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Background We examined effects of single-nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. Results Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P =.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P =.052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P =.030). Conclusions The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra- physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. Case Report: We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. Conclusions: The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection has claimed just over 1.1 million lives in the US since 2020. Globally, the SARS-CoV-2 respiratory infection spread to 771 million people and caused mortality in 6.9 million individuals to date. Much of the early literature showed that SARS-CoV-2 immunity was defective in the early stages of the pandemic, leading to heightened and, sometimes, chronic inflammatory responses in the lungs. This lung-associated 'cytokine storm' or 'cytokine release syndrome' led to the need for oxygen supplementation, respiratory distress syndrome, and mechanical ventilation in a relatively high number of people. In this study, we evaluated circulating PBMC from non-hospitalized, male and female, COVID-19+ individuals over the course of infection, from the day of diagnosis (day 0) to one-week post diagnosis (day 7), and finally 4 weeks after diagnosis (day 28). In our early studies, we included hospitalized and critically care patient PBMC; however, most of these individuals were lymphopenic, which limited our assessments of their immune integrity. We chose a panel of 30 interferon-stimulated genes (ISG) to evaluate by PCR and completed flow analysis for immune populations present in those PBMC. Lastly, we assessed immune activation by stimulating PBMC with common TLR ligands. We identified changes in innate cells, primarily the innate lymphoid cells (ILC, NK cells) and adaptive immune cells (CD4+ and CD8+ T cells) over this time course of infection. We found that the TLR-7 agonist, Resiquimod, and the TLR-4 ligand, LPS, induced significantly better IFN α and IFN γ responses in the later phase (day 28) of SARS-CoV-2 infection in those non-hospitalized COVID-19+ individuals as compared to early infection (day 0 and day 7). We concluded that TLR-7 and TLR-4 agonists may be effective adjuvants in COVID-19 vaccines for mounting immunity that is long-lasting against SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background: Presepsin (PSN) is a soluble CD14 subtype that has lately been presented as a novel biomarker in patients with sepsis. The aim of the current study was to detect the relation of PSN to COVID‑19 as well as its relation to other biomarkers. Materials and Methods: A total of 125 severe/critical COVID‑19 patients were involved in this work as well as 60 persons enrolled as a control group. Between February 2022 and July 2022, these patients were admitted to Marjan Medical City and Al‑Sadiq hospital. Patients were determined as severe cases according to the guidelines released by National Health World depending on SpO2 percentage. The inflammatory cytokine (PSN) was detected by the ELISA technique. Results: PSN revealed statistically significant differences between patients 261 pg/ml (244–324) and control groups 193 pg/ml (172–218) (P < 0.0001). Correlations between PSN and lymphocytes (LYM), as well as platelets (PLT), were nonsignificant (P > 0.05), while significant negative correlation was found between PSN and both white blood cell (WBC) (r = −0.21, P = 0.01) and granulocytes (GRA) (r = −0.25, P = 0.004). No significant differences between males 273.55 pg/ml and females 284.90 pg/ml regarding presepsin titer mean were detected (P = 0.67). Conclusion: This work adds to the mounting evidence that pro‑inflammatory cytokines directly influence COVID‑19 progression. The management of a cytokine storm that affects COVID‑19 patients and is mostly brought on by pro‑inflammatory cytokines may depend on the early detection and treatment of PSN. [ABSTRACT FROM AUTHOR]

Background: Variation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and − 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome. Methods: Genotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt. Results: A significant association between the − 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the − 1082. The − 592 /-1082 CG and the − 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with − 592, while positive association was observed with − 1082. Higher D-dimer levels were strongly associated with the − 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes. Conclusion: IL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Variation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and − 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome. Methods: Genotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt. Results: A significant association between the − 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the − 1082. The − 592 /-1082 CG and the − 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with − 592, while positive association was observed with − 1082. Higher D-dimer levels were strongly associated with the − 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes. Conclusion: IL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Autonomic dysfunction is a clinical hallmark of infection caused by SARS‐CoV‐2, but the underlying mechanisms are unknown. The vagus nerve inflammatory reflex is an important, well‐characterized mechanism for the reflexive suppression of cytokine storm, and its experimental or clinical impairment facilitates the onset and progression of hyperinflammation. Recent pathological evidence from COVID‐19 victims reveals viral infection and inflammation in the vagus nerve and associated nuclei in the medulla oblongata. Although it has been suggested that vagus nerve inflammation in these patients mediates dysregulated respiration, whether it also contributes to dysfunction of the vagus nerve inflammatory reflex has not been addressed. Because lethality and tissue injury in acute COVID‐19 are characterized by cytokine storm, it is plausible to consider evidence that impairment of the inflammatory reflex may contribute to overproduction of cytokines and resultant hyperinflammatory pathogenesis. Accordingly, here the authors discuss the inflammatory reflex, the consequences of its dysfunction in COVID‐19, and whether there are opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

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]

Paraguay is currently facing a new outbreak of Chikungunya virus. This report summarizes two severe cases of Chikungunya (CHIKV) infection, confirmed by real-time reverse transcription polymerase chain reaction. We present the cases of patients with acute CHIKV infection and multisystem involvement, with fever, rash, abdominal pain, vomiting, myocarditis, and coronary artery anomalies, very similar to the cases described in MIS-C related to SARS-CoV-2 during the COVID-19 Pandemic. Both patients received IVIG and methylprednisolone, with good clinical response. In this setting of cytokine storm in Chikungunya, can we call it "Multisystem inflammatory syndrome associated with Chikungunya"?. [ABSTRACT FROM AUTHOR]

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children. [Display omitted] • One third of 228 patients with Multisystem Inflammatory Syndrome in Children (MIS-C) presented with thrombocytopenia. • Hyperinflammation and elevated biomarkers associated with T-cell activation were observed in thrombocytopenic MIS-C patients. • Independent of disease severity, thrombocytopenic patients had reduced leukocytes and signs of liver injury as seen in HLH. • No pathogenic variants in HLH genes were identified in any of the 62 MIS-C patients analyzed using whole-exome-sequencing. [ABSTRACT FROM AUTHOR]

During the coronavirus disease 2019 (COVID-19) pandemic, cognitive impairment of varying degrees of severity began to be observed in a significant percentage of patients. The present study discussed the impact of immunological processes on structural and functional changes in the central nervous system and the related cognitive disorders. The purpose of the present review was to analyse and discuss available information from the scientific literature considering the possible relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection and cognitive impairment, including NeuroCOVID, frontal syndrome and cytokine storm. A systematic literature review was conducted using: Google Scholar, Elsevier and the PubMed database. When searching for materials, the following keywords were used: 'cognitive dysfunctions', 'SARS-CoV-2', 'COVID-19', 'Neuro-SARS2', 'NeuroCOVID', 'frontal syndrome', 'cytokine storm', 'Long COVID-19'. A total of 96 articles were included in the study. The analysis focused on the characteristics of each study's materials, methods, results and conclusions. SARS-CoV-2 infection may induce or influence existing cognitive disorders of various nature and severity. The influence of immunological factors related to the response against SARS-CoV-2 on the disturbance of cerebral perfusion, the functioning of nerve cells and the neuroprotective effect has been demonstrated. Particular importance is attached to the cytokine storm and the related difference between pro- and anti-inflammatory effects, oxidative stress, disturbances in the regulation of the hypothalamic-pituitary-adrenal axis and the stress response of the body. [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]

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]

Figure (S5): The diagram of the Mechanism of COVID-19 Infection and the role of Imatinib &Indinavir. [Display omitted] • The SARS-CoV-2 infection caused tissue damage. • Widely dispersed, uncontrolled immune dysregulation, often known as the "cytokine storm. • Anti-TNF therapy may be an option for COVID-19 patients. • COVID-19 patients had higher NF-κB plasma concentrations. A worldwide coronavirus pandemic has affected many healthcare systems in 2019 (COVID-19). Following viral activation, cytokines and chemokines are released, causing inflammation and tissue death, particularly in the lungs, resulting in severe COVID-19 symptoms such as pneumonia and ARDS. COVID-19 induces the release of several chemokines and cytokines in different organs, such as the cardiovascular system and lungs. COVID-19 and its more severe effects, such as an elevated risk of death, are more common in patients with metabolic syndrome and the elderly. Cytokine storm and COVID-19 severity may be mitigated by immunomodulation targeting NF-κB activation in conjunction with TNF- α -inhibition. In severe cases of COVID-19, inhibiting the NF-κB/TNF- α, the pathway may be employed as a therapeutic option. The study will elaborate on the Egyptian pattern for COVID-19 patients in the first part of our study. An Egyptian patient with COVID-19 inflammatory profiling will be discussed in the second part of this article using approved marine drugs selected to inhabit the significant inflammatory signals. A biomarker profiling study is currently being performed on Egyptian patients with SARS‐COV‐2. According to the severity of the infection, participants were divided into four groups. The First Group was non-infected with SARS-CoV-2 (Control, n = 16), the Second Group was non-intensive care patients (non-ICU, n = 16), the Third Group was intensive care patients (ICU, n = 16), and the Fourth Group was ICU with endotracheal intubation (ICU + EI, n = 16). To investigate COVID-19 inflammatory biomarkers for Egyptian patients, several inflammatory, oxidative, antioxidant, and anti-inflammatory biomarkers were measured. The following are examples of blood tests: CRP, Ferritin, D-dimer, TNF-α, IL-8, IL-6., IL-Ib, CD8, NF-κB, MDA, and total antioxidants. The results of the current study revealed many logical findings, such as the elevation of CRP, Ferritin, D-dimer, TNF- α, CD8, IL-6, IL-, NF-κB, and MDA. Where a significant increase showed in ICU group results (23.05 ± 0.30, 2.35 ± 0.86, 433.4 ± 159.3, 26.67 ± 3.51, 7.52 ± 1.48, 7.49 ± 1.04, 5.76 ± 1.31, 7.41 ± 0.73) respectively, and also ICU group results (54.75 ± 3.44, 0.65 ± 0.13, 460.2 ± 121.42, 27.43 ± 2.52, 8.63 ± 2.68, 10.65 ± 2.75, 5.93 ± 1.4, 10.64 ± 0.86) respectively, as well as ICU + EI group results (117.63 ± 11.89, 1.22 ± 0.65, 918.8 ± 159.27, 26.68 ± 2.00, 6.68 ± 1.08, 11.68 ± 6.16, 6.23 ± 0.07, 22.41 ± 1.39),respectively.The elevation in laboratory biomarkers of cytokines storm in three infected groups with remarkable increases in the ICU + EI group was due to the elevation of oxidative stress and inflammatory storm molecules, which lead to highly inflammatory responses, specifically in severe patients of COVID-19. Another approach to be used in the current study is investigating new computational drug compounds for SARS‐COV‐2 protective agents from the marine environment. The results revealed that (Imatinib and Indinavir) had the highest affinity toward Inflammatory molecules and COVID-19 proteins (PDB ID: −7CZ4 and 7KJR), which may be used in the future as possible COVID-19 drug candidates. The investigated inflammatory biomarkers in Egyptian COVID-19 patients showed a strong correlation between IL6, TNF-α, NF-κB, CRB, DHL, and ferritin as COVID-19 biomarkers and determined the severity of the infection. Also, the oxidative /antioxidant showed good biomarkers for infection recovery and progression of the patients. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 envelope (E) protein is highly conserved among different viral variants and important for viral assembly and production. Our recent study found that the E protein is ubiquitinated and degraded by the E3 ligase RNF5 through the proteasome pathway. However, whether E ubiquitination can be reversed by host deubiquitinase has not yet been determined. Here, we identify by mass spectrum analysis that the deubiquitinases USP14 and USP39 specifically interact with E, while USP39 potently reverses E polyubiquitination. USP39 interacts with E via the arginine-rich motif (AR) and deubiquitinates E polyubiquitination via the inactive ubiquitin-specific protease domain. Therefore, USP39 protects E from RNF5-mediated degradation, resulting in the enhancement of E stability and E-induced cytokine storms. Moreover, loss-and-gain assays demonstrated that USP39 promotes the replication of various SARS-CoV-2 strains by stabilizing protein level of E that can be ubiquitinated but not other viral proteins. Our findings provide useful targets for the development of novel anti-SARS-CoV-2 strategies. • Deubiqitinase USP39 specifically interacts with SARS-CoV-2 E and deubiquitinates E polyubiquitination. • USP39 enhances the stability of E. • USP39 promotes the virulence of various SARS-CoV-2 strains possibly by stabilizing E. [ABSTRACT FROM AUTHOR]