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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]

Background: Studies have highlighted a possible crosstalk between the pathogeneses of COVID-19 and systemic lupus erythematosus (SLE); however, the interactive mechanisms remain unclear. We aimed to elucidate the impact of COVID-19 on SLE using clinical information and the underlying mechanisms of both diseases. Methods: RNA-seq datasets were used to identify shared hub gene signatures between COVID-19 and SLE, while genome-wide association study datasets were used to delineate the interaction mechanisms of the key signaling pathways. Finally, single-cell RNA-seq datasets were used to determine the primary target cells expressing the shared hub genes and key signaling pathways. Results: COVID-19 may affect patients with SLE through hematologic involvement and exacerbated inflammatory responses. We identified 14 shared hub genes between COVID-19 and SLE that were significantly associated with interferon (IFN)-I/II. We also screened and obtained four core transcription factors related to these hub genes, confirming the regulatory role of the IFN-I/II-mediated Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway on these hub genes. Further, SLE and COVID-19 can interact via IFN-I/II and IFN-I/II receptors, promoting the levels of monokines, including interleukin (IL)-6/10, tumor necrosis factor-α, and IFN-γ, and elevating the incidence rate and risk of cytokine release syndrome. Therefore, in SLE and COVID-19, both hub genes and core TFs are enriched within monocytes/macrophages. Conclusions: The interaction between SLE and COVID-19 promotes the activation of the IFN-I/II-triggered JAK-STAT signaling pathway in monocytes/macrophages. These findings provide a new direction and rationale for diagnosing and treating patients with SLE–COVID-19 comorbidity. [ABSTRACT FROM AUTHOR]

Background: CAR-T cell therapy represents a novel approach for the treatment of hematologic malignancies and solid tumors. However, its implementation is accompanied by the emergence of potentially life-threatening adverse events known as cytokine release syndrome (CRS). Given the escalating number of patients undergoing CAR-T therapy, there is an urgent need to develop predictive models for severe CRS occurrence to prevent it in advance. Currently, all existing models are based on decision trees whose accuracy is far from meeting our expectations, and there is a lack of deep learning models to predict the occurrence of severe CRS more accurately. Results: We propose PrCRS, a deep learning prediction model based on U-net and Transformer. Given the limited data available for CAR-T patients, we employ transfer learning using data from COVID-19 patients. The comprehensive evaluation demonstrates the superiority of the PrCRS model over other state-of-the-art methods for predicting CRS occurrence. We propose six models to forecast the probability of severe CRS for patients with one, two, and three days in advance. Additionally, we present a strategy to convert the model's output into actual probabilities of severe CRS and provide corresponding predictions. Conclusions: Based on our findings, PrCRS effectively predicts both the likelihood and timing of severe CRS in patients, thereby facilitating expedited and precise patient assessment, thus making a significant contribution to medical research. There is little research on applying deep learning algorithms to predict CRS, and our study fills this gap. This makes our research more novel and significant. Our code is publicly available at https://github.com/wzy38828201/PrCRS. The website of our prediction platform is: http://prediction.unicar-therapy.com/index-en.html. [ABSTRACT FROM AUTHOR]

Background: Cytokine release syndrome (CRS) is the leading cause of mortality in advanced stages of coronavirus patients. This study examined the prophylactic effects of fraxin, quercetin, and a combination of fraxin+quercetin (FQ) on lipopolysaccharide-induced mice. Methods: Sixty mice were divided into six groups (n=10) as follows: control, LPS only, fraxin (120 mg/Kg), quercetin (100 mg/Kg), dexamethasone (5 mg/Kg), and FQ. All treatments were administered intraperitoneally (IP) one hour before induction by LPS (5 mg/Kg) IP injection. Twenty-four hours later, the mice were euthanized. Interleukin one beta (IL1-β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were quantified using an enzyme-linked immunosorbent assay (ELISA), and lung and kidney tissues were examined for histopathological alterations. This study was conducted at Al-Nahrain University, Baghdad, Iraq, in 2022. Results: FQ reduced IL-1β (P<0.001). All treatments significantly suppressed IL-6, fraxin, quercetin, dexamethasone, and FQ, all with P<0.001. The TNF-α level was reduced more with dexamethasone (P<0.001) and quercetin (P<0.001). Histopathological scores were significantly reduced mainly by quercetin and FQ in the lungs with scores of 12.30±0.20 (P=0.093), and 15.70±0.20 (P=0.531), respectively. The scores were 13±0.26 (P=0.074) and 15±0.26 (P=0.222) for quercetin and FQ in the kidneys, respectively. Conclusion: All used treatments reduced proinflammatory cytokine levels and protected against LPS-induced tissue damage. [ABSTRACT FROM AUTHOR]

COVID-19 is a significant worldwide health concern. The exaggerated immune response known as the "cytokine storm" is a key factor in this illness, and there are potential ways to address it. Janus kinase (JAK) inhibitors are a type of medication that might reduce inflammation and improve the body's production of antibodies. Pharmacokinetic profiles, toxicity characteristics, biological activities prediction, and molecular docking simulation will be conducted to discover, assess, and investigate the molecular interactions of Christinin compounds, including Christinin-A, Christinin-B, Christinin-C, and Christinin-D derived from Ziziphus spina-christi leaves as Janus kinase (JAK) inhibitors using bioinformatics approaches. Based on the molecular docking simulation, it can be concluded that the Christinin compound has a molecular interaction with Janus Kinase (JAK). However, Christinin-A and Christinin-C compounds have better affinity than Christinin-B and Christinin-D compounds, with binding free energy values of -7.59 kcal/mol and -5.37 kcal/mol, respectively. Therefore, these two compounds can be used as candidates for Janus Kinase (JAK) inhibitors in preventing hyperinflammation in the COVID-19 infectious disease. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) and interferon-gamma (IFNγ) are important inflammatory mediators in the development of cytokine storm syndrome (CSS). Single nucleotide polymorphisms (SNPs) regulate the expression of these cytokines, making host genetics a key factor in the prognosis of COVID-19. In this study, we investigated the associations of the TNF -308G/A and IFNG +874T/A polymorphisms with COVID-19. We analyzed the frequencies of the two polymorphisms in the control groups (CG: TNF -308G/A, n = 497; IFNG +874T/A, n = 397), a group of patients with COVID-19 (CoV, n = 222) and among the subgroups of patients with nonsevere (n = 150) and severe (n = 72) COVID-19. We found no significant difference between the genotypic and allelic frequencies of TNF -308G/A in the groups analyzed; however, both the frequencies of the high expression genotype (TT) (CoV: 13.51% vs. CG: 6.30%; p = 0.003) and the *T allele (CoV: 33.56% vs. CG: 24. 81%; p = 0.001) of the IFNG +874T/A polymorphism were higher in the COVID-19 group than in the control group, with no differences between the subgroups of patients with nonsevere and severe COVID-19. The *T allele of IFNG +874T/A (rs2430561) is associated with susceptibility to symptomatic COVID-19. These SNPs provided valuables clues about the potential mechanism involved in the susceptibility to developing symptomatic COVID-19. [ABSTRACT FROM AUTHOR]

Background & objective: Cytokine storms play a significant role in conditions leading to multi-organ failure in patients with severe corona virus disease-2019 (COVID-19). The eradication of pro-inflammatory cytokines through hemoperfusion has been suggested to be a possible strategy to improve outcomes in these patients. We evaluated the impact of adjunctive HA330 hemoperfusion on outcomes in severe COVID-19 patients. Methodology: A single-center retrospective cohort study was conducted from December 2021 to December 2022. We included severe COVID-19 patients with elevated pro-inflammatory markers, who received three consecutive sessions of HA330 hemoperfusion in addition to the standard treatment protocol. Clinical data, including demographic information, baseline characteristics, and treatment outcomes, were analyzed. Results: We evaluated 24 severe COVID-19 patients. We observed a significant reduction in levels of CRP (P < 0.001) and IL-6 (P = 0.042), as well as a significant increase in arterial partial pressure of oxygen (P = 0.041). Importantly, no patient experienced cytotoxicity after the HA330 hemoperfusion sessions, confirming the biocompatibility of the treatment. Conclusion: Three consecutive sessions of HA330 hemoperfusion, used as an adjunctive therapy to standard care in severe COVID-19 patients, effectively reduced pro-inflammatory cytokine levels and improved oxygenation. However, large multicenter trials are required to validate these clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. Methods: This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. Results: 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. Conclusions: No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. Trial registration: The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21. [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: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30–40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. Methods: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. Results: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA–approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. Conclusion: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm. [ABSTRACT FROM AUTHOR]

COVID-19 emerged in December 2019 in Wuhan, China, spread worldwide rapidly, and caused millions of deaths in a short time. Many preclinical and clinical studies were performed to discover the most efficient therapy to reduce the mortality of COVID-19 patients. Among various approaches for preventing and treating COVID-19, mesenchymal stem cell (MSC) therapy can be regarded as a novel and efficient treatment for managing COVID-19 patients. In this review, we explain the pathogenesis of COVID-19 infection in humans and discuss the role of MSCs in suppressing the inflammation and cytokine storm produced by COVID-19. Then, we reviewed the clinical trial and systematic review studies that investigated the safety and efficacy of MSC therapy in the treatment of COVID-19 infection. [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]

COVID-19 infection is always accompanied by a cytokine storm that causes acute respiratory distress syndrome (ARDS). The reduction of pro-inflammatory cytokines is expected to be used for treating COVID-19 patients. Guava (Psidium guajava L.) was believed to have properties as an antioxidant and anti-inflammatory. This study aims to determine the effect of guava extract (PGE) on the ARDS rats model so that it can be used as a PGE treatment for the effects caused by ARDS. This study was conducted on 25 Sprague Dawley rats model in 5 treatment groups. Lipopolysaccharides (LPS) induction was carried out to create ARDS rats model. Determination of pro-inflammatory cytokines in lung Interleukin-18 (IL-18), IL-12 and serum IL-1β, Tumour Necrosis Factor alpha (TNF-α) was performed by ELISA, NOD-, LRR- and Pyrin domain-containing protein 3 (NRLP3) expressions were determined by the quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) method and IL-6, Nuclear factor kappa B (NF-κB) were analysed by immunohisto-chemistry assay. The results showed that PGE contained phenolic compound, daidzin and genistin. The IL-18, IL-12, Il-1β, TNF-α, IL-6, NF-kB and NRLP3 in ARDS model rats were decreased by PGE treatment. In conclusion, PGE can be used as a therapy for treating ARDS by decreasing pro-inflammatory marker. [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]

Objective: Screening of feature genes involved in cytokine release syndrome (CRS) from the coronavirus disease 19 (COVID-19). Methods: The data sets related to COVID-19 were retrieved using Gene Expression Omnibus (GEO) database, the differentially expressed genes (DEGs) related to CRS were analyzed with R software and Venn diagram, and the biological processes and signaling pathways involved in DEGs were analyzed with GO and KEGG enrichment. Core genes were screened using Betweenness and MCC algorithms. GSE164805 and GSE171110 dataset were used to verify the expression level of core genes. Immunoinfiltration analysis was performed by ssGSEA algorithm in the GSVA package. The DrugBank database was used to analyze the feature genes for potential therapeutic drugs. Results: This study obtained 6950 DEGs, of which 971 corresponded with CRS disease genes (common genes). GO and KEGG enrichment showed that multiple biological processes and signaling pathways associated with common genes were closely related to the inflammatory response. Furthermore, the analysis revealed that transcription factors that regulate these common genes are also involved in inflammatory response. Betweenness and MCC algorithms were used for common gene screening, yielding seven key genes. GSE164805 and GSE171110 dataset validation revealed significant differences between the COVID-19 and normal controls in four core genes (feature genes), namely IL6R, TLR4, TLR2, and IFNG. The upregulated IL6R, TLR4, and TLR2 genes were mainly involved in the Toll-like receptor signaling pathway of the inflammatory pathway, while the downregulated IFNG genes primarily participated in the necroptosis and JAK-STAT signaling pathways. Moreover, immune infiltration analysis indicated that higher expression of these genes was associated with immune cell infiltration that mediates inflammatory response. In addition, potential therapeutic drugs for these four feature genes were identified via the DrugBank database. Conclusion: IL6R, TLR4, TLR2, and IFNG may be potential pathogenic genes and therapeutic targets for the CRS associated with COVID-19. [ABSTRACT FROM AUTHOR]

Background COVID-19 disease causes complications that are classified according to likelihood to high such as venous thromboembolism, acute kidney injury, and postintensive care syndrome. Other complications are low in likelihood such as cytokine release syndrome, pancreatic injury, gastrointestinal complications, and pregnancy-related complications. Mortality and morbidity are really high when it is combined with surgical intervention especially under general anesthesia. Objectives To evaluate the incidence of COVID-19 in general surgery emergency and complications associated in different types of management. Patient and method This is a retrospective study from June 2020 to January 2021 including all COVID-19 positive cases admitted in general surgery department during previously mentioned period. Before September 2020, screening for COVID was based on swab for only clinically suspected COVID-positive patients. Starting from September 2020, routine swab to all admitted patients was done. All data collected about included cases in study underwent statistical analysis to get results. Results In this study, incidence of COVID-19 is 1.35%, mortality incidence is 26.4% (about 92.9% of mortality cases underwent surgery) and morbidity incidence is 30.2%. About 74% (73.6%) of positive cases improved and discharged. Management of cases is according to guidelines of management to each disease and decision of ER consultant. About 77.4% of cases are managed surgically; about 70.7% of cases operated upon underwent exploration. However, 60.4% of cases are admitted with sepsis and septic shock. Asymptomatic cases for COVID during admission are 26.4%. Conclusion Incidence of COVID-19 in acute general surgery emergency in Kasr Al-Ainy is not that high. However, cases operated upon in the era of COVID are associated with high incidence of mortality. Cases are presented to our institute late, which might be an effect of lock down. [ABSTRACT FROM AUTHOR]

Background: Human coronaviruses can be divided based on their pathogenicity. The types with high pathogenicity including SARS-CoV, MERS-CoV, and the current novel SARS-CoV2. SARS COV2 has led to possibly the worst pandemic of this century in the form of Coronavirus disease 2019 (COVID-19). Initially recognized as a respiratory system disease, COVID-19 has been found to interact with functions of other organ systems like cardiovascular, GIT, CNS Peripheral nervous system, during the course of the disease and postcovid syndromic manifestations including Endocrinal and psychological. The acute manifestations primarily lung will be involved that leads to ARDS, in severe disease all the organs will be effected that may lead to multiorgan dysfunction (MODS), and death. AIM: Evaluation of various endocrinal manifestations secondary to endocrinal gland dysfunction, in COVID 19 peak of the pandemic causing morbidity and mortality. In this COVID 19 pandemic everywhere the mortality was very high, the researchers and all over the globe thought that this is not only viral invasion or host's immune mediated of it's not due to viral virulence and postulated the actual pathogenesis of the disease and its manifestations causing morbidity and mortality. Some patients with coronavirus disease 2019 (COVID-19) develop a life-threatening hyper-inflammatory state that is commonly referred to as cytokine storm. This is the prime cause of all the syndromes presenting in this SARS COV2. The mortality has been increasing and new biochemical parameters are increasing in moderate to severe disease. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection induces myocardiopathy in 19% of severe cases, with a mortality rate of up to 51%. The mainstay of treatment is supportive care, steroids, and tocilizumab (anti-IL-6). This is a case of a 43-year-old woman diagnosed with hormone-positive breast cancer with lung metastasis and pulmonary lymphangitis carcinomatosis (PLC). Her baseline cardiac function was within normal limits. She presented to the emergency department with respiratory distress. Chest CT showed multiple bilateral ground-glass opacities consistent with COVID-19 pneumonia and confirmed by COVID-19-PCR nasal swab. Her condition deteriorated, and she was urgently admitted to the intensive care unit with evidence of a cytokine storm. She was started on tocilizumab, dexamethasone, and meropenem. Echocardiogram (echo) showed a severely reduced ejection fraction with severe global hypokinesis. A second dose of tocilizumab was given, and the dexamethasone dose was increased. Fortunately, the patient had significant clinical and biochemical improvement and regained her normal cardiac function. In conclusion, dexamethasone and tocilizumab could be promising aids in treating cardiomyopathy secondary to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 has been declared a pandemic by the WHO. Most mortality cases were linked to the presence of cytokine storms induced by the virus. Platelet parameters and IL-6 may provide significant results in the disease severity and input in a COVID-19 patient's management. This study aimed to determine the usefulness of platelet parameters and IL-6 with disease severity and outcomes amongst COVID-19 patients admitted to Hospital Kuala Lumpur (HKL). Methods: A retrospective study utilising clinical data of confirmed COVID-19 cases. Demographic data, platelet parameters on admission, serum IL-6 level, and treatment outcomes were retrieved and analysed. Results: 283 patients' data were analysed. The mean age of patients was 54.10 ±14.9 years old. Sixty percent of the patients were with comorbidities and (n=65, 23%) of them had succumbed to the disease. Males and females were equally affected and (n=139, 49.1%) were Malays. Ethnicity was an independent predictor for COVID-19 severity. A significant association was found between platelet count, MPV, and IL-6 with COVID-19 severity and outcomes. PDW was not associated with disease outcomes (p=0.236). Comorbidity and platelet count were independent predictors of COVID-19 death. A multivariate analysis of patients' platelet count, MPV, and IL-6 level using binary logistic analysis showed that platelet count of the non-survivor group significantly decreased by 0.004, compared to the survivor group. Conclusion: Combining a readily available routine blood investigation of low platelet count, raised MPV, and IL-6 level signifies an increased risk of COVID-19 severity, and thus, warrants close clinical attention in reducing mortality. [ABSTRACT FROM AUTHOR]

Objectives: Cytokine release triggered by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) depends on a dysregulated immune response and is associated with high mortality. Extracorporeal cytokine hemoadsorption (HA) can be considered a possible adjuvant therapy. This study aimed to review the outcomes of critically ill patients with COVID-19 treated with HA and analyze possible factors associated with mortality. Methods: Data of patients who received HA for at least one cycle from April 17, 2020, to January 31, 2021, were collected. Clinical and laboratory features were recorded, and mortality was evaluated based on the extracorporeal treatment application time and intensive care units (ICU) admission. Results: Data from 177 patients among 4733 ICU patients were analyzed. Their mean age was 60.9±10.9, and 40 (22.6%) of them were females. About 83% of them were mechanically ventilated, and the overall mortality was 76%. In univariate analysis, the mean age, median acute physiology and chronic health evaluation (APACHE)-II score, respiratory support rate, and duration between ICU admission and first cytokine filter were lower in the survivor group than in the non-survivor group. In binary logistic regression analysis, higher APACHE-II with an odds ratio of 1.06 (95% confidence interval [CI]: 1.005–1.128, p=0.033), invasive mechanical ventilation with an odds ratio of 138.4 (95%CI: 24.2–791.8, p<0.001), and later application of HA with an odds ratio of 1.190 (95%CI: 1.009–1.404, p=0.039) were independently associated with in-hospital mortality. Conclusion: Cytokine HA was applied to a large number of patients at our center. Although this was conducted in a severe population with high mortality, besides invasive mechanical ventilation, late application of the cytokine filter was found as one of the factors independently associated with higher mortality [ABSTRACT FROM AUTHOR]

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18–93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19. [ABSTRACT FROM AUTHOR]

Inflammation and inflammasomes have been proposed as important regulators of the host–microorganism interaction, playing a key role in morbidity and mortality due to the coronavirus disease 2019 (COVID-19) in subjects with chronic conditions and compromised immune system. The inflammasome consists of a multiprotein complex that finely regulates the activation of caspase-1 and the production and secretion of potent pro-inflammatory cytokines such as IL-1β and IL-18. The pyrin containing NOD (nucleotide-binding oligomerization domain) like receptor (NLRP) is a family of intracellular receptors, sensing patterns associated to pathogens or danger signals and NLRP3 inflammasome is the most deeply analyzed for its involvement in the innate and adaptive immune system as well as its contribution to several autoinflammatory and autoimmune diseases. It is highly expressed in leukocytes and up-regulated in sentinel cells upon inflammatory stimuli. NLRP3 expression has also been reported in B and T lymphocytes, in epithelial cells of oral and genital mucosa, in specific parenchymal cells as cardiomyocytes, and keratinocytes, and chondrocytes. It is well known that a dysregulated activation of the inflammasome is involved in the pathogenesis of different disorders that share the common red line of inflammation in their pathogenetic fingerprint. Here, we review the potential roles of the NLRP3 inflammasome in cardiovascular events, liver damage, pulmonary diseases, and in that wide range of systemic inflammatory syndromes named as a cytokine storm. [ABSTRACT FROM AUTHOR]

Severe course of COVID-19 is largely determined by hyperactivation of the immune system, or cytokine storm, in which immune cells (lymphocytes, monocytes, etc.) play a major role. Using low-voltage scanning electron microscopy, we studied the morphology of lymphocytes and monocytes during cytokine storm. Monocytes and lymphocytes were isolated by fluorescence sorting from the blood of healthy volunteers (n=6) and patients with COVID-19 (n=5) during cytokine storm (IL-6>23 ng/ml, smear positive for SARS-CoV-2). For each patient, 11-32 individual cells were analyzed at magnification of 18-32,000 times. Measurements showed that monocyte size was increased during cytokine storm (p=0.0001). [ABSTRACT FROM AUTHOR]

COVID-19, caused by the SARS-CoV-2 virus, has emerged as a global health threat. Due to coronovirus mutations and genetic variations, effective treatments remain elusive. Currently, the primary strategy for disease management revolves around coronovirus vaccines, representing the sole avenue for disease control. A prominent factor in the pathogenesis of COVID-19 is the severe inflammation triggered by a phenomenon known as cytokine storm. This review delves into the pivotal role of interleukin-6 (IL-6) in orchestrating the cytokine storm and explores the intricate network of signaling pathways and inhibitors, including phytochemicals. Numerous clinical trials have explored the potential of anti-cytokine agents and medicinal plants with cytokine-modulating attributes in COVID-19 patients. According to various studies investigating the effects of medicinal plants on COVID-19, four specific plants—Silybum marianum L., Tanacetum parthenium L., Curcuma longa L., and Zingiber officinale Rosc.—have exhibited significant anti-IL-6 signaling properties. However, further rigorous clinical data are needed to establish their prophylactic or therapeutic efficacy. Overall, both in-vivo and clinical studies suggest that the aforementioned medicinal plants, endowed with proven anti-inflammatory and immune-modulatory properties, particularly through IL-6 reduction, could make valuable contributions to the management of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

COVID-19-associated intensive care unit (ICU) admissions were recognized as critical health issues that contributed to morbidity and mortality in SARS-CoV-2-infected patients. Severe symptoms in COVID-19 patients are often accompanied by cytokine release syndrome. Here, we analyzed publicly available data from the Yale IMPACT cohort to address immunological misfiring and sex differences in early COVID-19 patients. In 2020, SARS-CoV-2 was considered far more pathogenic and lethal than other circulating respiratory viruses, and the inclusion of SARS-CoV-2 negative patients in IMPACT cohorts confounds many findings. We ascertained the impact of several important biological variables such as days from symptom onset (DFSO); pre-existing risk factors, including obesity; and early COVID-19 treatments on significantly changed immunological measures in ICU-admitted COVID-19 patients that survived versus those that did not. Deceased patients had 19 unique measures that were not shared with ICU patients including increased granzyme-B-producing GzB+CD8+ T cells and interferon-γ. Male COVID-19 patients in ICU experienced many more changes in immunological and clinical measures than female ICU patients (25% vs. ~16%, respectively). A total of 13/124 measures including CCL5, CCL17, IL-18, IFNα2, Fractalkine, classical monocytes, T cells, and CD4Temra exhibited significant sex differences in female vs. male COVID-19 patients. A total of nine measures including IL-21, CCL5, and CD4Temra differed significantly between female and male healthy controls. Immunosuppressed patients experienced the most decreases in CD4Temra and CD8Tem cell numbers. None of the early COVID-19 treatments were effective in reducing levels of IL-6, a major component of the cytokine storm. Obesity (BMI >30) was the most impactful risk factor for COVID-19-related deaths and worst clinical outcomes. Our analysis highlights the contribution of biological sex, risk factors, and early treatments with respect to COVID-19-related ICU admission and progression to morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: In the severe forms of COVID-19 and many other infectious diseases, the patients develop a cytokine storm syndrome (CSS) where pro-inflammatory cytokines such as IL-6 and TNF-α play a key role in the development of this serious process. Selenium and iron are two important trace minerals, and their metabolism is tightly connected to immune system function. Numerous studies highlight the role of selenium and iron metabolism changes in the procedure of COVID-19 inflammation. The immunomodulator effect of nanomedicines that are synthesized based on nanochelating technology has been proved in previous studies. In the present study, the effects of the combination of BCc1(with iron-chelating property) and Hep-S (containing selenium) nanomedicines on mentioned cytokines levels in hospitalized moderate COVID-19 patients were evaluated. Methods: Laboratory-confirmed moderate COVID-19 patients were enrolled to participate in a randomized, double-blind, placebo-controlled study in two separate groups: combination of BCc1 and Hep-S (N = 62) (treatment) or placebo (N = 60) (placebo). The blood samples were taken before medications on day zero, at discharge, and 28 days after consumption to measure hematological and biochemical parameters and cytokine levels. The clinical symptoms of all the patients were recorded according to an assessment questionnaire before the start of the treatment and on days 3 and discharge day. Results: The results revealed that consumption of the nanomedicines led to a significant decrease in the mean level of IL-6 cytokine, and at the end of the study, there was a 77% downward trend in IL-6 in the nanomedicine group, while an 18% increase in the placebo group (p < 0.05). In addition, the patients in the nanomedicines group had lower TNF-α levels; accordingly, there was a 21% decrease in TNF-α level in the treatment group, while a 31% increase in this cytokine level in the placebo was observed (p > 0.05). On the other hand, in nanomedicines treated groups, clinical scores of coughing, fatigue, and need for oxygen therapy improved. Conclusions: In conclusion, the combination of BCc1 and Hep-S inhibits IL-6 as a highly important and well-known cytokine in COVID-19 pathophysiology and presents a promising view for immunomodulation that can manage CSS. Trial registration: Iranian Registry of Clinical Trials RCT20170731035423N2. Registered on June 12, 2020. [ABSTRACT FROM AUTHOR]

Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection. The neurons were exposed to SARS-CoV-2, followed by RT-qPCR, immunocytochemistry, and proteomic analyses of the infected neurons. Our findings showed that SARS-CoV-2 infects neurons at a lower rate than other human cells; however, the virus could not replicate or produce infectious virions in this neuronal model. Despite the aborted SARS-CoV-2 replication, the infected neuronal nuclei showed irregular morphology compared to other human cells. Since cytokine storm is a significant effect of SARS-CoV-2 infection in COVID-19 patients, in addition to the direct neuronal infection, the neurons were treated with pre-conditioned media from SARS-CoV-2-infected lung cells, and the neuroproteomic changes were investigated. The limited SARS-CoV-2 infection in the neurons and the neurons treated with the pre-conditioned media showed changes in the neuroproteomic profile, particularly affecting mitochondrial proteins and apoptotic and metabolic pathways, which may lead to the development of neurological complications. The findings from our study uncover a possible mechanism behind SARS-CoV-2-mediated neuropathology that might contribute to the lingering effects of the virus on the human brain. [ABSTRACT FROM AUTHOR]

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction. [ABSTRACT FROM AUTHOR]

The impact of SARS-CoV-2 infection remains substantial on a global scale, despite widespread vaccination efforts, early therapeutic interventions, and an enhanced understanding of the disease's underlying mechanisms. At the same time, a significant number of patients continue to develop severe COVID-19, necessitating admission to intensive care units (ICUs). This study aimed to provide evidence concerning the most influential predictors of mortality among critically ill patients with severe COVID-19, employing machine learning (ML) techniques. To accomplish this, we conducted a retrospective multicenter investigation involving 684 patients with severe COVID-19, spanning from 1 June 2020 to 31 March 2023, wherein we scrutinized sociodemographic, clinical, and analytical data. These data were extracted from electronic health records. Out of the six supervised ML methods scrutinized, the extreme gradient boosting (XGB) method exhibited the highest balanced accuracy at 96.61%. The variables that exerted the greatest influence on mortality prediction encompassed ferritin, fibrinogen, D-dimer, platelet count, C-reactive protein (CRP), prothrombin time (PT), invasive mechanical ventilation (IMV), PaFi (PaO2/FiO2), lactate dehydrogenase (LDH), lymphocyte levels, activated partial thromboplastin time (aPTT), body mass index (BMI), creatinine, and age. These findings underscore XGB as a robust candidate for accurately classifying patients with COVID-19. [ABSTRACT FROM AUTHOR]

Depression is among the psychiatric sequelae of COVID-19, affecting more than 20% of the convalescents. Its underlying pathophysiology remains unclear. Interleukin 6 (IL-6), a pro-inflammatory cytokine, plays a critical role in the COVID-19-associated cytokine storm, has been implicated in depressive disorders, and may thus be involved in post-COVID-19 depression. PubMed, Scopus, Embase, and Web of Science were systematically searched for relevant studies assessing peripheral IL-6 levels in convalescents who developed depression after COVID-19 vs. convalescents who did not. Five studies were included in our systematic review, and four entered the meta-analysis. The meta-analysis revealed that post-COVID people with de novo depression did not have statistically significant differences in IL-6 levels compared to those without depression (standardised mean difference (SMD) = 0.09, 95% confidence interval (CI) = −0.35, 0.54, p-value = 0.68). Although convalescents with depression did not have significantly higher IL-6 levels than convalescents without depression, the results should be interpreted considering the limited sample size and the low power of the included studies. [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]

Background: Coronavirus disease 19 (COVID-19) is the disease caused by SARS-CoV-2, a highly infectious member of the coronavirus family, which emerged in December 2019 in "Wuhan, China". It induces respiratory illness ranging from mild symptoms to severe disease. It was declared a "pandemic" by the World Health Organization (WHO) in March 2020. Since then, a vast number of clinical and experimental studies have been conducted to identify effective approaches for its prevention and treatment. Main body: The pathophysiology of COVID-19 represents an unprecedented challenge; it triggers a strong immune response, which may be exacerbated by "a cytokine storm syndrome". It also induces thrombogenesis and may trigger multi-organ injury. Therefore, different drug classes have been proposed for its treatment and prevention, such as antivirals, anti-SARS-CoV-2 antibody agents (monoclonal antibodies, convalescent plasma, and immunoglobulins), anti-inflammatory drugs, immunomodulators, and anticoagulant drugs. To the best of our knowledge, this review is the first to present, discuss, and summarize the current knowledge about the different drug classes used for the treatment of COVID-19, with special emphasis on their targets, mechanisms of action, and important adverse effects and drug interactions. Additionally, we spotlight the latest "October 2023" important guidelines (NIH, IDSA, and NICE) and FDA approval or authorization regarding the use of these agents in the management of COVID-19. Conclusion: Despite the wide array of therapeutic strategies introduced for the treatment of COVID-19, one of the most prominent therapeutic challenges is SARS-CoV-2 mutations and emerging new variants and subvariants. Currently, the anti-COVID-19 drug pipeline is continuously affording novel treatments to face this growing challenge. [ABSTRACT FROM AUTHOR]

Background: COVID-19 pandemic has caused more than 6 million deaths worldwide. Co-morbid conditions such as Type 2 Diabetes (T2D) have increased mortality in COVID-19. With limited translatability of in vitro and small animal models to human disease, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. Methods: T2D or non-diabetic patient-derived macrophages and human liver sinusoidal endothelial cells were seeded, along with normal hepatocytes and stellate cells in the liver-on-a-chip (LAMPS – liver acinus micro physiological system), perfused with media mimicking non-diabetic fasting or T2D (high levels of glucose, fatty acids, insulin, glucagon) states. The macrophages and endothelial cells were transduced to overexpress the SARS-CoV2-S (spike) protein with appropriate controls before their incorporation into LAMPS. Cytokine concentrations in the efflux served as a read-out of the effects of S-protein expression in the different experimental conditions (non-diabetic-LAMPS, T2D-LAMPS), including incubation with tocilizumab, an FDA-approved drug for severe COVID-19. Findings: S-protein expression in the non-diabetic LAMPS led to increased cytokines, but in the T2D-LAMPS, this was significantly amplified both in the number and magnitude of key pro-inflammatory cytokines (IL6, CCL3, IL1β, IL2, TNFα, etc.) involved in cytokine storm syndrome (CSS), mimicking severe COVID-19 infection in T2D patients. Compared to vehicle control, tocilizumab (IL6-receptor antagonist) decreased the pro-inflammatory cytokine secretion in T2D-COVID-19-LAMPS but not in non-diabetic-COVID-19-LAMPS. Interpretation: macrophages and endothelial cells play a synergistic role in the pathophysiology of the hyper-inflammatory response seen with COVID-19 and T2D. The effect of Tocilizumab was consistent with large clinical trials that demonstrated Tocilizumab's efficacy only in critically ill patients with severe disease, providing confirmatory evidence that the T2D-COVID-19-LAMPS is a robust platform to model human in vivo pathophysiology of COVID-19 in T2D and for screening potential therapeutics. [ABSTRACT FROM AUTHOR]

The first cases of COVID-19 were identified in China in 2019, and the disease subsequently spread rapidly around the world, leading it to be declared a pandemic. The disease affects the lungs through the upper and lower respiratory tracts, and with the development of pneumonia, a clinical picture leading to respiratory failure referred to as cytokine storm occurs as a result of excessive cytokine production associated with an excessive inflammatory immune response. The increase in inflammatory markers is related to acute respiratory distress syndrome, disseminated intravascular coagulation and hypercoagulation. We present here an explanation of cytokine storm and the associated immune damage mechanisms. [ABSTRACT FROM AUTHOR]

Infection with SARS-CoV-2 is a growing concern to the global well-being of the public at present. Different amino acid mutations alter the biological and epidemiological characteristics, as well as immune resistance of SARS-CoV-2. The virus-induced pulmonary impairment and inflammatory cytokine storm are directly related to its clinical manifestations. But, the fundamental mechanisms of inflammatory responses are found to be the reason for the death of immune cells which render the host immune system failure. Apoptosis of immune cells is one of the most common forms of programmed cell death induced by the virus for its survival and virulence property. ORF3a, a SARS-CoV-2 accessory viral protein, induces apoptosis in host cells and suppress the defense mechanism. This suggests, inhibiting SARS-CoV-2 ORF3a protein is a good therapeutic strategy for the treatment in COVID-19 infection by promoting the host immune defense mechanism. [ABSTRACT FROM AUTHOR]

(1) Background: Some severe COVID-19 patients develop hyperinflammatory cytokine storm syndrome (CSS). We assessed the efficacy of anakinra added to standard of care (SoC) in hospitalized COVID-19 CSS patients. (2) Methods: In this single-center, randomized, double-blind, placebo-controlled trial (NCT04362111), we recruited adult hospitalized patients with SARS-CoV-2 infection, evidence of pneumonia, new/increasing oxygen requirement, ferritin ≥ 700 ng/mL, and at least three of the following indicators: D-dimer ≥ 500 ng/mL, platelet count < 130,000/mm3, WBC < 3500/mm3 or lymphocyte count < 1000/mm3, AST or ALT > 2X the upper limit of normal (ULN), LDH > 2X ULN, C-reactive protein > 100 mg/L. Patients were randomized (1:1) to SoC plus anakinra (100 mg subcutaneously every 6 h for 10 days) or placebo. All received dexamethasone. The primary outcome was survival and hospital discharge without need for intubation/mechanical ventilation. The data were analyzed according to the modified intention-to-treat approach. (3) Results: Between August 2020 and January 2021, 32 patients were recruited, of which 15 were assigned to the anakinra group, and 17 to the placebo group. Two patients receiving the placebo withdrew within 48 h and were excluded. The mean age was 63 years (SD 10.3), 20 (67%) patients were men, and 20 (67%) were White. At Day 10, one (7%) patient receiving anakinra and two (13%) patients receiving the placebo had died (p = 1.0). At hospital discharge, four (27%) patients receiving anakinra and four (27%) patients receiving the placebo had died. The IL-6 level at enrollment was predictive of death (p < 0.01); anakinra use was associated with decreases in CXCL9 levels. (4) Conclusions: Anakinra added to dexamethasone did not significantly impact the survival of COVID-19 pneumonia patients with CSS. Additional studies are needed to assess patient selection and the efficacy, timing, and duration of anakinra treatment for COVID-19 CSS. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients. [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]

COVID-19 patients suffer from the detrimental effects of cytokine storm and not much success has been achieved to overcome this issue. We sought to test the ability of selenium to reduce the impact of two important cytokine storm players: IL-6 and TNF-α. The effects of four selenium compounds on the secretion of these cytokines from THP-1 macrophages were evaluated in vitro following an LPS challenge. Also, the potential impact of methylseleninic acid (MSeA) on Nrf2 and IκBα was determined after a short treatment of THP-1 macrophages. MSeA was found to be the most potent selenium form among the four selenium compounds tested that reduced the levels of IL-6 and TNF-α secreted by THP-1 macrophages. In addition, an increase in Nrf2 and decrease in pIκBα in human macrophages was observed following MSeA treatment. Our data indicate that COVID-19 patients might benefit from the addition of MSeA to the standard therapy due to its ability to suppress the key players in the cytokine storm. [ABSTRACT FROM AUTHOR]

Dexamethasone (DEX) given at a dose of 6 mg once‐daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID‐19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti‐inflammatory effects in COVID‐19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed‐effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID‐19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL‐6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL‐6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti‐inflammatory compounds as well as drug combinations in the treatment of cytokine storms. [ABSTRACT FROM AUTHOR]

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a "cytokine storm", and neuroinflammation. COVID-19's upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN's Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 (coronavirus disease 2019) was first identified in China in December 2019 and is rapidly spreading worldwide as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this context have focused on pathogenesis primarily in the respiratory system. However, evidence shows that the central nervous system (CNS) may also be affected by COVID-19. Since COVID-19 is spreading, it is necessary to study its possible cognitive effects on COVID-19 patients and their recovery. Methods: The articles used in this study were searched by keywords, such as cytokine storm and COVID-19, COVID-19 and executive dysfunction, cognitive disorder, and COVID-19, central nervous system (CNS) and COVID-19, coronavirus, neuroinvasion in Science Direct, Scopus, PubMed, Embase, and Web of Science databases based on preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The study evaluates all observational studies published between December 2019 and April 2021 in peer-reviewed journals, including cross-sectional, cohort, case-control studies, case reports, and case series. The search result was 106 articles, of which 73 articles related to COVID-19, the stages of infection by this virus, its effect on the nervous system and neurological symptoms, the cytokine storm caused by this infection, and the possible cognitive consequences caused by this virus in patients, has been reviewed. Other articles were not checked due to their limited relevance to the topic under discussion. Results: Studies showed that neurons may be directly affected by severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and SARS-CoV-2. Furthermore, various studies indicated that systemic inflammation (so-called “cytokine storm”) is also responsible for brain damage induced by infection with SARS-CoV-1 and SARS-CoV-2. In such a way that these patients showed elevated levels of interleukin (IL-), 6, 8, and 10 and of tumor necrosis factor- alpha (TNF-α) in their blood. Conclusion: Various cognitive defects have been observed following an increased level of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, 8. Therefore, due to the increased level of these pro-inflammatory factors in the brains of these patients, cognitive deficits can be expected, which need further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The clinical signs of COVID-19 include ageusia and anosmia. Anosmia and ageusia haven't been evaluated as prognostic factors in any prior studies, though. Therefore, the purpose of this review is to assess the effectiveness of ageusia and anosmia as prognostic indicators in COVID-19 patients. Methods: Literature was collected from various databases systematically using the PRISMA until May 25th, 2022. The screening process was performed based on inclusion and exclusion criteria, before being analyzed qualitatively. The risk of bias was assessed using Newcastle-Ottawa Quality Assessment Scale converted by AHRQ. Results: Anosmia and ageusia could be used as the indicator for the good prognostic associated with lower mortality, milder trajectory rate, ICU, and hospital admission risk, and shorter length of stay. Anosmia and ageusia have shown high prevalence to predict a prognosis for the COVID-19 infection. Although COVID-19 prognosis also depends on the other lying conditions, patients with anosmia or ageusia had a lower mortality risk due to the lower body mechanism and cell inflammation mechanism toward the viral load that may not lead to the maladaptive cytokine release in response to infection generally called as a cytokine storm. Conclusion: In COVID-19 patients, anosmia and ageusia have been shown to be indicators of a favorable prognosis due to lower disease severity, mortality, risk of ICU and hospital admission, and shorter duration of stay. Therefore, in order to determine the prognosis, it is important to assess the clinical symptoms of the patients. [ABSTRACT FROM AUTHOR]

Introduction: SARS-CoV-2 infection (COVID-19) induces dysregulated production of pro- and anti-inflammatory cytokines, called the cytokine storm, leading to the development of severe pneumonia and ARDS. We aimed to examine the dynamic cytokine response on different days of the disease in adult COVID-19 patients. Methodology: Our study included 142 patients (with SARS-CoV-2 PCR-positive nasopharyngeal samples) with varying disease severity and admitted on different days of the disease. We examined the presence and mean levels of TNF-a and IL-10 and did a correlation and logistic regression analysis. Results: TNF-a levels were high in all patients, with mean levels being the highest on day 5 of the disease. IL-10 was high only in a quarter of the patients. The levels of IL-10 were also the highest on day 5, which was significantly different from the mean levels on the other days of the disease. Average IL-10 levels were not any higher than the normal range on the other days. We found a significant positive correlation between the levels of TNF-a and IL-10 during the first week of the infection. In the second week, the positive correlation was no longer significant, and starting from day 10, there was even a slight negative correlation. IL-10 level increase showed prognostic significance for severe, but not the critical forms of the disease. Conclusions: The uncontrolled immune response to SARS-CoV-2 in the second week of the disease can be the result of dysregulated production of endogenous anti-inflammatory cytokines. This leads to a severe disease course and a possible unfavorable outcome. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) shares similar immune characteristics with autoimmune diseases like systemic lupus erythematosus (SLE). However, such associations have not yet been investigated at the single-cell level. Methods: We integrated and analyzed RNA sequencing results from different patients and normal controls from the GEO database and identified subsets of immune cells that might involve in the pathogenesis of SLE and COVID- 19. We also disentangled the characteristic alterations in cell and molecular subset proportions as well as gene expression patterns in SLE patients compared with COVID-19 patients. Results: Key immune characteristic genes (such as CXCL10 and RACK1) and multiple immune-related pathways (such as the coronavirus disease-COVID-19, T-cell receptor signaling, and MIF-related signaling pathways) were identified. We also highlighted the differences in peripheral blood mononuclear cells (PBMCs) between SLE and COVID-19 patients. Moreover, we provided an opportunity to comprehensively probe underlying B-cell‒cell communication with multiple ligand–receptor pairs (MIF-CD74+CXCR4, MIF-CD74+CD44) and the differentiation trajectory of B-cell clusters that is deemed to promote cell state transitions in COVID-19 and SLE. Conclusions: Our results demonstrate the immune response differences and immune characteristic similarities, such as the cytokine storm, between COVID-19 and SLE, which might pivotally function in the pathogenesis of the two diseases and provide potential intervention targets for both diseases. [ABSTRACT FROM AUTHOR]