Development Of Cytokine Storm Research Articles

Etiological and immunopathogenetic aspects of multiorgan failure development in coronavirus disease (COVID-19)

The COVID-19 epidemic has already come to be seen as an emergency of international concern. This relates not only to the wide occurrence of the infection, but also to a fairly high mortality rate, currently more than 6.5 million deaths in the world. The aim of this study was to analyze, generalize and systematize the currently available literary data on the study of the novel coronavirus infection pathogenesis in the human body and to determine key changes that occur after the SARS-CoV-2 penetration into cells. In this way to target physicians primarily based on the pathogenetic processes that occur in the human body, syndromes and symptom complexes that are observed in treatments. Results. The article presents a literature review demonstrating that the specific interaction between the virus and somatic cells is the triggering mechanism for the pathogenesis of coronavirus infection. The main route for SARS-CoV-2 entry into the body is the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed not only in type 2 alveolar epithelial cells, but also in cells of the kidney, heart, blood vessels and gastrointestinal tract, including endotheliocytes and pericytes. Expression of the ACE2 receptor has also been shown in various structures and parts of the brain, cells of the conjunctiva, limbus, cornea and cells of the substantia propria. A high expression of the ACE2 receptor has been found in the epithelial cells of the oral mucosa, salivary glands, tonsils and tongue. These factors explain a possible involvement of different organs and systems in the development of multiorgan failure. Conclusions. In the development of multiorgan disfunction, two components are important: first, direct cell tropism and viral load, that may be unique in each patient. Secondly, it is the development of immune-mediated reactions to infected cells. Under conditions of hyperimmune inflammation, that is, the development of cytokine storm, acute respiratory distress syndrome progresses, and multiple organ failure develops. Endothelial damage is directly involved in the pathophysiology of this process, that results in the development of endothelial dysfunction, disruption of microcirculation, as well as perivascular inflammation, which aggravates damage to the endothelium and can lead to thrombus formation. The use of modern knowledge about the immunopathogenesis of COVID-19 would help to estimate the risk for severe infection and the possible development of complications, allowing for the timely implementation of effective pathogenetic therapy.

Impaired arginine/ornithine metabolism drives severe HFMD by promoting cytokine storm.

The Hand, Foot and Mouth Disease (HFMD), caused by enterovirus 71 infection, is a global public health emergency. Severe HFMD poses a significant threat to the life and well-being of children. Numerous studies have indicated that the occurrence of severe HFMD is associated with cytokine storm. However, the precise molecular mechanism underlying cytokine storm development remains elusive, and there are currently no safe and effective treatments available for severe HFMD in children. In this study, we established a mouse model of severe HFMD to investigate the molecular mechanisms driving cytokine storm. We specifically analyzed metabolic disturbances, focusing on arginine/ornithine metabolism, and assessed the potential therapeutic effects of spermine, an ornithine metabolite. Our results identified disturbances in arginine/ornithine metabolism as a pivotal factor driving cytokine storm onset in severe HFMD cases. Additionally, we discovered that spermine effectively mitigated the inflammatory injury phenotype observed in mice with severe HFMD. In conclusion, our findings provide novel insights into the molecular mechanisms underlying severe HFMD from a metabolic perspective while offering a promising new strategy for its safe and effective treatment.

Effect of increasing doses of colchicine on the treatment of 333 COVID-19 inpatients.

Previous research done in Bulgaria demonstrated a fivefold reduction in mortality from COVID-19 with increased doses of colchicine from two hospitals in the country. We report here a further 333 cases of COVID-19 inpatients, treated with different doses of colchicine and its effect on mortality. A case-control comparison from two additional hospitals was conducted between increased doses of colchicine and added bromhexine to standard of care (SOC) versus current SOC. Risk and odds ratio, as well as subgroup analysis, was conducted with newly reported data, alongside aggregate data from all hospital centers to determine the extent of mortality reduction in COVID-19 inpatients. There was a clear reduction in the mortality of inpatients with increasing doses of colchicine-between twofold and sevenfold. Colchicine loading doses of 4 mg are more effective than those with 2 mg. Despite these doses being higher than the so-called "standard doses," colchicine inpatients experienced lower mortality than SOC patients (5.7% vs. 19.53%). This mortality benefit was evident in different age subgroups, with a 4-mg loading dose of colchicine proving slightly superior to a 2-mg loading dose. Colchicine led to an overall relative risk reduction of 70.7%, with SOC patients having 3.91 higher odds of death. The safety of the doses was not different than the reported in the summary of product characteristics. Inpatients in Bulgaria with added colchicine and bromhexine to SOC achieved better clinical and mortality outcomes than those on SOC alone. These results question the World Health Organization-recommended strategy to inhibit viral replication. We posit that our treatment strategy to inhibit the Severe acute respiratory syndrome coronavirus 2 entry into the cell with inhaled bromhexine and the hyperactivated NLRP3 inflammasome with higher doses of colchicine, prevents the development of cytokine storm. The timing of the initiation of treatment seems critical.

The possible role of nuclear factor erythroid-2-related factor 2 activators in the management of Covid-19.

COVID-19 is caused by a novel SARS-CoV-2 leading to pulmonary and extra-pulmonary manifestations due to oxidative stress (OS) development and hyperinflammation. COVID-19 is primarily asymptomatic though it may cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), systemic inflammation, and thrombotic events in severe cases. SARS-CoV-2-induced OS triggers the activation of different signaling pathways, which counterbalances this complication. One of these pathways is nuclear factor erythroid 2-related factor 2 (Nrf2), which induces a series of cellular interactions to mitigate SARS-CoV-2-mediated viral toxicity and OS-induced cellular injury. Nrf2 pathway inhibits the expression of pro-inflammatory cytokines and the development of cytokine storm in COVID-19. Therefore, Nrf2 activators may play an essential role in reducing SARS-CoV-2 infection-induced inflammation by suppressing NLRP3 inflammasome in COVID-19. Furthermore, Nrf2 activators can attenuate endothelial dysfunction (ED), renin-angiotensin system (RAS) dysregulation, immune thrombosis, and coagulopathy. Thus this mini-review tries to clarify the possible role of the Nrf2 activators in the management of COVID-19. Nrf2 activators could be an effective therapeutic strategy in the management of Covid-19. Preclinical and clinical studies are recommended in this regard.

The Effectiveness of Using Herbal Packages (VCO, Honey, Black Seed) as Alternative Treatment for Covid-19 in the Community

<div><table cellspacing="0" cellpadding="0" align="left"><tbody><tr><td align="left" valign="top"><p><em>Covid-19 is an infectious disease that can cause death. Herbal medicines have anti-inflammatory properties associated with cytokine storm development. This means it prevents increases in inflammatory mediators, erythrocyte sedimentation rate (ESR), interleukin (IL)-6, and C-reactive protein (CRP). This study aimed to determine the effectiveness of using herbal packages (VCO, honey, Black Seed) as an alternative treatment for Covid-19 in the community. This research is a Quasi-experimental quantitative study with a control group design (control group design) Pretest-Posttest Control Group Design design. This research was conducted in Boyolali Regency. This research was conducted from October 2022 - January 2023. The population in this study were individuals with a history of Covid-19 disease in Boyolali Regency, 82 in December 2022. The research sampling technique was simple random sampling. The research sample consisted of 46 people consisting of the intervention group of 23 respondents and the control group of 23 respondents. The research instruments were questionnaires, observation forms, and other forms, and measurements were made using a sphygmomanometer, oxymeter, and thermometer. Analysis of bivariate analysis research data using the Paired Sample t-test, Independent Sample t-test, and the help of the SPSS software computer application. The analysis results obtained the p-value for saturation measurement in the treatment group, namely p = 0.024 <0.05, and for temperature measurements, p = 0.014 <0.05, so it can be concluded that herbal packages are effective as an alternative treatment for the Covid-19 virus in the community. It is known that most respondents in the treatment group felt better after consuming the herbal package. Herbal packages have proven effective in dealing with the sequelae caused by Covid-19 and are effective as a companion to the treatment of Covid-19 patients.<strong></strong></em></p><p><strong><em> </em></strong></p></td></tr></tbody></table></div><strong><em>Keywords:</em></strong><em> <strong> Black Seed, Covid-19, Effectiveness, Honey, Virgin Coconut Oil</strong></em>

Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19

The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 PLpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 infection. In this context, we performed a phenotypic screening using an in-house pilot compounds collection possessing a diverse skeleta against SARS-CoV-2 PLpro. This screen identified SIMR3030 as a potent inhibitor of SARS-CoV-2. SIMR3030 has been shown to exhibit deubiquitinating activity and inhibition of SARS-CoV-2 specific gene expression (ORF1b and Spike) in infected host cells and possessing virucidal activity. Moreover, SIMR3030 was demonstrated to inhibit the expression of inflammatory markers, including IFN-α, IL-6, and OAS1, which are reported to mediate the development of cytokine storms and aggressive immune responses. In vitro absorption, distribution, metabolism, and excretion (ADME) assessment of the drug-likeness properties of SIMR3030 demonstrated good microsomal stability in liver microsomes. Furthermore, SIMR3030 demonstrated very low potency as an inhibitor of CYP450, CYP3A4, CYP2D6 and CYP2C9 which rules out any potential drug-drug interactions. In addition, SIMR3030 showed moderate permeability in Caco2-cells. Critically, SIMR3030 has maintained a high in vivo safety profile at different concentrations. Molecular modeling studies of SIMR3030 in the active sites of SARS-CoV-2 and MERS-CoV PLpro were performed to shed light on the binding modes of this inhibitor. This study demonstrates that SIMR3030 is a potent inhibitor of SARS-CoV-2 PLpro that forms the foundation for developing new drugs to tackle the COVID-19 pandemic and may pave the way for the development of novel therapeutics for a possible future outbreak of new SARS-CoV-2 variants or other Coronavirus species.

Mixed storm in SARS-CoV-2 infection: A narrative review and new term in the Covid-19 era.

Coronavirus disease 2019 (Covid-19) is caused by a novel severe acute respiratory syndrome coronavirus virus type 2 (SARS-CoV-2) leading to the global pandemic worldwide. Systemic complications in Covid-19 are mainly related to the direct SARS-CoV-2 cytopathic effects, associated hyperinflammation, hypercytokinemia, and the development of cytokine storm (CS). As well, Covid-19 complications are developed due to the propagation of oxidative and thrombotic events which may progress to a severe state called oxidative storm and thrombotic storm (TS), respectively. In addition, inflammatory and lipid storms are also developed in Covid-19 due to the activation of inflammatory cells and the release of bioactive lipids correspondingly. Therefore, the present narrative review aimed to elucidate the interrelated relationship between different storm types in Covid-19 and the development of the mixed storm (MS). In conclusion, SARS-CoV-2 infection induces various storm types including CS, inflammatory storm, lipid storm, TS and oxidative storm. These storms are not developing alone since there is a close relationship between them. Therefore, the MS seems to be more appropriate to be related to severe Covid-19 than CS, since it develops in Covid-19 due to the intricate interface between reactive oxygen species, proinflammatory cytokines, complement activation, coagulation disorders, and activated inflammatory signaling pathway.

Cytokine profiling during conditioning in haploidentical stem cell transplantation and its prognostic impact on early transplant outcomes

Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival.

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection.

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.

Antigen-Specific T Cells and SARS-CoV-2 Infection: Current Approaches and Future Possibilities

COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective "off-the-shelf" approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration.

PSAT235 The Role of Systemic Immune Activation in the Development of Thyroid Dysfunction in COVID-19

Abstract Background The research of cytokine-induced thyropathies in the midst of continuing COVID-19 pandemic is a very important and urgent problem. This work is based on the hypothesis that the hyperactivation of the immune system during COVID-19 is accompanied by a massive production of proinflammatory cytokines, and this could lead to thyroid gland disruption. Aim The primary endpoint is to assess the relationship between the levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3f), and free thyroxine (T4f) with the inflammatory process markers. The secondary endpoint is the identification of an association between TSH, T3f, T4f values, and patient survival. Materials and Methods This retrospective, single-center study included 122 patients hospitalized at the National Endocrinology Research Centre with a clinical and laboratory analysis of COVID-19 and bilateral polysegmental viral pneumonia. To assess the functional status of the thyroid gland all patients underwent observation of the TSH, T3f, T4f, AT-TPO, and AT-recTSH. Additionally, the markers of the inflammatory process were assessed in all patients, including: interleukin-6 (IL-6). Results Five patients (4%) were found with subclinical thyrotoxicosis. Serum TSH values were inversely correlated with IL-6 (r: -0.221; p = 0.024). Analysis of the level of hospital mortality, stratified by TSH, revealed statistically significantly lower TSH values in the group of deceased patients (p = 0.012). The median TSH in surviving patients was 1.34 [0.85; 1.80], for the deceased 0.44 [0.29; 0.99]. Based on the hypothesis that the immunosuppressive effect of genetically engineered biological therapy may have a protective role against thyroid damage in the development of cytokine storm, a comparative analysis of TSH values in two groups of patients with cytokine storm was performed (p=0.080). Conclusion Our research shows that the trigger of thyropathies in coronavirus infection is most likely thyroid tissue damage by the proinflammatory cytokines. In addition to the pathophysiological aspects of thyrotoxicosis, this study shows some specific clinical aspects regarding the clinical relevance in patients with thyrotoxicosis and COVID-19, namely, the high hospital mortality rate. The results obtained indicate a high risk of developing cytokine-induced thyropathies in patients with COVID-19. In support of the hypothesis of thyroid tissue damage being caused by pro-inflammatory cytokines, the differences in detected TSH values rose to the level of a statistical trend in 2 groups of patients with cytokine storm (i.e., patients who received tocilizumab therapy, and patients who received symptomatic therapy). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Diabetes and severe COVID-19 infection: Connecting the dots.

Diabetes is a significant risk factor for coronavirus disease 2019 (COVID-19) severity, poor prognosis, and mortality. Uncontrolled hyperglycaemia is associated with impaired innate and adaptive immunity predisposing to severe infection. In addition, there are other mechanisms linked to diabetes such as the upregulation of angiotensin-converting enzyme-2 receptor that might aid in viral entry and spread. The chronic low-grade inflammation and endothelial dysfunction might provide the backdrop to the development of cytokine storm and thromboembolic complications. Understanding the pathophysiology behind severe COVID-19 in diabetes will help to optimise management.

5-HT/CGRP pathway and Sumatriptan role in Covid-19.

Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.

Gut bacteria, bacteriophages, and probiotics: Tripartite mutualism to quench the SARS-CoV2 storm.

Patients with SARS-CoV-2 infection, exhibit various clinical manifestations and severity including respiratory and enteric involvements. One of the main reasons for death among covid-19 patients is excessive immune responses directed toward cytokine storm with a low chance of recovery. Since the balanced gut microbiota could prepare health benefits by protecting against pathogens and regulating immune homeostasis, dysbiosis or disruption of gut microbiota could promote severe complications including autoimmune disorders; we surveyed the association between the imbalanced gut bacteria and the development of cytokine storm among COVID-19 patients, also the impact of probiotics and bacteriophages on the gut bacteria community to alleviate cytokine storm in COVID-19 patients. In present review, we will scrutinize the mechanism of immunological signaling pathways which may trigger a cytokine storm in SARS-CoV2 infections. Moreover, we are explaining in detail the possible immunological signaling pathway-directing by the gut bacterial community. Consequently, the specific manipulation of gut bacteria by using probiotics and bacteriophages for alleviation of the cytokine storm will be investigated. The tripartite mutualistic cooperation of gut bacteria, probiotics, and phages as a candidate prophylactic or therapeutic approach in SARS-CoV-2 cytokine storm episodes will be discussed at last.

SARS-CoV-2 Infection and C1-Esterase Inhibitor: Camouflage Pattern and New Perspective.

In Covid-19, the pathological effect of SARS-CoV-2 infection is arbitrated through direct viral toxicity, unusual immune response, endothelial dysfunction, deregulated renin-angiotensin system [RAS], and thrombo-inflammation, leading to acute lung injury (ALI), with a succession of acute respiratory distress syndrome (ARDS) in critical conditions. C1 esterase inhibitor (C1INH) is a protease inhibitor that inhibits the spontaneous activation of complement and contact systems and kinin pathway, clotting, and fibrinolytic systems. Therefore, targeting the complement system through activation of C1INH might be a novel therapeutic modality in the treatment of Covid-19. Therefore, this study aims to illustrate the potential nexus between C1INH and the pathophysiology of SARS-CoV-2 infection. C1INH is highly dysregulated in Covid-19 due to inflammatory and coagulation disorders. C1INH is up-regulated in Covid-19 and sepsis as an acute phase response, but this increase is insufficient to block the activated complement system. In addition, the C1INH serum level predicts the development of ARDS in Covid-19 patients, as its up-regulation is associated with the development of cytokine storm. In Covid-19, C1INH might be inhibited or dysregulated by SARS-CoV-2, leading to propagation of complement system activation with subsequent uncontrolled immunological stimulation due to activation of bradykinin and FXII with sequential activation of coagulation cascades and polymerization of fibrin. Thus, suppression of C1INH by SARS-CoV-2 infection leads to thrombosis and excessive inflammation due to uncontrolled activation of complements and contact systems.

COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic

BackgroundKidney transplant recipients have an increased risk of complications from COVID-19. However, data on the risk of allograft damage or death in kidney transplant recipients recovering from COVID-19 is limited. In addition, the first and second waves of the pandemic occurred at different times all over the world. In Turkey, the Health Minister confirmed the first case in March 2020; after that, the first wave occurred between March and August 2020; afterward, the second wave began in September 2020. This study aims to demonstrate the clinical presentations of kidney transplant recipients in the first two waves of the pandemic in Turkey and explore the impact of COVID-19 on clinical outcomes after the initial episode.MethodsPatients with COVID-19 from seven centers were included in this retrospective cohort study. Initially, four hundred and eighty-eight kidney transplant recipients diagnosed with COVID-19 between 1 March 2020 to 28 February 2021 were enrolled. The endpoints were the occurrence of all-cause mortality, acute kidney injury, cytokine storm, and acute respiratory distress syndrome. In addition, longer-term outcomes such as mortality, need for dialysis, and allograft function of the surviving patients was analyzed.ResultsFour hundred seventy-five patients were followed up for a median of 132 days after COVID-19. Forty-seven patients (9.9%) died after a median length of hospitalization of 15 days. Although the mortality rate (10.1% vs. 9.8%) and intensive care unit admission (14.5% vs. 14.5%) were similar in the first two waves, hospitalization (68.8% vs. 29.7%; p < 0.001), acute kidney injury (44.2% vs. 31.8%; p = 0.009), acute respiratory distress syndrome (18.8% vs. 16%; p = 0.456), and cytokine storm rate (15.9% vs. 10.1%; p = 0.072) were higher in first wave compared to the second wave. These 47 patients died within the first month of COVID-19. Six (1.4%) of the surviving patients lost allografts during treatment. There was no difference in the median serum creatinine clearance of the surviving patients at baseline (52 mL/min [IQR, 47–66]), first- (56 mL/min [IQR, 51–68]), third- (51 mL/min [IQR,48–67]) and sixth-months (52 mL/min [IQR, 48–81]). Development of cytokine storm and posttransplant diabetes mellitus were independent predictors for mortality.ConclusionsMortality remains a problem in COVID-19. All the deaths occur in the first month of COVID-19. Also, acute kidney injury is common in hospitalized patients, and some of the patients suffer from graft loss after the initial episode.

A raising dawn of pentoxifylline in management of inflammatory disorders in Covid-19.

The existing pandemic viral infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) leads to coronavirus disease 2019 (Covid-19). SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as an entry-point into affected cells and down-regulation of ACE2 by this virus triggers the release of pro-inflammatory cytokines and up-regulation of angiotensin II. These changes may lead to hypercytokinemia and the development of cytokine storm with the development of acute lung injury and acute respiratory distress syndrome. Different repurposed had been in use in the management of Covid-19, one of these agents is pentoxifylline (PTX) which has anti-inflammatory and antioxidant properties. Therefore, the objective of the present mini-review is to highlight the potential role of PTX in Covid-19 regarding its anti-inflammatory and antioxidant effects. PTX is a non-selective phosphodiesterase inhibitor that increases intracellular cyclic adenosine monophosphate which stimulates protein kinase A and inhibits leukotriene and tumor necrosis factor. PTX has antiviral, anti-inflammatory and immunomodulatory effects, thus it may attenuate SARS-CoV-2-induced hyperinflammation and related complications. As well, PTX can reduce hyper-viscosity and coagulopathy in Covid-19 through increasing red blood cell deformability and inhibition of platelet aggregations. In conclusion, PTX is a non-selective phosphodiesterase drug, that has anti-inflammatory and antioxidant effects thereby can reduce SARS-CoV-2 infection-hyperinflammation and oxidative stress. Besides, PTX improves red blood cells (RBCs) deformability and reduces blood viscosity so can mitigate Covid-19-induced hyper-viscosity and RBCs hyper-aggregation which is linked with the development of coagulopathy. Taken together, PTX seems to be an effective agent against Covid-19 severity.

High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons.

High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.

Obesity and COVID-19: Mechanistic Insights From Adipose Tissue.

Obesity is associated with an increase in morbidity and mortality from COVID-19. The risk is related to the cytokine storm, a major contributor to multiorgan failure and a pathological character of COVID-19 patients with obesity. While the exact cause of the cytokine storm remains elusive, disorders in energy metabolism has provided insights into the mechanism. Emerging data suggest that adipose tissue in obesity contributes to the disorders in several ways. First, adipose tissue restricts the pulmonary function by generation of mechanical pressures to promote systemic hypoxia. Second, adipose tissue supplies a base for SARS-CoV-2 entry by overexpression of viral receptors (ACE2 and DPP4). Third, impaired antiviral responses of adipocytes and immune cells result in dysfunction of immunologic surveillance as well as the viral clearance systems. Fourth, chronic inflammation in obesity contributes to the cytokine storm by secreting more pro-inflammatory cytokines. Fifth, abnormal levels of adipokines increase the risk of a hyper-immune response to the virus in the lungs and other organs to enhance the cytokine storm. Mitochondrial dysfunction in adipocytes, immune cells and other cell types (endothelial cells and platelets, etc.) is a common cellular mechanism for the development of cytokine storm, which leads to the progression of mild COVID-19 to severe cases with multiorgan failure and high mortality. Correction of energy surplus through various approaches is recommended in the prevention and treatment of COVID-19 in the obese patients.

Cytokine Profiling in COVID-19 Patients in a Tertiary Hospital in Saudi Arabia; the Pre-Storm Phase

Background As COVID-19 immunomodulation has been a part of interest for studies, it has been found that severe coronavirus disease 2019 (COVID-19) is associated with hyper-inflammatory response and increased levels of interleukin-6 (IL-6) and interleukin-10 (IL-10). This can progress to cytokine storm syndrome and eventually development of acute respiratory distress syndrome (ARDS). Interleukin-1 receptor antagonist (IL-1RA) is a protein that is a member of the interleukin 1 cytokine family. Monocyte chemoattractant protein 1 (MCP1) is a small cytokine that belongs to the CC chemokine family. Interferon gamma-induced protein 10 (IP-10) is a protein secreted by several cell types in response to Interferon-Gamma (IFN-γ). All of these have roles in the immune response and eventually development of a cytokine storm. Methods Serum levels of IL-1RA, MCP-1 and IP-10 were measured in a cohort of 21 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 4 uninfected controls. The study population was classified into severe, moderate, mild and controls. Results Serum levels of IL-1RA, MCP-1 and IP-10 were found to be elevated before the clinical deterioration. Conclusion These cytokines may play a role in early detection of disease severity especially in the pre-storm phase. Medications that target cytokines may prevent the development of an overt cytokine storm.