COVID-19 Cytokine Storm Research Articles

Labor Could Increase Systemic Inflammation and Cause or Deteriorate Cytokine Storm in COVID-19.

Pregnant women with coronavirus disease 2019 (COVID-19) have a higher risk of morbidity and mortality compared with the general population. Possible pathways are: I) in patients with COVID-19, cytokine storm defined as the excess release of pro-inflammatory cytokines such as interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) has been associated with morbidities and an even higher rate of mortality. II) Labor, despite being a term/preterm, has an inflammatory nature, although, inflammation is more prominent in preterm delivery. During labor, different pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved which as mentioned, all are crucial role players in the cytokine storm. III) Tissue injury, and during labor, (especially cesarean section) is shown to cause inflammation via pro-inflammatory cytokines release including those involved in the cytokine storm through the activation of nuclear factor κB (NFκB). IV) post-partum hemorrhage with a notable amount of blood loss which can cause significant hypoxemia. In this condition, hypoxia-inducible factor 1α which has a cross-talk with NFκB, leads to the expression of IL-1β, IL-6, and TNF-α as both angiogenic and pro-inflammatory factors. Considering all the mentioned issues and pathways, we suggest that clinicians be careful about the escalation of the inflammatory status in their pregnant COVID-19 patients during/following labor.

502P Association of immunotherapy and immunosuppression with severe COVID-19 disease in patients with cancer

Cytokine storm due to COVID-19 can cause high morbidity and mortality. Patients with cancer treated with immunotherapy (IO) and those with immunosuppression may have higher rates of cytokine storm due to immune dysregulation. We sought to evaluate the association of IO and immunosuppression with COVID-19 outcomes and cytokine storm occurrence among patients with cancer and COVID-19, based on data from the COVID-19 and Cancer Consortium (CCC19).

Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice.

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC50 0.79 μM) while also showing a reduction of >3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1β caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

IL-6 drives T cell death to participate in lymphopenia in COVID-19

Lymphopenia is a common observation in patients with COVID-19. To explore the cause of T cell lymphopenia in the disease, laboratory results of 64 hospitalized COVID-19 patients were retrospectively analyzed and six patients were randomly selected to trace their changes of T lymphocytes and plasma concentration of IL-6 for the course of disease. Results confirmed that the T-cell lymphopenia, especially CD4+ T cell reduction in COVID-19 patients, was a reliable indicator of severity and hospitalization in infected patients. And CD4+ T cell count below 200 cells/μL predicts critical illness in COVID-19 patients. In vitro assay supported that exposure to key contributors (IL-1β, IL-6, TNF-α and IFN-γ) of COVID-19 cytokine storm caused substantial death of activated T cells. Among these contributors, IL-6 level was found to probably reversely correlate with T cell counts in patients. And IL-6 alone was potent to induce T cell reduction by gasderminE-mediated pyroptosis, inferring IL-6 took a part in affecting the function and status of T cells in COVID-19 patients. Intervention of IL-6 mediated T cell pryprotosis may effectively delay disease progression, maintain normal immune status at an early stage of infection.

Effectivity of Dexamethasone Fighting Cytokine Storm in Severe COVID-19 Patients; Does it still reliable used for COVID-19?

Covid-19 has been declared a pandemic by WHO (World Health Organization) since March 2020. However, there is confusion about the therapy that should be used for covid-19. This virus enters the human body by binding to ACE-II receptors in the human body, causing an inflammatory response and a decrease in the body's immune response. The overproduction of pro-inflammatory cytokines relates to COVID-19's cytokine storm, also known as cytokine release syndrome (CRS). The aim of this article is to determine the effectiveness of dexamethasone in treating cytokine storms in severe COVID-19 patients using ventilator respiratory. This study used a narrative review journal from several leading platforms such as PubMed, NEJM, NCBI, and others, as well as from government websites, selected between 2019 and 2021 in the English language. Dexamethasone is a corticosteroid class of drugs that can act as anti-inflammatory and immunosuppressive. The drug inhibits the expression of genes that induce inflammatory proteins. In the case of severity covid-19, dexamethasone was used in patients who had decreased oxygen saturation. After being treated using this drug intravenously, the patient showed a positive increase in oxygen saturation levels. Dexamethasone therapy was effective and may have been acceptable in severe Covid-19 patients that actively ventilator respiratory. Then, a more rigorous investigation of the impact of dexamethasone is needed.

Comprehensive Cytokine Profiling of Patients with COVID-19 Receiving Tocilizumab Therapy.

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3–5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.

JAK Inhibitors as a Barrier to the Destructive Cytokine Storm in COVID-19

JAK Inhibitors as a Barrier to the Destructive Cytokine Storm in COVID-19

Human cardiac organoids to model COVID-19 cytokine storm induced cardiac injuries.

Acute cardiac injuries occur in 20%–25% of hospitalized COVID‐19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID‐19 hyperinflammation. As IL‐1β is an upstream cytokine and a core COVID‐19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID‐19 cytokine storm. The IL‐1β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID‐19 hearts. The comparison of IL‐1β treated hCOs with cardiac tissue from COVID‐19 autopsies illustrated the critical roles of hyper‐inflammation in COVID‐19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL‐1β treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID‐19 cardiac injuries at baseline and simulated exercise conditions.

Safe use of ibuprofen in COVID-19 in children

The literature review presents current data on the use of ibuprofen in COVID-19. Features of оmicron-variant of the disease are presented, which, unlike previous outbreaks, has a very high level of transmission, shorter average incubation period, increased incidence among children. Because most children have mild to moderate COVID-19, nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are the most commonly used drugs in childhood to relieve pain and fever. During the first outbreak of COVID-19, NSAID and ibuprofen have been suggested to be dangerous for use in COVID-19 because they may increase the risk of severe and fatal COVID-19 disease. Experimental and clinical data on the safe use of ibuprofen in COVID-19 are presented. To date, there is no increased risk of COVID-19 infection with ibuprofen. In addition, there was no increased risk of hospitalization or severe COVID-19, death of patients taking ibuprofen. A lower risk of death has been found in patients with COVID-19 who received NSAIDs, consistent with a reduction in inflammation and a cytokine storm in severe COVID-19 and a protective role for NSAIDs. According to the Protocol ”Provision of medical care for the treatment of coronary heart disease (COVID-19)“ in mild to moderate disease in children, symptomatic treatment of fever and pain with ibuprofen is indicated. Thus, according to WHO guidelines and available clinical data, ibuprofen can be safely used for analgesic and antipyretic effects in children with COVID-19.

Therapeutic Potential of P2X7 Purinergic Receptor Modulation in the Main Organs Affected by the COVID-19 Cytokine Storm.

Defined by the World Health Organization as a global public health pandemic, coronavirus 2019 (COVID-19) has a global impact and has caused the death of thousands of people. The "severe acute respiratory syndrome coronavirus 2" virus (SARS-CoV-2) is the etiologic agent of this disease, which uses the angiotensinconverting enzyme receptor 2 (ACE2) to infect the body, so any organ that expresses the gene ACE2 is a possible target for the new coronavirus. In addition, in severe cases of COVID-19, a cytokine storm occurs, which triggers widespread systemic inflammation due to the uncontrolled release of proinflammatory cytokines. In this perspective, the modulation of purinergic receptors is highlighted in the literature as a possible therapy, considering its application in other viral infections and systemic inflammation. Therefore, this review aims to gather information on the modulation of the P2X7 receptor in the main organs directly affected by the virus and by the cytokine storm: the heart, brain, lung, liver and kidneys. Thus, demonstrating possible therapies for reducing inflammation and the level of morbidity and mortality of COVID-19. In severe cases of COVID-19, SARS-CoV-2 infection is capable of triggering an exacerbated release of cytokines, called a cytokine storm. With this inflammation, or less the direct infection of the virus, the whole organism can be affected. In this way, major and important organs such as the heart, lung, brain, and liver are affected, triggering different pathologies. In this perspective, purinergic signaling is highlighted in the literature for its anti-inflammatory role and has been listed in the pandemic scenario as a potential therapy. Therefore, knowing the expression of the purinergic receptor P2X7 in these tissues, the modulation of its inflammatory activity may be favorable in this severe and systemic condition.

Immunopathogenesis and Immunogenetic Variants in COVID-19.

Coronavirus disease 2019 (COVID-19) continues to spread globally despite the discovery of vaccines. Many people die due to COVID-19 as a result of catastrophic consequences, such as acute respiratory distress syndrome, pulmonary embolism, and disseminated intravascular coagulation caused by a cytokine storm. Immunopathology and immunogenetic research may assist in diagnosing, predicting, and treating severe COVID-19 and the cytokine storm associated with COVID-19. This paper reviews the immunopathogenesis and immunogenetic variants that play a role in COVID-19. Although various immune-related genetic variants have been investigated in relation to severe COVID-19, the NOD-like receptor protein 3 (NLRP3) and interleukin 18 (IL-18) have not been assessed for their potential significance in the clinical outcome. Here, we a) summarize the current understanding of the immunogenetic etiology and pathophysiology of COVID-19 and the associated cytokine storm; and b) construct and analyze protein-protein interaction (PPI) networks (using enrichment and annotation analysis) based on the NLRP3 and IL18 variants and all genes, which were established in severe COVID-19. Our PPI network and enrichment analyses predict a) useful drug targets to prevent the onset of severe COVID-19, including key antiviral pathways such as Toll-Like-Receptor cascades, NOD-like receptor signaling, RIG-induction of interferon (IFN) α/β, and interleukin (IL)-1, IL-6, IL-12, IL-18, and tumor necrosis factor signaling; and b) SARS-CoV-2 innate immune evasion and the participation of MYD88 and MAVS in the pathophysiology of severe COVID-19. The PPI network genetic variants may be used to predict more severe COVID-19 outcomes, thereby opening the door for targeted preventive treatments.

Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative?

The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the options proposed for emergency treatment. One of the cytokines that requires a more exhaustive review is the tumor necrosis factor (TNF) and its receptors (TNFRs) as increased values of soluble formats for both TNFR1 and TNFR2 have been identified. TNF is a versatile cytokine with different impacts at the cellular level depending on the action form (transmembrane or soluble) and the receptor to which it is associated. In that sense, the triggered mechanisms can be diversified. Furthermore, there is the possibility of the joint action provided by synergism between one or more cytokines with TNF, where the detonation of combined cellular processes has been suggested. This review aims to discuss some roles of TNF and its receptors in the pro-inflammatory stage of COVID-19, understand its ways of action, and let to reposition this cytokine or some of its receptors as therapeutic targets.

Glycyrrhetinic acid: A potential drug for the treatment of COVID-19 cytokine storm

BackgroundThe cytokine storm (CS) triggered by coronavirus disease 2019 (COVID-19) has caused serious harm to health of humanity and huge economic burden to the world, and there is a lack of effective methods to treat this complication. PurposeIn this research, we used network pharmacology and molecular docking to reveal the interaction mechanism in the glycyrrhetinic acid (GA) for the treatment of CS, and validated the effect of GA intervention CS by experiments. Study designFirst, we screened corresponding target of GA and CS from online databases, and obtained the action target genes through the Venn diagram. Then, protein-protein interaction (PPI) network, Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of the action target genes were acquired by R language to predict its mechanism. Next, molecular docking was performed on core targets. Finally, experiments in which GA intervened in lipopolysaccharide (LPS)-induced CS were implemented. Results84 action target genes were obtained from online database. The PPI network of target genes showed that TNF, IL6, MAPK3, PTGS2, ESR1 and PPARG were considered as the core genes. The results of GO and KEGG showed that action target genes were closely related to inflammatory and immune related signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, Human cytomegalovirus infection, PPAR signaling pathway and so on. Molecule docking results prompted that GA had fine affinity with IL6 and TNF proteins. Finally, in vivo and in vitro experimental results showed that GA could significantly inhibit LPS-induced CS. ConclusionGA has a potential inhibitory effect on CS, which is worthy of further exploration.

Sarilumab Administration in COVID-19 Patients: Literature Review and Considerations.

Two years have passed since WHO declared a pandemic state for SARS-CoV-2 infection. COVID-19 pathogenesis consists of a first viral phase responsible for early symptoms followed by an inflammatory phase, cytokine-mediated, responsible for late-onset manifestations up to ARDS. The dysregulated immune response has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through the induction of pro-inflammatory chemokines and cytokines, plays a key role in the development and maintenance of inflammation, acting as a pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, drugs targeting both IL-6 and IL-6 receptors have been evaluated in order to blunt the abnormal SARS-CoV-2-induced cytokine release. Sarilumab, a high-affinity anti-IL-6 receptor antibody, may represent a promising weapon to treat the fearsome hyperinflammatory phase by improving the outcome of patients with moderate-to-severe COVID-19 pneumonia. Further prospective and well-designed clinical studies with larger sample sizes and long-term follow-up are needed to assess the efficacy and the safety of this therapeutic approach to achieve improved outcomes in COVID-19.

Gene expression pattern in severely progressing covid-19 patients is related to diabetes mellitus type 1: A functional annotation analysis

AimsThe aim of this study was to extract the signaling mediators or biological pathways that link covid-19 to other diseases such as type 1 diabetes mellitus (T1DM). MethodsMicroarray data of covid-19 (GSE164805) was extracted from Gene Expression Omnibus (GEO) and analyses were performed by R package and GEO2R. Functional enrichment analysis was done to extract enriched molecular pathways (MP), biological process (BP) and molecular function (MF). Then commonly up- and down-regulated genes in covid-19 and T1DM were extracted by comparing deferentially expressed genes (DEGs) of GSE164805 and GSE9006. ResultsDown-regulated DEGs in the severely progressing covid-19 patients (SPCP) had a link to T1DM. Major histocompatibility system (MHC) class II, gamma interferon (IFNγ), and IL-1B were enriched in extracted pathway that leads to T1DM. In addition, comparing extracted DEGs from GSE164805 and GSE9006 indicated that MTUS1, EGR1 and EGR3 are the genes that are up-regulated in both SPCP and T1DM. ConclusionThe findings of this study indicate that coincidence of SARS-COV-2 infection and T1DM may increase the severity of both diseases. Although covid-19 reduced the T cell mediated immune response, but increased mediators of T-cell signaling pathway such as IL-1 in both diseases. This could potentiate the inflammation response and worsens the severity of covid-19 cytokine storm or increase the resistance to insulin.

COVID-19 Cytokine Storm in Myasthenia Gravis Treated with Mesenchymal Stem Cells: A Case Report (P4-1.002)

COVID-19 Cytokine Storm in Myasthenia Gravis Treated with Mesenchymal Stem Cells: A Case Report (P4-1.002)

IgG targeting distinct seasonal coronavirus- conserved SARS-CoV-2 spike subdomains correlates with differential COVID-19 disease outcomes.

Despite SARS-CoV-2 being a “novel” virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (β-CoVs), and FcγR activation. Analysis of IgG targeting β-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2′FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2′FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2′FP ratios. These findings suggest that HR2/S2′FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.

Bead-based Multiplex Assay Panels for Quantifying COVID-19 Vaccine-induced Serological Response, Neutralizing Antibodies and Cytokines

Abstract The COVID-19 pandemic, caused by SARS-CoV-2 virus infection, has resulted in more than 5 million deaths and triggered severe social and economic disruptions worldwide. The emergence of multiple variants of the virus (Alpha, Beta, Gamma, Delta, and Omicron) has further made the pandemic to be one of the most dangerous in history. In order to enable biomedical researchers to understand the disease and develop advanced vaccines and treatments, BioLegend has developed a series of bead-based multiplex panels including SARS-CoV-2 serological IgA, IgM and IgG Panel, Variants Neutralization Antibody, and COVID-19 Cytokine Storm Panels. These panels can quantify simultaneously either various isotype of antibodies, functional antibodies or cytokines in one sample using commonly available flow cytometers. Highly specific antibodies were used in order to ensure assay specificities and robust performance. In addition, these multiplex assay panels are validated in biological samples (serum and plasma) obtained from donors before and after vaccination. Our preliminary data indicate that three types of vaccines induced different antibody responses and cytokine profiles. The experimental data demonstrated that these panels can be reliable, convenient and cost-effective tools for vaccine developers and COVID-19 research.

Selinexor and COVID-19: The Neglected Warden.

A novel severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed as the cause of the global pandemic coronavirus disease 2019 (COVID-19). Different repurposed drugs have been trialed and used in the management of COVID-19. One of these agents was the anti-cancer Selinexor (SXR). SXR is an anti-cancer drug that acts by inhibition of nuclear exportin-1 (XPO1), which inhibits transport of nuclear proteins from the nucleus to the cytoplasm, leading to the induction of cell-cycle arrest and apoptosis. XPO1 inhibitors had antiviral effects, mainly against respiratory syncytial virus (RSV) and influenza virus. SXR inhibits transport of SARS-CoV-2 nuclear proteins to the cytoplasm with further inhibition of SARS-CoV-2 proliferation. SXR has the ability to prevent the development of a cytokine storm in COVID-19 by inhibiting the release of pro-inflammatory cytokines with the augmentation release of anti-inflammatory cytokines. In conclusion, SARS-CoV-2 infection is linked with activation of XPO1, leading to the triggering of inflammatory reactions and oxidative stress. Inhibition of XPO1 by Selinexor (SXR), a selective inhibitor of nuclear export (SINE), can reduce the proliferation of SARS-CoV-2 and associated inflammatory disorders. Preclinical and clinical studies are warranted in this regard.

The Cytokine Storm in COVID-19: The Strongest Link to Morbidity and Mortality in the Current Epidemic

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. The clinical presentations of the SARS-CoV-2 infection are widely variable and treatment strategies for COVID-19 are dependent on the infection phase. Timing the right treatment for the right phase of this disease is paramount, with correlations detected between the phase of the infection and the type of drug used to treat. The immune system activation following COVID-19 infection can further develop to a fulminant cytokine storm which can progress to acute respiratory distress syndrome. The inflammatory phase, or the hyperinflammation phase, is a later stage when patients develop acute respiratory distress syndrome (ARDS), sepsis, and kidney and other organ failure. In this stage, the virus is probably not necessary and all the damage is due to the immune system’s cytokine storm. Immunosuppressive or immunomodulatory agent administration is the major strategy in treating COVID-19 patients at this stage. On the other hand, immunodeficient patients who are treated with immunomodulator agents have attenuated immune systems that do not produce enough cytokines. Current data do not show an increased risk of severe COVID-19 in patients taking biologic therapies or targeted disease-modifying antirheumatic drugs. However, more comprehensive studies are needed to assess the effect of these medications, and whether they may actually be protective of the severe type of disease. Although medications for COVID-19 and for the cytokine storm are important, the main breakthrough in slowing down the pandemic was developing effective vaccines. These vaccines showed a dramatic result in reducing morbidity and mortality up to the Delta variant’s spread. However, the emergence of the new variant, Omicron, influenced the successful results we had before. This variant is more contagious but less dangerous than Delta. The aim now is to develop vaccines based on the Omicron and Delta immunogens in the future for broad protection against different variants.