Search

The influence of SARS-CoV-2 antigen on the cytokine-producing function of immune cells was studied. We observed suppression of the production of proinflammatory cytokines by 11-46% relative to the spontaneous level under the influence of SARS-CoV-2 antigen vaccine simulator, as well as when it was co-administered with cortisol (IL-6 by 1.8 times and IFNγ by 1.57 times) compared with control samples. IL-8 production was reduced by 1.72 times relative to its spontaneous level. IL-8 production was reduced by 1.72 times relative to its spontaneous level. Under conditions of SARS-CoV-2 stimulation with the vaccine antigen in vitro, an increase in the relative scaled expression of the VEGFA gene by 2.16 times relative to the spontaneous level was observed, which can be regarded as a model "cytokine storm" scenario. The obtained experimental data verify the ideas about the pathogenetic mechanisms of the COVID-19 and can contribute to the development of new approaches to the correction of its complications. [ABSTRACT FROM AUTHOR]

First reports of the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the disease caused by the virus--coronavirus disease 2019 (COVID-19), were announced in late December 2019. Ever since, the disease has taken more than 6 million lives worldwide. COVID-19 is considered as dominantly respiratory and vascular disease which pathogenesis could be explained by hyperactivation of the immune response. Innate immunity receptors are responsible for the first contact with the virus and subsequent activation of transcription factors leading to the production of the high amounts of interferons (IFNs) and proinflammatory cytokines (IL-1ß, IL-6, TNF, etc.). Such an inflammatory response limits viral replications. However, SARS-CoV-2 have developed several ways to avoid immune protection by the host. Dysregulated secretion of these cytokines may lead to cytokine storm and PANoptosis, a life-threatening condition. This review article aims to describe the main characteristics of the innate immune response during the SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Infection with the SARS-CoV-2 virus results in manifestation of several clinical observations from asymptomatic to multi-organ failure. Biochemically, the serious effects are due to what is described as cytokine storm. The initial infection region for COVID-19 is the nasopharyngeal/oropharyngeal region which is the site where samples are taken to examine the presence of virus. We have now carried out detailed proteomic analysis of the nasopharyngeal/oropharyngeal swab samples collected from normal individuals and those tested positive for SARS-CoV-2, in India, during the early days of the pandemic in 2020, by RTPCR, involving high throughput quantitative proteomics analysis. Several proteins like annexins, cytokines and histones were found differentially regulated in the host human cells following SARS-CoV-2 infection. Genes for these proteins were also observed to be differentially regulated when their expression was analyzed. Majority of the cytokine proteins were found to be up regulated in the infected individuals. Cell to Cell signaling interaction, Immune cell trafficking and inflammatory response pathways were found associated with the differentially regulated proteins based on network pathway analysis. [ABSTRACT FROM AUTHOR]

Objective: In coronavirus disease -- 19 (COVID-19) patients, cytokine storm develops due to the increase of pro-inflammatory cytokines. Tocilizumab (TCZ), has been used in the treatment of COVID-19 patients and successful results have been obtained. The aim of this study was to determine the efficacy of TCZ and also investigate the prognostic factors affecting the success of treatment and mortality in COVID-19 patients treated with TCZ. Patients and Methods: Between March 2020 and August 2021, a total of 326 confirmed severe COVID-19 pneumonia patients, treated in the intensive care unit, were included in the study. Results: The mean age of the patients was 63.02±11.58 years, and 203 (62.3%) of the patients were male. Patients treated with TCZ had a longer survival time compared with the standard therapy (p=0.012). It was found that type of respiratory support (HR:2.19, CI:1.10- 4.36, p=0.025) and hyperlactatemia on the day of TCZ therapy admission (HR:2.93 CI:1.53-5.64, p=0.001) were the significant and independent prognostic factors of survival in severe COVID-19 pneumonia patients treated with TCZ. Conclusion: Tocilizumab therapy improved 30-days survival in critically ill COVID-19 pneumonia patients. Also, among the patients with TCZ, types of respiratory support and hyperlactatemia on the day of TCZ admission were the independent prognostic factors. [ABSTRACT FROM AUTHOR]

The severity of coronavirus disease 2019 is closely linked to dysregulated immune responses. The search for viral proteins associated with immune regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to reveal the pathogenicity of the virus. In this study, accessory proteins ORF7a (referred to as ORF7a-1 and ORF7a-2, respectively) from two SARS-related coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, were produced through the denaturing and refolding of inclusion body proteins. The recombinant protein was incubated with alveolar epithelial cells, and the transcription and expression levels of major cytokines were determined by reverse transcription-quantitative PCR and enzyme-linked immunosorbent assay. SARS-related coronavirus ORF7a can up-regulate the transcription and expression of interleukin-6, C-C motif chemokine ligand 8, interferon α, and interferon β. The results also indicated that the two highly conserved ORF7a had certain differences in promoting the transcription and expression of cytokines. The study showed that ORF7a is a virus-encoded immune regulator by alveolar epithelial cells that plays an important role in the pathogenicity of SARS-related coronaviruses. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia. [Display omitted] • SARS-CoV-2 infection of mice and Syrian hamsters activates the Ire1α-Xbp1 arm of UPR. • Ire1α-Xbp1 arm activity is associated with proinflammatory cytokine production. • SARS-CoV-2 leverages the Ire1α-Xbp1 arm for replication in lung epithelial cells. • The IRE1α-XBP1 arm is activated by Spike proteins from different variants of concern. [ABSTRACT FROM AUTHOR]

Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, and MCP-1 by increasing IκBα protein levels and significantly decreasing p65 nuclear translocation. Furthermore, we found that the combination of ciclesonide and dbq33b, a potent tylophorine-based coronavirus inhibitor that affects coronavirus-induced NF-κB activation a little, additively and synergistically decreased coronavirus-induced IL-6, IL-8, and MCP-1 cytokine levels, and synergistically inhibited the replication of both HCoV-OC43 and SARS-CoV-2. Collectively, the combination of ciclesonide and dbq33b merits consideration as a treatment for COVID-19 patients who may otherwise be overwhelmed by high viral loads and an NF-κB-mediated cytokine storm. [ABSTRACT FROM AUTHOR]

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID‐19 infection. The pathogenesis of COVID‐19‐related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS‐CoV‐2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF‐α + IFN‐γ or a cocktail of TNF‐α + IFN‐γ + IL‐6, increased expression of ACE2/DPP4, accentuated the pro‐inflammatory senescence‐associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence‐like state. IL‐6 by itself failed to induce substantial effects on viral entry receptors or SASP‐related genes, while synergy between TNF‐α and IFN‐γ initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper‐inflammation, normalized SARS‐CoV‐2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine‐mediated viral entry receptor activation and links with senescence and hyper‐inflammation. [ABSTRACT FROM AUTHOR]

In the beginning of the third year of the fight against COVID-19, the virus remains at least still one step ahead in the pandemic "war". The key reasons are evolving lineages and mutations, resulting in an increase of transmissibility and ability to evade immune system. However, from the immunologic point of view, the cytokine storm (CS) remains a poorly understood and difficult to combat culprit of the extended number of in-hospital admissions and deaths. It is not fully clear whether the cytokine release is a harmful result of suppression of the immune system or a positive reaction necessary to clear the virus. To develop methods of appropriate treatment and therefore decrease the mortality of the so-called COVID-19-CS, we need to look deeply inside its pathogenesis, which is the purpose of this review. [ABSTRACT FROM AUTHOR]

This study involves the histological analysis of samples taken during autopsies in cases of COVID-19 related death to evaluate the inflammatory cytokine response and the tissue localization of the virus in various organs. In all the selected cases, SARS-CoV-2 RT-PCR on swabs collected from the upper (nasopharynx and oropharynx) and/or the lower respiratory (trachea and primary bronchi) tracts were positive. Tissue localization of SARS-CoV-2 was detected using antibodies against the nucleoprotein and the spike protein. Overall, we tested the hypothesis that the overexpression of proinflammatory cytokines plays an important role in the development of COVID-19-associated pneumonia by estimating the expression of multiple cytokines (IL-1β, IL-6, IL-10, IL-15, TNF-α, and MCP-1), inflammatory cells (CD4, CD8, CD20, and CD45), and fibrinogen. Immunohistochemical staining showed that endothelial cells expressed IL-1β in lung samples obtained from the COVID-19 group (p < 0.001). Similarly, alveolar capillary endothelial cells showed strong and diffuse immunoreactivity for IL-6 and IL-15 in the COVID-19 group (p < 0.001). TNF-α showed a higher immunoreactivity in the COVID-19 group than in the control group (p < 0.001). CD8 + T cells where more numerous in the lung samples obtained from the COVID-19 group (p < 0.001). Current evidence suggests that a cytokine storm is the major cause of acute respiratory distress syndrome (ARDS) and multiple organ failure and is consistently linked with fatal outcomes. [ABSTRACT FROM AUTHOR]

The cytokine signature present in COVID-19 could provide information on the pathogenic mechanisms of the disease and could identify possible prognostic biomarkers and possible therapeutic targets. In this longitudinal work, we studied the clinical and biochemical parameters and circulating cytokine levels of 146 patients at the time of admission for COVID-19 and 4–6 weeks later. The main objective of this study was to determine whether basal cytokines could be early prognostic biomarkers of COVID-19, and also to analyze the impact of comorbidities, such as obesity or metabolic syndrome (MS), in the cytokine profile. The levels of most inflammatory cytokines were elevated on admission in relation to the level that was reached 4–6 weeks later, except for IL-1β, which was lower on admission; these levels were irrespective of the presence of obesity or MS since the cytokine storm masks these inflammatory processes. Among the cytokines analyzed, those that correlated with a worse prognosis of COVID-19 were resistin, IL-6, IL-8, IL-15, MCP-1 and TNF-α. Specifically, resistin and IL-15 are the best early predictors of requiring invasive ventilation. Therefore, resistin and IL-15 should be included in the personalized treatment decision algorithm of patients with COVID-19. [ABSTRACT FROM AUTHOR]

Background and Objectives Clinical features of SARS-COV-2 virus include fever, headache, cough, sore throat, and shortness of breath, and in severe forms it leads to disseminated intravascular coagulation, septic shock, and ultimately death. Excessive secretion of proinflammatory cytokines such as TNF-α, IL-6, and IL-1 leads to cytokine storms in this disease. The emergence of new variants of the SARS-CoV-2 virus, which occurs following a high mutation of the virus, increases its ability to escape the immune system and improve its transmission power. This process, in turn, can lead to ineffective vaccines against the virus. Due to the effect of the emerging viruses on the safety of blood and its products, in the first part of this article, the topic of virology, immune responses, and immunopathogenesis of this virus were discussed. The second part will discuss the viral-related issues of blood safety and its products. Materials and Methods In this review, keywords were searched in Science Direct, PubMed, Scopus databases and the sites of Nature, Science, Elsevier, Cell, BMJ, and Lancet journals, and finally 148 articles were used. Results In this article, in addition to a brief review of SARS-CoV-2 and its new variants from a virological point of view, its immunology and immunopathogenesis are also discussed. Conclusions Due to the widespread SARS-CoV-2 virus and its unprecedented nature in causing the disease, it is essential to address it. However, based on the genomic nature of the virus, the high probability of various mutations and the emergence of new variants, accurate and comprehensive information on the virus abilities to escape the immune system and its pathogenic mechanisms is not yet available. There are many contradictions in these topics. However, the latest available and reliable scientific materials at the time of the preparation of this article have been tried to be reviewed. [ABSTRACT FROM AUTHOR]

• COVID-19 asymptomatic patients had high levels of IL-8. • IL-12, IL-2, IL-13, IL-17 and GM-CSF were undetectable in COVID-19 asymptomatic patients. • IL-6, IL-10, MIP-1α, MCP-1 and IP-10 are associated with COVID-19 disease progression. • IL-4 tends to decrease with COVID-19 disease progression. • SARS-CoV-2 is associated with the cytokine storm. COVID-19 is a viral infection that disturbs the host's immune system and causes an overproduction of cytokines leading to a cytokine storm. The present study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with COVID-19 disease severity. The serum levels of 89 patients with different degrees of COVID-19 disease severity [asymptomatic (n = 14), moderate (n = 14), severe (n = 30), and critical (n = 31)] and 14 healthy individuals were tested for a panel of 27 cytokines and chemokines using Luminex assay (27 Bio‑Plex Pro Human Cytokine, Bio-rad™). IL-12, IL-2 and IL-13, as well as IL-17 and GM-CSF were clearly undetectable in asymptomatic patients. IL-8 levels were higher in asymptomatic compared with other groups. Very high levels of IL-6, IL-10 and the chemokines MIP-1α, MCP-1 and IP10 were associated with disease progression, while IL-4 tends to decrease with disease severity. Our study provides more evidence that excessive cytokine synthesis is linked to the disease progression. [ABSTRACT FROM AUTHOR]

Extreme response of the immune system develops cytokine storm which might be crucial in the pathology of COVID-19. The research aims to evaluate the serum level of IL-6, TNF-α, and IP-10 in severe, mild, and pre-vaccinated one-dose COVID-19 patients and investigate their clinical value and effect in the disease development among different groups of patients. A total of 72 samples were collected 18 as healthy control and 54 from confirmed COVID-19 patients including 18 mild, 18 severe, and 18 pre-vaccinated (one dose). It was confirmed that the severe group of COVID-19 patients had the highest circulating IL-6, TNF- α, and IP-10. IL-6 level in mild and pre-vaccinated (one dose) was significantly lower than in severe. In conclusion, IL-6, TNF-α, and IP-10 are associated with the pathogenicity of COVID-19, furthermore, vaccination could help to control severity of the disease. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm.Methods: In this study, we report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines.Results: Our results show abnormal cytokine levels upon T-cell stimulation, in a nonpolarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28-CD57+ cells. Of note, we demonstrated for the first time an increased frequency of CD3+CD4+CD28-CD57+ T cells with expression of programmed death 1, one of the hallmarks of T-cell exhaustion.Conclusions: These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4+ T-cell compartment, and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events. [ABSTRACT FROM AUTHOR]

Introduction: Severe acute respiratory syndrome coronavirus-2 may lead to high levels of expression of inflammatory cytokines. Medium cut-off (MCO) membranes may make greater clearances for large-middle molecules (including cytokines) than low-flux (LF) membranes. In this study, we aimed to evaluate the impact of MCO membranes on outcome of COVID-19 patients on hemodialysis (HD). Methods: Sixty COVID-19 HD patients were included in this study. The patients were categorized into 2 groups regarding type of HD membranes. Clinical data were taken from medical records. Results: Initial crp and ferritin levels, which are surragates of cytokine storm and severity of disease in COVID-19, were significantly higher in MCO membrane group compared to LF group (p = 0.037 and 0.000, respectively). Although there were more patients with severe disease in MCO group, there were no significant differences regarding need for intensive care unit and death. Conclusion: It may be an option to use MCO membranes in HD patients with COVID-19 in order to reduce cytokine levels and prevent cytokine storm. [ABSTRACT FROM AUTHOR]

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 represents usually a variety range of symptoms related to influenza-like syndrome and respiratory tract infections. Likewise, kidney involvement and acute kidney injury (AKI) were reported in many previous studies. Although a hypovolemic circulation would be the most common reason in patients with AKI, some strong proofs are suggesting a cytokine storm due to immune system exaggeration and inflammation-mediated tubular injury in COVID-19 infections. The inflammatory response in cytokine storm leads to the high release of cytokines mostly including TNFα, IL-1β, IL-6, INFγ, IL-2, IL-7, and endothelial mediators. The main culprits in the AKI and consequent organ failure are resident leukocytes in specific tissues, activated following the cytokine release, and systemic inflammatory response. AKI management and cytokine profile evaluation should be highly emphasized in patients with COVID-19 to prevent the progression of chronic kidney disease or permanent renal failure. Treatment options in COVID-19 regarding no specific drugs should be supportive and based on stabilizing the patients; however, combination therapy with different antiviral have shown promising outcomes. As a result, utilizing the anti-TNFα and anti-IL-1 agents should be noticed if indicated. Additionally, the hematopoietic stem cell transplantation is a curative approach. [ABSTRACT FROM AUTHOR]

COVID-19 has caused significant morbidity and mortality around the world. Recent reports point toward the "cytokine storm" as core of pathogenesis in SAR-CoV-2-induced acute lung injury, acute respiratory distress syndrome (ARDS), coagulopathy, and multiorgan failure. We have presented clinical data here wherein cytokine levels in COVID-19 patients do not match typical cytokine storm seen in ARDS. Interestingly, COVID-19 patients in early disease present with hypoxemia with no significant respiratory dysfunction. In addition, it is reported that hospitalized COVID-19 patients have a high incidence of thrombotic complications, especially involving the pulmonary vasculature. We hypothesized that core to pathogenesis of COVID-19 is the dysregulation of neutrophils, which culminates in excessive release of neutrophil extracellular traps (NETs). Recently, an increasing amount of NETs have been seen in sera of severe COVID-19 patients. We have discussed here mechanisms involved which lead to thrombogenesis and vasculitis because of excessive release of NETs. [ABSTRACT FROM AUTHOR]

An understanding of the pathological inflammatory mechanisms involved in SARS-CoV-2 virus infection is necessary in order to discover new molecular pharmacological targets for SARS-CoV-2 cytokine storm. In this study, the effects of a recombinant SARS-CoV-2 spike glycoprotein S1 was investigated in human peripheral blood mononuclear cells (PBMCs). Stimulation of PBMCs with spike glycoprotein S1 (100 ng/mL) resulted in significant elevation in the production of TNFα, IL-6, IL-1β and IL-8. However, pre-treatment with dexamethasone (100 nM) caused significant reduction in the release of these cytokines. Further experiments revealed that S1 stimulation of PBMCs increased phosphorylation of NF-κB p65 and IκBα, and IκBα degradation. DNA binding of NF-κB p65 was also significantly increased following stimulation with spike glycoprotein S1. Treatment of PBMCs with dexamethasone (100 nM) or BAY11-7082 (1 μM) resulted in inhibition of spike glycoprotein S1-induced NF-κB activation. Activation of p38 MAPK by S1 was blocked in the presence of dexamethasone and SKF 86002. CRID3, but not dexamethasone pre-treatment, produced significant inhibition of S1-induced activation of NLRP3/caspase-1. Further experiments revealed that S1-induced increase in the production of TNFα, IL-6, IL-1β and IL-8 was reduced in the presence of BAY11-7082 and SKF 86002, while CRID3 pre-treatment resulted in the reduction of IL-1β production. These results suggest that SARS-CoV-2 spike glycoprotein S1 stimulated PBMCs to release pro-inflammatory cytokines through mechanisms involving activation of NF-κB, p38 MAPK and NLRP3 inflammasome. It is proposed that the clinical benefits of dexamethasone in COVID-19 are possibly due to its anti-inflammatory activity in reducing SARS-CoV-2 cytokine storm. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome is an important clinical presentation of respiratory complications caused by severe acute respiratory syndrome coronavirus 2, a novel coronavirus responsible for the ongoing pandemic. The disease is poorly understood, and immunopathogenesis is constantly evolving. Cytokine release syndrome remains central to pathology of coronavirus disease 2019. Antivirals, anticytokine treatment, and other pharmacological approaches have failed to treat it. CytoSorb, an extracorporeal cytokine adsorber that reduces the cytokine storm and other inflammatory mediators in the blood, seems promising in treating severely ill patients with coronavirus disease 2019.Case Presentation: This article presents three cases of Asian ethnicity of severely ill adult patients with coronavirus disease 2019 admitted to intensive care unit who were treated with CytoSorb therapy. All patients used single CytoSorb device. During their clinical course, all patients were prescribed tocilizumab (an interleukin-6 receptor blocker), antivirals, hydroxychloroquine, azithromycin, and other antibiotics and general antipyretic drugs. No vasopressor treatment was required. The patients' average duration of stay in intensive care unit was 30 days; the average duration of stay in hospital was 31 days. All three patients showed significant improvement in biochemical parameters and clinical outcomes post CytoSorb therapy. C-reactive protein levels decreased by 91.5%, 97.4%, and 55.75 %, and mean arterial pressure improved by 18%, 23%, and 17 % in patient 1, 2, and 3, respectively, on day 7 post-therapy.Conclusions: All three patients improved clinically and survived. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) continues to ravage communities across the world. Despite its primary effect on the respiratory system, the virus does not solely impact those with underlying lung conditions as initially predicted. Indeed, prognosis is worsened (often fatal) in patients with pre‐existing hyperinflammatory responses (e.g., hypertension, obesity and diabetes), yet the mechanisms by which this occurs are unknown. A number of psychological conditions are associated with inflammation, suggesting that these may also be significant risk factors for negative outcomes of COVID‐19. In this review, we evaluate preclinical and clinical literature suggesting that chronic stress‐induced hyperinflammation interacts synergistically with COVID‐19‐related inflammation, contributing to a potentially fatal cytokine storm syndrome. In particular, we hypothesize that both chronic stress and COVID‐19‐related hyperinflammation are a product of glucocorticoid insufficiency. We discuss the devastating effects of SARS‐CoV‐2 on structural and functional aspects of the biological stress response and how these induce exaggerated inflammatory responses, particularly interleukin (IL)‐6 hypersecretion. We postulate that chronic stress should be considered a significant risk factor for adverse COVID‐19‐related health outcomes, given overlapping peripheral and central immune dysregulation in both conditions. We conclude by discussing how people with a history of chronic stress could mitigate their risk for COVID‐19 complications, identifying specific strategies that can be implemented during self‐isolation. [ABSTRACT FROM AUTHOR]

In March 2020, COVID-19 infection caused by SARS-CoV-2 has been declared to be a global pandemic, where its complications, severity and mortality are reported to be due to the released inflammatory cytokines or the so-called cytokine storm. This is quite similar to that observed in the autoimmune and chronic inflammatory rheumatic disease, rheumatoid arthritis (RA). It was hypothesized that RA patients are at a higher risk of acquiring COVID-19; however, recent studies reported that they are not when compared to the rest of the population. In this review, we aim to highlight the mutual pathological features, cytokine profiles and risk factors between COVID-19 and RA. Also, many researchers are currently working to explore therapeutic agents that could aid in the eradication of COVID-19 infection. Due to the similarity between the inflammation status in COVID-19 and RA, many anti-rheumatic drugs such as hydroxychloroquine, tocilizumab, baricitinib and anakinra were proposed to be therapeutic modalities for COVID-19 infection. [ABSTRACT FROM AUTHOR]

We describe the cytokine profiles of a large cohort of hospitalized patients with moderate to critical COVID-19, focusing on IL-6, sIL2R, and IL-10 levels before and after receiving immune modulating therapies, namely, tocilizumab and glucocorticoids. We also discuss the possible roles of sIL2R and IL-10 as markers of ongoing immune dysregulation after IL-6 inhibition. We performed a retrospective chart review of adult patients admitted to a tertiary care center with moderate to critical SARS-CoV-2 infection. Disease severity was based on maximum oxygen requirement during hospital stay to maintain SpO2 > 93% (moderate, 0–3 L NC; severe, 4–6 L NC or non-rebreather; critical, HFNC, NIPPV, or MV). All patients were treated using the institution's treatment algorithm, which included consideration of tocilizumab for severe and critical disease. The most common cytokine elevations among all patients included IL-6, sIL2R, IFN-γ, and IL-10; patients who received tocilizumab had higher incidence of IL-6 and sIL2R elevations. Pre-tocilizumab IL-6 levels increased with disease severity (p =.0151). Both IL-6 and sIL2R levels significantly increased after administration of tocilizumab in all severity groups; IL-10 levels decreased in severe (p =.0203), but not moderate or critical, patients after they received tocilizumab. Cluster analysis revealed association between higher admission IL-6, sIL2R, and CRP levels and disease severity. Mean IL-6, sIL2R, and D-dimer were associated with mortality, and tocilizumab-treated patients with elevated IL-6, IL-10, and D-dimer were more likely to also receive glucocorticoids. Accessible clinical cytokine panels may be useful for monitoring response to treatment in COVID-19. The increase in sIL2R post-tocilizumab, despite administration of glucocorticoids, may indicate the need for combination therapy in order to modulate more than one hyperinflammatory pathway in COVID-19. We also discuss the role of cytokines as potential biomarkers for use of adjunct glucocorticoid therapy. [ABSTRACT FROM AUTHOR]

• The "cytokine storm" is one of the most dangerous and potentially life-threatening event related to COVID-19 sustaining its major clinical complications. • Early studies already indicated that the chemokine/chemokine receptor system largely contributed to the onset of the "cytokine storm". • Rapidly growing evidences supported a major role of specific chemokines in driving a more or less severe clinical course of Sars-Cov-2 infection. • At the present, CXCL10 and CCL2 represent, at the present, the chemokines identified to play a major role in driving a more severe course of COVID-19, potentially serving as a marker for predicting the clinical outcome. • Owing to the great effort of the Scientific Community, in increasing our knowledge on COVID-19, it is likely that also other chemokines will be further investigated in the next future. SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is the result of massive pro-inflammatory cytokine release and imbalance in the absence of adequate immunomodulation from signals such as interleukin (IL)-10, resulting in ongoing inflammation, tissue damage and death if left uncontrolled. Although CRS can result from different pro-inflammatory insults, the treatments proposed are similar, regardless of the phase of response. SARS-CoV-2 causes COVID-19, and CRS has been a defining feature of severe disease. Common approaches to treating CRS in other conditions are now applied to COVID-19 and, although some patients respond, it begs the following questions: (1) are all cytokine storms the same regardless of initiating insult, (2) can treatments be considered equally for all CRS events at any phase of the response, (3) can CRS be predicted based on dynamic acute biomarkers and, (4) should patients with CRS undergo long-term monitoring for secondary effects? The aim of this commentary is not to provide a review of COVID-19 pathophysiology or of cytokine storm, but rather to establish a foundation which could act as a platform to inform treatment approaches to CRS, regardless of cause, and the short- and long-term follow-up which may be necessary for affected patients. [ABSTRACT FROM AUTHOR]

Inflammation is an intrinsic defence mechanism triggered by the immune system against infection or injury. Chronic inflammation allows the host to recover or adapt through cellular and humoral responses, whereas acute inflammation leads to cytokine storms resulting in tissue damage. In this review, we present the overlapping outcomes of cancer inflammation with virus-induced inflammation. The study emphasises how anti-inflammatory drugs that work against cancer inflammation may work against the inflammation caused by the viral infection. It is established that the cytokine storm induced in response to SARS-CoV-2 infection contributes to disease-associated mortality. While cancer remains the second among the diseases associated with mortality worldwide, cancer patients' mortality rates are often observed upon extended periods after illness, usually ranging from months to years. However, the mortality rates associated with COVID-19 disease are robust. The cytokine storm induced by SARS-CoV-2 infection appeared to be responsible for the multi-organ failure and increased mortality rates. Since both cancer and COVID-19 disease share overlapping inflammatory mechanisms, repurposing some anticancer and anti-inflammatory drugs for COVID-19 may lower mortality rates. Here, we review some of these inflammatory mechanisms and propose some potential chemotherapeutic agents to intervene in them. We also discuss the repercussions of anti-inflammatory drugs such as glucocorticoids and hydroxychloroquine with zinc or antiviral drugs such as ivermectin and remdesivir against SARS-CoV-2 induced cytokine storm. In this review, we emphasise on various possibilities to reduce SARS-CoV-2 induced cytokine storm. [ABSTRACT FROM AUTHOR]

Recent studies on Coronavirus Disease 2019 (COVID-19) have shown that obesity and vitamin D deficiency increase the risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) infection and its complications. The levels of cytokines are increased in SARS-CoV-2 infection, obesity, and vitamin D deficiency aggravating the complications related to COVID-19. The Angiotensin-converting Enzyme 2 (ACE2), through which SARS-CoV-2 enters the host cell, is highly expressed in adipose tissue showing the vulnerability to the infection. In this review we have explained how obese individuals are more prone and contagious than lean to COVID-19, the role of adipose tissue as a reservoir of infection, vitamin D sequestration and deficiency in obese, and its association with COVID-19 and the combined release of cytokines in obesity, vitamin D deficiency and SARS-CoV-2 infection leading to cytokine storm both locally and systemically, hence leading to multi-organ failure in elderly and younger generations. [ABSTRACT FROM AUTHOR]

Among the pathways and mediators that may be dysregulated in COVID-19 infection, there are proinflammatory cytokines, lymphocyte apoptosis, and the coagulation cascade. Venous and arterial thromboembolisms also are frequent in COVID-19 patients with the increased risk of some life-threatening complications such as pulmonary embolism, myocardial infarction, and ischemic stroke. In this regard, overproduction of proinflammatory cytokines such as IL-6, IL-1β, and TNF-α induce cytokine storms, increase the risk of clot formation, platelet activation, and multiorgan failure that may eventually lead to death among these patients. Surface S protein of SARS-CoV-2 binds to its target transmembrane receptor, named as angiotensin converting enzyme 2 (ACE2(, on various cells such as lymphocyte, alveolar cells, monocytes/macrophages, and platelets. Notably, the activation of the coagulation cascade occurs through tissue factor (TF)/FVIIa-initiated hemostasis. Accordingly, TF plays the major role in the activation of coagulation system during viral infection. In viral infections, the related coagulopathy multiple factors such as inflammatory cytokines and viral specific TLRs are involved, which consequently induce TF expression aberrantly. SARS-COV-2 may directly infect monocytes/ macrophages. In addition, TF expression/release from these cells may play a critical role in the development of COVID-19 coagulopathy. In this regard, the use of TF- VIIa complex inhibitor may reduce the cytokine storm and mortality among COVID-19 patients. [ABSTRACT FROM AUTHOR]

Novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in Wuhan, China. Since then, COVID-19 has become a pandemic affecting more than 4.1 million people worldwide. Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH). Anti-cytokine therapy such as tocilizumab, an IL-6 receptor antagonist, is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking. We report two cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab. Both patients progressed to sHLH despite treatment with tocilizumab, and one developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS. These cases highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has potential for the treatment of patients with coronavirus disease 2019 (COVID-19). [ABSTRACT FROM AUTHOR]

SARS-CoV-2 can vary on a spectrum of an asymptomatic disease process, to a severe stage characterized by a "Cytokine Storm". This phenomenon is a pro-inflammatory state marked by an intricate interplay of a cocktail of chemokines and cytokines. An excessively raised serum levels of cytokines and chemokines can lead to the development of acute respiratory distress syndrome. This article highlights the pathophysiologic mechanisms responsible for creating this cytokine havoc and delves into potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Rapidly spreading outbreak of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is causing serious health concerns worldwide. It started as an epidemic in Wuhan, Hubei province, central China, and has now become a pandemic, spreading over most of the continents of the planet. The major clinical symptoms of the infection are dry cough, fever, pneumonia, respiratory failure, hypoxia, and in certain cases, even death. Alveolar damage and respiratory system failure are observed in severe cases. Initial mild infection leads to activation of the immune system in the lungs and accumulation of various inflammatory cells and molecules. At a later phase during the infection, a "cytokine storm" causes an Acute Respiratory Distress Syndrome (ARDS), leading to an increase in the production of pro-inflammatory cytokines, migration of a large number of immune cells to the site of infection, and ultimately pulmonary damage. The rapid and uncontrolled outbreak requires putative therapeutic drugs for treatment of patients suffering from COVID-19. Amongst the currently used antiviral drugs, such as hydroxychloroquine, lopinavir, remdesivir etc. we would like to present an update on another effective drug, pentoxifylline. Pentoxifylline has anti-inflammatory, immunomodulatory, anti-viral, and bronchodilatory properties. Pentoxifylline is known to reduce cytokine production, immune cell migration, and suppress certain signal transduction pathways (e.g. NF-ĸβ and STAT3). Thus, it minimizes inflammatory damage in the lung tissues. [ABSTRACT FROM AUTHOR]

The coronavirus invades the nervous system with the spread we call neuroinvasion, and "cytokine storm" becomes an important factor affecting the course of the disease. Serious damage occurs in the brain and other organs as a result of cytokine storm. Evidence is accumulating that the coronavirus, which infects millions of people all over the world, affects both the central and peripheral nervous system and muscles as well as the respiratory tract. Increasing evidence has revealed neurological involvement in 36-54% of the patients, which corresponds to almost one in every 2 or 3 patients. In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, we frequently encounter neurological symptoms such as smell and taste disturbances, fatigue and muscle pain, headache, nausea, vomiting, impaired consciousness, numbness in hands and feet. To a lesser extent, we encounter neurological handicaps such as dizziness, inflammation of the meninges, loss of myelin in nerve tissue, muscle inflammation, and severe rhabdomyolysis. Some of the nervous system diseases accompanying SARS-CoV-2 disease recover with complete or partial sequelae. Observation of permanent dysfunction in patients with neurological findings draws attention to the importance of a detailed neurological evaluation in the examination of these cases. [ABSTRACT FROM AUTHOR]

Rapidly spreading outbreak of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is causing serious health concerns worldwide. It started as an epidemic in Wuhan, Hubei province, central China, and has now become a pandemic, spreading over most of the continents of the planet. The major clinical symptoms of the infection are dry cough, fever, pneumonia, respiratory failure, hypoxia, and in certain cases, even death. Alveolar damage and respiratory system failure are observed in severe cases. Initial mild infection leads to activation of the immune system in the lungs and accumulation of various inflammatory cells and molecules. At a later phase during the infection, a “cytokine storm” causes an Acute Respiratory Distress Syndrome (ARDS), leading to an increase in the production of pro-inflammatory cytokines, migration of a large number of immune cells to the site of infection, and ultimately pulmonary damage. The rapid and uncontrolled outbreak requires putative therapeutic drugs for treatment of patients suffering from COVID-19. Amongst the currently used antiviral drugs, such as hydroxychloroquine, lopinavir, remdesivir etc. we would like to present an update on another effective drug, pentoxifylline. Pentoxifylline has anti-inflammatory, immunomodulatory, anti-viral, and bronchodilatory properties. Pentoxifylline is known to reduce cytokine production, immune cell migration, and suppress certain signal transduction pathways (e.g. NF-κβ and STAT3). Thus, it minimizes inflammatory damage in the lung tissues. [ABSTRACT FROM AUTHOR]

The article talks about the effectiveness of Vitamin C in treating the Covid-19 virus. It mentions that vitamin C could play a key role in modulation and the efficiency of immune defenses of an individual; and vitamin C could be added to the therapeutic arsenal deployed in the face of the cytokine storm. It mentions products, developed in the context of other pathologies, however seem to present antiviral efficacy against Sars-CoV-2.

Trypsin is a protease-activated receptor-2 (PAR2) activator that upregulates the interleukin (IL)-17 receptor signal in the airway epithelial cells and amplifies the inflammatory response, but does not modify the growth kinetics of the metapneumovirus. How does the coronavirus spread from cell to cell is yet an enigma. The present study analyzed the possible role of trypsin in the activation of coronavirus in vitro and in vivo. We found that the overexpression of trypsin in A549 cells upregulated IL-17 and angiotensin-converting enzyme (ACE). In the humanized transgenic mice, trypsin activated M1 macrophages. Together, our results suggested that the upregulation of trypsin may support a new pathway for coronavirus transmission in patients. • The spike protein of CoV is cleaved by trypsin, cathepsin and other active proteases and activated for fusion. • The cutting event of CoV leads to the fusion of cells and virus. • Trypsin may play an important role in the process of virus aggregation, release and replication. [ABSTRACT FROM AUTHOR]

The severity of COVID-19 is largely determined by the inflammatory response, a "Cytokine storm," that involves both pro- and anti-inflammatory cytokines. In the current study we investigated the balance of pro- and anti-inflammatory status as represented by the levels of IL-6/IL-10 in severe to critical COVID-19 patients. 66 confirmed COVID-19 patients admitted to the ICU were categorized into groups according to the mortality and respiratory failure. Data were collected retrospectively in ICU, including a peripheral immune cells and infection-related biomarker CRP. The measurements of cytokine levels were performed by Immulite analyzer for IL-6 and ELISA sandwich for IL-10. In addition, longitudinal measurement of IL-6 was performed during 5 days post admission. Longitudinal assays showed that IL-6 was sustained at a medium level within 5 days post admission in severe cases who survived or not requiring mechanical ventilation, whereas it was sustained at high levels throughout the disease course in either deceased cases or who developed respiratory failure. The ratio of IL-6/lymphocytes was positively correlated with the risk of mortality, while IL-10/lymphocytes ratio could predict respiratory failure in ICU. IL-6/IL-10 profiling revealed that deceased patients have different magnitudes of both IL-6 and IL-10 cytokine release. Notably, excessive levels of IL-6 concomitant with high levels of IL-10 were more common in diseased COVID-19 patients. Taking into account the IL-6/IL-10 profiling may help clinicians to identify the right time of anti-inflammation treatment and select patients who will respond to anti-cytokine therapies and maintain an adequate inflammatory response for SARS-CoV-2 clearance. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease. • IL-6 is a hallmark of inflammatory feature in severe/critical SARS-CoV-2 induced disease. • CRP level is a predictor of response to IL-6 inhibitor therapy. • The efficacy of tocilizumab is moderate in severe SARS-CoV-2 induced disease. • SARS-CoV-2-induced IL-6 seemingly strengthens cancer aggression. • IL-6 inhibitors can go with ICI in cancer (not in SARS-CoV-2 induced disease). [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called "cytokine storm". Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1β and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response. [ABSTRACT FROM AUTHOR]

The outburst of inflammatory response and hypercoagulability are among the factors contributing to increased mortality in severe COVID-19 cases. Pentoxifylline (PTX), a xanthine-derived drug registered for the treatment of vascular claudication, has been reported to display broad-spectrum anti-inflammatory and immunomodulatory properties via adenosine A2A receptor (A2AR)-related mechanisms, in parallel to its rheological actions. Prior studies have indicated the efficacy of PTX in the treatment of various pulmonary diseases, including the management of acute respiratory distress syndrome of infectious causes. Therefore, PTX has been proposed to have potential benefits in the treatment of SARS-CoV-2 symptoms, as well as its complications. The aim of this review is to discuss available knowledge regarding the role of PTX as a complementary therapeutic in SARS-CoV-2. [ABSTRACT FROM AUTHOR]

• COVID-19 positive patients who smoke are more often asymptomatic or exhibit less severe respiratory symptoms than non-smokers. • The macrophages, which are directly infected by the SARS-CoV-2 virus, may drive the cytokine storm in the lings. • Stimulation of macrophage ACh receptors by nicotine inhibits pro-inflammatory cytokines production and inflammatory response. • The nicotine use may lessen or eliminate ARDS in the smoking COVID -19 patients. Statistical surveys of COVID-19 patients indicate, against all common logic, that people who smoke are less prone to the infection and/or exhibit less severe respiratory symptoms than non-smokers. This suggests that nicotine may have some preventive or modulatory effect on the inflammatory response in the lungs. Because it is known that the response to, and resolution of the SARS-CoV-2 infection depends mainly on the lung macrophages, we discuss the recent scientific findings, which may explain why and how nicotine may modulate lung macrophage response during COVID-19 infection. [ABSTRACT FROM AUTHOR]

The outbreak of the coronavirus disease 2019 (COVID-19) began at the end of 2019. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with COVID-19 may exhibit poor clinical outcomes. Some patients with severe COVID-19 experience cytokine release syndrome (CRS) or a cytokine storm—elevated levels of hyperactivated immune cells—and circulating pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. This severe inflammatory response can lead to organ damage/failure and even death. The inflammasome is an intracellular immune complex that is responsible for the secretion of IL-1β and IL-18 in various human diseases. Recently, there has been a growing number of studies revealing a link between the inflammasome and COVID-19. Therefore, this article summarizes the current literature regarding the inflammasome complex and COVID-19. [ABSTRACT FROM AUTHOR]

The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1β, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS , the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19. • SARS-CoV-2 infection is associated with an exacerbated inflammatory responses. • IL-6, IL-1β, TNF-α, IL-17, IL-8 are involved in COVID19 cytokine release syndrome. • Cytokines exacerbation participates in thrombo-embolism associated with poor outcome. • CRS may be due to pyroptosis, microbiota alteration or delayed IFN response. [ABSTRACT FROM AUTHOR]

• Anti-viral therapy significantly. • Reduced CT scan scores and the elevated serum levels of CRP and LDH, serum levels of IL-6, CXCL8 and IFNγ were elevated at baseline in COVID-19. • IL-1β and TNFα levels were also enhanced after treatment. • Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4 M patients and resulted in 1,86 M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, IL-8 and interferon (IFN)γ. To investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients. Blood was obtained from 29 patients (aged 32–79 yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied. Anti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, serum levels of IL-6, IL-8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p = 0.006) and IL-8 (p = 0.011) levels being further elevated after antiviral therapy. IL-1β (p = 0.01) and TNFα (p = 0.069) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit. Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects. [ABSTRACT FROM AUTHOR]

As an emerging global health crisis, coronavirus disease 2019 (COVID-19) has been labeled a worldwide pandemic. Growing evidence is revealing further pathophysiological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Amongst these dysregulated pathways inflammation seems to play a more critical role toward COVID-19 complications. In the present study, precise inflammatory pathways triggered by SARS-CoV-2, along with potential therapeutic candidates have been discussed. Prevailing evidence has indicated a close correlation of inflammatory cascades with severity, pathological progression, and organ damages in COVID-19 patients. From the mechanistic point of view, interleukin-6, interleukin-1β receptor, interferon-gamma, tumor necrosis factor-alpha receptor, toll-like receptor, receptor tyrosine kinases, growth factor receptor, Janus kinase/signal transducers and transcription pathway, mammalian target of rapamycin, cytokine storm and macrophage activation have shown to play critical roles in COVID-19 complications. So, there is an urgent need to provide novel mechanistic-based anti-inflammatory agents. This review highlights inflammatory signaling pathways of SARS-CoV-2. Several therapeutic targets and treatment strategies have also been provided in an attempt to tackle COVID-19 complications. • Inflammatory pathways are in a close linkage with COVID-19 complications. • Targeting IL-6, IL-1β receptor, TLR, IFN-γ, TNF-α and mTOR could pave the road in combating COVID-19. • JAK/STAT and related interconnected pathways are of pivotal pathways to be targeted in COVID-19. • PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and TRAF/TRADD/caspase could be promising targets in combating COVID-19. [ABSTRACT FROM AUTHOR]

Encephalopathy is emerging as a recurrent complication of COVID-19 yet remains poorly characterized. We report the case of a middle-aged woman with COVID-19-related encephalopathy presenting as expressive aphasia and inattentiveness, subsequently progressing to agitation and marked confusion. Brain MRI and CSF analysis were unremarkable, while EEG showed slowing with frontal sharp waves. Neuropsychiatric symptoms resolved following treatment with tocilizumab. CNS involvement in COVID-19 may present as a subacute encephalopathy characterized by prominent frontal lobe dysfunction, with language disturbances as first neurological manifestation. Future studies should further investigate the role of tocilizumab in treating COVID-19-related encephalopathy. Unlabelled Image • CNS involvement in COVID-19 may present as a subacute encephalopathy. • COVID-19-related encephalopathy may present with early language disturbances. • Cytokine-mediated neuroinflammation has been suggested as the underlying mechanism. • Tocilizumab has shown efficacy in treating cytokine release syndrome. • In our patient, neuropsychiatric symptoms resolved following tocilizumab therapy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 first emerged in China during late 2019 and rapidly spread all over the world. Alterations in the inflammatory cytokines pathway represent a strong signature during SARS-COV-2 infection and correlate with poor prognosis and severity of the illness. The hyper-activation of the immune system results in an acute severe systemic inflammatory response named cytokine release syndrome (CRS). No effective prophylactic or post-exposure treatments are available, although some anti-inflammatory compounds are currently in clinical trials. Studies of plant extracts and natural compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation. The aim of this manuscript is to review the published background on the possible effectiveness of polyphenols to fight SARS-COV-2 infection, contributing to the reduction of inflammation. Here, some of the anti-inflammatory therapies are discussed and although great progress has been made though this year, there is no proven cytokine blocking agents for COVID currently used in clinical practice. In this regard, bioactive phytochemicals such as polyphenols may become promising tools to be used as adjuvants in the treatment of SARS-CoV-2 infection. Such nutrients, with anti-inflammatory and antioxidant properties, associated to classical anti-inflammatory drugs, could help in reducing the inflammation in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e. , cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of CP are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality. • Coronavirus disease 19 (COVID-19) is an emerging viral threat with major repercussions for public health. • There is not specific treatment for COVID-19. • Convalescent plasma (CP) emerges as the first option of management for hospitalized patients with COVID-19. • Transference of neutralizing antibodies helps to control COVID-19 infection and modulates inflammatory response. • Other plasma components may enhance the antiviral and anti-inflammatory properties of CP. [ABSTRACT FROM AUTHOR]

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation. Melatonin as a potential adjuvant treatment for COVID-19. Unlabelled Image [ABSTRACT FROM AUTHOR]