxia. HIF-1α exerts detrimental effects on the immune system, characterized by unopposed pro-inflammation at the macrophages, dendritic cells, T cells, and complement levels resulting in cytokines’ storm, which is linked to the poor outcomes of COVID-19. On the other hand, HIF-2α role is regulatory and largely opposes the actions mediated by HIF-1α. In view of this, inhibiting HIF-1α release or switching its production to HIF-2α by natural products such as resveratrol or by synthetic drugs, offer a good therapeutic strategy that can prevent COVID-19 worst outcome in infected patients. The approach of breaking the vicious circle between lung damage-induced hypoxia and HIF-1α pro-inflammatory stimulant through drugs is considered to be extremely promising as a therapeutic manner to combat further deterioration of COVID19 cases., Highlights • HIFɑ exists in two isoforms HIF-1α (pro-inflammatory) and HIF-2α (regulatory); HIF-1α is increased in obesity, due to the presence of ATH and OSA. • Despite being a transcription factor, HIFɑ circulates to nearby cells through the so called extracellular vesicles. • COVID-19 associated lung damage induces an acute hypoxic state, which activates HIF-1α. • HIF-1α, in turn, exacerbates the production of pro-inflammatory cytokines, thus increasing the likelihood of cytokine storm in COVID-19. • In view of the above, HIF-1α inhibitors or alternatively switchers to HIF-2α can prevent COVID-19-induced cytokine storm.

Background:As more than 37 million confirmed cases and 1 million deaths worldwide from COVID-19, we flied to think about supporting immunity, So, there are more than 150 coronavirus vaccines and clinical trials are being developed. The success of those vaccines depends mainly on immunologic memory. People who are at high risk of re-infection with COVID-19 don’t show any evidence of having B-cell memory. 10-20% of infected patients don’t develop antibody response. randomized controlled trials and cross-sectional studies proved variant results about the effect of chronic exercise on vaccination function.The aim of this review is to suggest that exercise is an important adjuvant strategy for prevention of re-infection and for development of better protective responses following vaccination.Methods:Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “COVID-19” OR “SARS-CoV-2” AND “Re-infection” for relevant publications up to 1st of Nov. 2020. The systematic review was performed using PRISMA protocol.Results:According to inclusion criteria, 6 case reports from search and one case from a press conference were identified. The average age of re-infected patients was 36 years. The average intervening period between initial infection and reinfection was 105 days. 75% of cases who have been tested for antibodies after 1st infection were negative, and turned seropositive after second infection. 57% of cases developing re-infection had worse clinical manifestation.Conclusion:Regular moderate intensity exercise not only can enhance the secondary antibody response of B cell memory but also decrease the severity of re-infection and the adverse reactogenicity of potential vaccines under development.

Background: As more than 37 million confirmed cases and 1 million deaths worldwide from COVID-19, we flied to think about supporting immunity, So, there are more than 150 coronavirus vaccines and clinical trials are being developed. The success of those vaccines depends mainly on immunologic memory. People who are at high risk of re-infection with COVID-19 don’t show any evidence of having B-cell memory. 10-20% of infected patients don’t develop antibody response. randomized controlled trials and cross-sectional studies proved variant results about the effect of chronic exercise on vaccination function.The aim of this review is to suggest that exercise is an important adjuvant strategy for prevention of re-infection and for development of better protective responses following vaccination.Methods: Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “COVID-19” OR “SARS-CoV-2” AND “Re-infection” for relevant publications up to 1st of Nov. 2020. The systematic review was performed using PRISMA protocol.Results: According to inclusion criteria, 6 case reports from search and one case from a press conference were identified. The average age of re-infected patients was 36 years. The average intervening period between initial infection and reinfection was 105 days. 75% of cases who have been tested for antibodies after 1st infection were negative, and turned seropositive after second infection. 57% of cases developing re-infection had worse clinical manifestation.Conclusion: Regular moderate intensity exercise not only can enhance the secondary antibody response of B cell memory but also decrease the severity of re-infection and the adverse reactogenicity of potential vaccines under development.

Background Coronavirus disease 2019 (COVID-19) emerged as a small outbreak in Wuhan rapidly progressing into the deadliest pandemic since the Spanish flu of 1918. The disease was deemed trivial in children, until the reporting, few days ago, of an emerging pediatric multi-inflammatory syndrome mimicking Kawasaki disease (KD). Main body This report reveals that coronaviridae were implicated in induction of several post-infectious vasculitides, namely, KD, AHEI, and HSP. This occurs in genetically susceptible individuals to vascular inflammation. Shared genetic susceptibilities between KD and CoV include genes encoding for CD 40, HLAB-15:03, and ACE. This leads to augmented inflammation with hypersecretion of cytokines especially IL-6. Conclusion The revealed relationships between KD and CoV can help to predict the risk of KD in COVID-19 patients through screening levels of upregulated cytokines. It might also signify that classic treatment of KD with IVIG might need to be replaced with anti-cytokine therapy in COVID-19 patients.

Furin, a cleavage enzyme, is increasingly recognized in the pathogenesis of metabolic syndrome. Its cleavage action is an essential activation step for the endothelial pathogenicity of several viruses including SARS-CoV-2. This Furin-mediated endothelial tropism seems to underlie the multi-organ system involvement of COVID-19; which is a feature that was not recognized in the older versions of coronaviridae. Obese and diabetic patients, males, and the elderly, have increased serum levels of Furin, with its increased cellular activity; this might explain why these subgroups are at an increased risk of COVID-19 related complications and deaths. In contrast, smoking decreases cellular levels of Furin, this finding may be at the origin of the decreased severity of COVID-19 in smokers. Chinese herbal derived luteolin is suggested to be putative Furin inhibitor, with previous success against Dengue Fever. Additionally, Furin intracellular levels are largely dependent on concentration of intracellular ions, notably sodium, potassium, and magnesium. Consequently, the use of ion channel inhibitors, such as Calcium Channel blockers or Potassium Channel blockers, can prevent cellular transfection early in the course of the illness. Nicotine patches and Colchicine have also been suggested as potential therapies due to Furin mediated inhibition of COVID-19., Highlights • 1-SARS-CoV-2 harbors a polybasic cleavage site. • 2-This polybasic cleavage site leads to its canonical activation by a cellular enzyme termed Furin. • 3-Furin is highly expressed in Endothelial, leading to endothelitis and vascular inflammation in COVID-19. • 4-This also explains the augmented manifestations of COVID-19 in Obese and Diabetic patients. • 5-The use of Chinese herbals and ion channel inhibitors can block the endothelial penetration of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is a serious illness that has rapidly spread throughout the globe. The seriousness of complications puts significant pressures on hospital resources, especially the availability of ICU and ventilators. Current evidence suggests that COVID-19 pathogenesis majorly involves microvascular injury induced by hypercytokinemia, namely interleukin 6 (IL-6). We recount the suggested inflammatory pathway for COVID-19 and its effects on various organ systems, including respiratory, cardiac, hematologic, reproductive, and nervous organ systems, as well examine the role of hypercytokinemia in the at-risk geriatric and obesity subgroups with upregulated cytokines' profile. In view of these findings, we strongly encourage the conduction of prospective studies to determine the baseline levels of IL-6 in infected patients, which can predict a negative outcome in COVID-19 cases, with subsequent early administration of IL-6 inhibitors, to decrease the need for ICU admission and the pressure on healthcare systems. Video abstract: http://links.lww.com/CAEN/A24.

Prothrombotic states, similar to Heparin induced thrombocytopenia (HIT) in recipients of the ChAdOx vaccine, sounded alarm bells internationally. Equivalent episodes of HIT were detailed in several case reports of Coronavirus Disease 2019 (COVID-19) patients. This suggests a common pathogenesis and warrants a shift in the management of implicated cases.

COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones.. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one., Highlights • ScRNA-seq focuses on the analysis of individual cells, instead of bulk cell populations, and can lead to a more insightful characterization of local microenvironments. • ScRNA-seq unleashed that tissue tropism in COVID-19 is not solely determinant by ACE2 distribution but rather by Furin. • ScRNA-seq in COVID-19 revealed two distinct types of immunologic reactions, deleterious type 1 characterized by inefficient antigen presentation, decreased memory B cells, imbalance between M1 and M2 macrophages and T cell exhaustion, and beneficial type 2 reaction which exactly the reverse of the type 1. • The immunotype 1 reaction is intriguingly similar to the immune landscape seen in obese individuals when leptin resistance sets in. • This might indicate that the use of leptin sensitizers to induce an immunologic switch from immunotype 1 to immunotype 2 can greatly improve the outcome of COVID-19 cases. • ScRNA-seq was also able to unveil the disparity between aggressive and milder strains of SARS-CoV-2, which are mainly related to their affinity to cellular activation by Furin. • The applications of ScRNA-seq may help to anticipate cases at higher risk of severe COVID-19 at their earliest encounter.