Cytokine Storm Research Articles

S100A9: The Unusual Suspect Connecting Viral Infection and Inflammation.

The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.

Striking the Balance with a PD-L1×4-1BB Bispecific Antibody.

Antibody-based immune checkpoint blockade therapy has revolutionized the field of cancer immunotherapy, yet its efficacy remains limited in immunologically cold tumors. Combining checkpoint inhibitors with costimulatory agonists improves tumoricidal activity of T cells but also can lead to off-target hepatotoxicity. Although bispecific antibodies confer tumor selectivity to alleviate undesirable adverse effects, toxicity concerns persist with increased dosing. In this issue of Cancer Research, Yuwen and colleagues introduce ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody with high programmed death ligand 1 (PD-L1) affinity and low 4-1BB affinity, aiming to mitigate hepatotoxicity. ATG-101 demonstrates PD-L1-dependent 4-1BB activation, leading to selective T-cell activation within the tumor microenvironment. ATG-101 exhibits potent antitumor activity, even in large, immunologically cold, and monotherapy-resistant tumor models. Single-cell RNA sequencing reveals significant shifts of immune cell populations in the tumor microenvironment from protumor to antitumor phenotypes following ATG-101 treatment. In cynomolgus monkeys, no serious cytokine storm and hepatotoxicity are observed after ATG-101 treatment, indicating a broad therapeutic window for ATG-101 in cancer treatment. This study highlights the potential of tetravalent bispecific antibodies in cancer immunotherapy, with implications for various antibody-based treatment modalities across different fields. See related article by Yuwen et al., p. 1680.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

Cerebral Malformations Related to Coronavirus Disease 2019 during Pregnancy

AbstractThe pandemic of severe-acute-respiratory-syndrome-related coronavirus (SARS-Cov-2) has shown a wide spectrum of possible consequences in children, ranging from asymptomatic patients to the development of severe conditions, such as multisystem inflammatory syndrome in children and encephalopathies related to cytokine storm. Specifically, neurological and neuroimaging abnormalities, ranging from mild-to-the severe ones, have been documented in children as well, such as postinfectious immune-mediated acute disseminated encephalomyelitis, myelitis, neural enhancement, cranial nerve enhancement, and cortical injury, also without neurological symptoms. Considering the neurotropism of coronaviruses and SARS-Cov-2, which has been well described in the literature, we reviewed the literature reporting possible cerebral malformation in neonates due to the infection of SARS-Cov-2 in pregnancy. Coronavirus disease 2019 (COVID-19) during pregnancy might develop cerebral disorders in several ways. Articles in English in the literature were screened using the following search terms: (1) “brain malformations” AND “COVID-19”; (2) “cerebral malformations” AND “COVID-19”; (3) brain malformations AND “Sars-Cov-2”; (4) “cerebral malformations “AND “Sars-Cov-2.” Considering the congenital brain malformation found in newborns exposed to infection of SARS-Cov-2 pre- or neonatally, we identified one paper which reported three neonates with cerebral malformation. Although sporadic, cerebral malformations like atypical signals in white matter with delayed myelination, brain dysplasia/hypoplasia with delayed myelination, and unusual signals in the periventricular regions have been documented.

Гідроген сульфід: біологічні та патохімічні ефекти

Hydrogen sulfide (H2S) belongs to the family of «gasotransmitters» can by synthesized by enzymatic systems and also formed non-enzymatically. At physiological concentrations, it regulates a range of biological functions in various organs and tissues. H2 S is involved in biochemical changes that play an important role in the pathogenesis of diseases such as cancer, COVID-19, diabetes mellitus, and neurodegenerative pathologies. In carcinogenesis, H2S influences cancer cell proliferation, inhibits cancer cell apoptosis, regulates the cell cycle, intracellular signaling pathways, stimulates angiogenesis, and autophagy of cancer cells. In lung inflammation caused by COVID-19, H2S disrupts disulfide bonds in mucus, reducing its viscosity, blocks NF-κB pathway activation, preventing the onset of a «cytokine storm», promotes Nrf2 activation, increasing the expression of antioxidant molecules and enzymes, activates potassium channels, and blocks Na+/K+-ATPase, promoting electrolyte absorption. In the pancreas, H 2 S regulates insulin secretion and plays a significant role in insulin sensitivity regulation in insulin-responsive tissues. It inhibits glucose uptake and glycogen accumulation, which is crucial in diabetes mellitus. In adipose tissue, H 2 S promotes adipogenesis, inhibits lipolysis, and regulates the secretion of adiponectin and MCP-1 in type 2 diabetes. In neural tissue, H2S acts as a neuromodulator, increases GABA expression, induces Ca2+ concentration increase, participates in long-term potentiation, neurotransmitter modulation, affects NADPH levels, and exerts epigenetic effects. Understanding the role of H2 S may be crucial in developing effective therapy strategies for various diseases.

Helminth alleviates COVID-19-related cytokine storm in an IL-9-dependent way.

Hyperactivation of pro-inflammatory type 1 cytokines (e.g., tumor necrosis factor alpha [TNF-α] and interferon gamma [IFN-γ]) mirrors the inflammation of coronavirus disease 2019. Helminths could alleviate excessive immune responses. Here, helminth Trichinella spiralis (Ts) infection was shown to protect against TNF-α- and IFN-γ-induced shock. Mechanistically, Ts-induced protection was interleukin-9 (IL-9) dependent but not IL-4Rα. Recombinant IL-9 treatment not only improved the survival of wild-type mice with TNF-α- and IFN-γ-induced shock but also that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected K18-human angiotensin-converting enzyme 2 (hACE2) mice, emphasizing the significance of IL-9 in alleviating cytokine storm syndromes during SARS-CoV-2 infection. Interestingly, Ts excretory/secretory (TsES)-induced protection was also observed in SARS-CoV-2 infection, indicating that identifying anti-inflammatory molecules from TsES could be a novel way to mitigate adverse pathological inflammation during pathogen infection.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is linked to cytokine storm triggered by type 1 pro-inflammatory immune responses. TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19. Helminths (e.g., Trichinella spiralis, Ts) can potently activate anti-inflammatory type 2 immune response. Here, we found that helminth Ts-induced protection against TNF-α and IFN-γ shock was IL-9 dependent. Treatment with recombinant IL-9 could protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in K18-hACE2 mice. Helminth Ts excretory/secretory (TsES) products also ameliorated SARS-CoV-2 infection-related cytokine storm. In conclusion, our study emphasizes the significance of IL-9 in protecting from cytokine storm syndromes associated with SARS-CoV-2 infection. Anti-inflammatory molecules from TsES could be a new source to mitigate adverse pathological inflammation associated with infections, including COVID-19.

Severe fever with thrombocytopenia syndrome with central nervous system symptom onset: a case report and literature review

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is SFTS virus (SFTSV). SFTS can rapidly progress to severe disease, with multiple-organ failure (MOF) manifestations such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, but cases of SFTS patients with central nervous system (CNS) symptoms onset and marked persistent involuntary shaking of the perioral area and limbs have rarely been reported.Case presentationA 69-year-old woman with fever and persistent involuntary shaking of the perioral area and limbs was diagnosed with SFTS with CNS symptom onset after metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and peripheral blood identified SFTSV. The patient developed a cytokine storm and MOF during the course of the disease, and after aggressive antiviral, glucocorticoid, and gamma globulin treatments, her clinical symptoms improved, her laboratory indices returned to normal, and she had a good prognosis.ConclusionThis case gives us great insight that when patients with CNS symptoms similar to those of viral encephalitis combined with thrombocytopenia and leukopenia are encountered in the clinic, it is necessary to consider the possibility of SFTS involving the CNS. Testing for SFTSV nucleic acid in CSF and blood (mNGS or polymerase chain reaction (PCR)) should be carried out, especially in critically ill patients, and treatment should be given accordingly.

Tocilizumab in the treatment of hyperferritinemic syndrome and capillary leak syndrome secondary to rheumatoid arthritis: Case report and literature review.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is mainly characterized by joint swelling, pressure pain and joint destruction. Some patients may suffer from a variety of serious complications, which require prompt diagnosis and treatment. Otherwise, the patient condition may deteriorate rapidly, leading to premature death. We reported a case of RA combined with hyperferritinemic syndrome and capillary leak syndrome (CLS) that was successfully treated with tocilizumab (TCZ), with the aim of improving diagnostic ideas for clinicians and consequently improving the diagnosis and treatment of the hyperferritinemic syndrome and CLS. A 55-year-old female patient was admitted to the Department of Infectious Diseases of our hospital due to "recurrent fever for more than 1 month and aggravation for 3 days." The patient was diagnosed with fever of unknown origin (lung infection?) and received anti-infective therapy with large encirclement of anti-bacterial, antifungal and empirical anti-tuberculosis successively during hospitalization in the Department of Infectious Diseases. Yet her condition continues to progress. The patient was eventually diagnosed with RA combined with hyperferritinemic syndrome and CLS. Then she received glucocorticoids (GC) (160 mg qd) combined with intravenous immunoglobulin (IVIG, 20 g/d, for 3 days). We considered that the patient also had an overwhelming proinflammatory cytokine storm, so she received a strong anti-inflammatory treatment with TCZ (400 mg qm). The patient symptoms and follow-up chest CT showed significant improvement following treatment. TCZ has good efficacy in the treatment of RA combined with hyperferritinemic syndrome and CLS and is expected to be a promising treatment.

How COVID-19 Can Damage the Heart? – Association of Cardiac Injury with COVID-19: A Narrative Review

Abstract Severe acute respiratory syndrome coronavirus 2 and its resulting disease, COVID-19, remain a significant public health concern. Cardiovascular injury is the second most common complication, following respiratory disease, encompassing conditions such as myocarditis, acute myocardial injury, acute coronary syndrome, arrhythmia, and heart failure. It presents with high-troponin levels, reduced left ventricular systolic function, and/or electrocardiographic abnormalities. Cardiac involvement is an independent risk factor for worse clinical outcomes and higher mortality, particularly in the elderly patients. The debate continues regarding whether the cardiac manifestations of COVID-19 result from direct viral infection or indirect cellular injuries. The virus attaches directly to angiotensin-converting enzyme 2 receptor, which is extensively expressed in the heart, invades myocardial tissue, and triggers an excessive inflammatory response. Indirect mechanisms stem from endothelial damage, hypercoagulability and micro-thrombosis, cytokine storm, respiratory failure and hypoxia, and autoimmunity. The pathophysiology of cardiac injury in COVID-19 patients is important to frame the main pathways and biomarkers to encourage new therapeutic trials to improve the disease prognosis and to understand the course of the disease.

Overview of acute liver failure in India.

Acute liver failure (ALF) is an infrequent, but serious complication subsequent to severe acute liver injury (sALI) due to various hepatotoxic agents such as hepatotropic virus(es) and drugs such as anti-tubercular medications, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and anti-cancer and anti-epileptic therapy and due to metabolic and autoimmune disease flares. ALF after sALI presents with encephalopathy associated with prolonged international normalized ratio (INR). Mortality in ALF is high and ranges between 50% and 80%. Due to severe liver damage, multiple sequels consequent to hepatic dysfunction result in complications such as hyperammonemia that culminates in encephalopathy associated with cerebral edema; innate immune paralysis resulting in increased frequency of infections and endotoxemia causing decrease in systemic vascular resistance (SVR) and tissue hypoperfusion and damage-associated molecular patterns (DAMPs) released from damaged hepatic parenchyma inducing pro-inflammatory cytokine storm, which may cause other organ dysfunctions. Certain etiologies such as hepatitis E virus and hepatitis A virus-related ALF or paracetamol-ALF (hyper-acute presentation) have better survival than remaining causes. In addition, if etiology-specific treatment (antivirals for ALF related to hepatitis B virus (HBV) or Herpes simplex virus (HSV) or N-acetylcysteine for paracetamol) is available, then the outcome with treatment is better. About half of the patients can be salvaged with medical therapy. All patients need intensive care and organ support to provide time for the liver to regenerate. Various prognostic models to predict high probability of mortality have been described, which should be used to select patient early during the disease for liver transplantation, which is associated with high long-term survival in these sick patients. The Indian National Association for Study of the Liver (INASL) recommends the ALF-Early Dynamic (ALFED) model as a preferred prognostic model in the Indian scenario, where hepatitis viruses are a dominant etiology of ALF and occur on a naïve liver with good regenerative capacity.

Markers of hemophagocytic lymphohistiocytosis are associated with survival in critically ill patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Cluster for Cardiovascular Research Background/Introduction Patients admitted to the intensive care unit (ICU) often show systemic immune dysregulation paired with significantly increased inflammatory activity. Haemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome characterized by fever, inflammation, cytopenia, and organ dysfunction. Inappropriate survival of cytotoxic T cells as well as histiocytes triggers cytokine storm, accompanied by the occurrence of hemophagocytosis and multi-organ failure. prevalence of HLH in critical illness continues to be a topic of discussion but most certainly remains underreported. This circumstance often leads to delays in the necessary immunosuppressive therapy due to difficulty in early diagnosis. Purpose In the present study, we aimed to illuminate the prospective value of the individual HLH criteria in a cohort of critically ill patients. Although the prevalence of this syndrome might be low, isolated markers of HLH could help to assess the extent of inflammatory activation and further be of use in predicting the outcome of patients admitted to the ICU. Methods This was a prospective, observational cohort study. 176 consecutive patients admitted to a cardiac ICU were included over the course of one year. Available HLH criteria were recorded except for biopsy samples of bone marrow and measurements of low or absent natural killer cell activity. For soluble CD25 (sCD25) a specific ELISA kit was used according to the manufacturer's instructions. Results The median age was 67.51 years (IQR: 57.50-77.41) and 38.64% of the included patients were female. The total 30-day mortality was calculated to be 25.57% and positivity for two or more criteria of HLH was found to be associated with depicted mortality (p = 0.033). Analyzing the individual parameters, only sCD25 was found to be a predictor of death within the first 30 days (p < 0.001). The combination of triglycerides and fibrinogen did not predict outcomes. However, low fibrinogen values were found to possess prognostic merit in regard to mortality (p= 0.019). In multivariate analysis, both sCD25 and fibrinogen remained a significant predictor of 30-day survival after adjustment for age, sex, and BMI (sCD25 p < 0.001, fibrinogen p = 0.042). Finally, the addition of fibrinogen was able to improve the prognostic value of the SAPS II score significantly (ROC curve, SAPS II – AUC: 0.790, SAPS II & fibrinogen – AUC: 0.827, p = 0.045). Conclusion We provided evidence for the prognostic value of certain markers of HLH in critically ill patients. Positivity for two or more criteria was found to be associated with an increased 30-day mortality. Moreover, sCD25 and fibrinogen independently predicted outcomes in multivariate analysis after adjustment for age, sex, and BMI. The addition of fibrinogen was able to improve the prognostic properties of the SAPS II score.Figure 1Figure 2

Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people

BackgroundAgeing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.ResultsOne hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity.ConclusionsOur results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

Updated COVID-19 Pharmacotherapy in Different Diseases Such as Cancer

Background: Studies suggest that cancer is a main complication regarding life expectancy and a foremost reason for death worldwide. For the treatment of COVID-19 infected 703,525,337 cases with 6,984,801 deaths worldwide up to February 21, 2024, well-designed pharmacotherapy management in different diseases, such as cancer, is respected. This investigation aims to review the current accessible medical treatment for patients with different diseases, cancer, and COVID-19. Methods: The appropriate documents for this review were achieved by searching databases such as Web of Science, Scopus, and PUBMED. Relevant studies included in review articles, clinical trials, and case reports that were evaluated and used (n=109 articles). Results: In those with cancer and COVID-19, publications reported worsened clinical conditions with a considerably higher risk of death. The result of existing regular antitumor management could be a basis of debate. In the general population, asymptomatic patients with positive nasopharyngeal swabs are recommended to receive antibiotic prophylaxis, and in those with symptomatic signs, adjustment of angiotensin-converting enzyme based on anti-hypertensive therapy should be considered. In patients with liver disease, nitazoxanide plus sofosbuvir, ivermectin, tocilizumab, convalescent plasma, and low molecular weight heparin in certain situations is recommended. Furthermore, favipiravir, chloroquine, and hydroxychloroquine could also be recommended, but with caution regarding to polypharmacy interactions. For those with moderate disease, hydroxychloroquine or chloroquine/ azithromycin was recommended. In the patients with respiratory failure, convalescent plasma was suggested. In the populations where those symptoms progress to the sign of a cytokine storm, the antagonists of interleukin-6 (IL-6) were suggested. To reduce fever, however, ibuprofen showed more potent efficacy compared to acetaminophen, but it may delay the benefits of a fever response. Conclusion: Owing to the immune suppression that could be caused by anti-cancer drugs and deterioration of lung functions due to COVID-19, for proposed management regarding pharmacotherapy strategies, further evidence-based studies seem to be advantageous.

A cross-linked macropore hydrogel based on M1 macrophage lysate and alginate regulates tumor-associated macrophages for the treatment of melanoma

Pro-inflammatory M1 macrophages possess the ability to change the immunosuppressive tumor microenvironment by releasing various inflammatory factors simultaneously, which can effectively inhibit tumor progression and relapse. Promoting macrophage polarization towards M1 may be an effective way to treat Melanoma. However, the risk of cytokine storm caused by the proliferation and excessive activation of M1 macrophages greatly limits it as a biosafety therapeutic strategy in anti-tumor immunotherapy. Therefore, how to engineer natural M1 macrophage to a biocompatible biomaterial that maintains the duration time of tumor suppressive property duration time still remains a huge challenge. To achieve this goal, we developed an injectable macroporous hydrogel (M1LMHA) using natural M1 macrophage lysates and alginate as raw materials. M1LMHA had excellent biocompatibility, adjustable degradation rate and could sustainably release varieties of natural inflammatory factors, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), etc. M1LMHA could repolarize anti-inflammatory M2 macrophages to M1 macrophages by the synergistic effect of released tiny inflammatory factors via the NF-κB pathway. This study supported that M1LMHA might be an effective and safe tool to activate tumor-associated immune cells, improving the efficiency of anti-tumor immunotherapy.

Endoscopic Changes of Tracheobronchial Tree Caused by Mucormycosis in Patients with a Novel Coronavirus Infection

The most severe manifestation of COVID-19 is bilateral pneumonia with development of acute respiratory distress syndrome accompanied by cytokine storm, pulmonary edema and death of the patient. In a number of patients, occurrence of mucormycosis of mucous membranes was one of the stages of the lethal outcome development. The arctile presents a clinical case of mucormycosis of the tracheobronchial tree detected by bronchoscopy several days before death in a patient with COVID-19 who was on mechanical ventilation. The endoscopic signs (endoscopic image) are described.

Frontiers and Hotspots Evolution in Cytokine Storm: A Bibliometric Analysis from 2004 to 2022

BackgroundAs a fatal disease, cytokine storm has garnered research attention in recent years. Nonetheless, as the body of related studies expands, a thorough and impartial evaluation of the current status of research on cytokine storms remains absent. Consequently, this study aimed to thoroughly explore the research landscape and evolution of cytokine storm utilizing bibliometric and knowledge graph approaches. MethodsResearch articles and reviews centered on cytokine storms were retrieved from the Web of Science Core Collection database. For bibliometric analysis, tools such as Excel 365, CiteSpace, VOSviewer, and the Bibliometrix R package were utilized. ResultsThis bibliometric analysis encompassed 6647 articles published between 2004 and 2022. The quantity of pertinent articles and citation frequency exhibited a yearly upward trend, with a sharp increase starting in 2020. Network analysis of collaborations reveals that the United States holds a dominant position in this area, boasting the largest publication count and leading institutions. Frontiers in Immunology ranks as the leading journal for the largest publication count in this area. Stephan A. Grupp, a prominent researcher in this area, has authored the largest publication count and has the second-highest citation frequency. Research trends and keyword evaluations show that the connection between cytokine storm and COVID-19, as well as cytokine storm treatment, are hot topics in research. Furthermore, research on cytokine storm and COVID-19 sits at the forefront in this area. ConclusionThis study employed bibliometric analysis to create a visual representation of cytokine storm research, revealing current trends and burgeoning topics in this area for the first time. It will provide valuable insights, helping scholars pinpoint critical research areas and potential collaborators.

Cytokine storm modulation using cholecalciferol and low dose gamma radiation in Escherichia coli infected mice.

This work investigates the efficiency of cholecalciferol and low dose gamma radiation in modulating cytokine storm through their impact on inflammatory and anti-inflammatory cytokine and protecting against lung and liver injuries. Male Swiss albino mice were exposed to 0.2 Gy gamma radiation/week for four consecutive weeks then injected intraperitoneally (i.p) with a single dose of 8.3 × 106 CFU Escherichia coli/g b.w. then injected i.p. with 1.0 mg/kg cholecalciferol (Vit D3) for 7 days starting 4 h after E. coli injection. The results revealed that Cholecalciferol and low dose gamma radiation caused significant depletion in the severity of E. coli infection (colony forming unit per milliliter), log10 of E. coli, Tumor necrosis factor alpha, Interleukin 6, VEGF, alanine aminotransferase, and aspartate aminotransferase levels and significant elevation in IL-10, IL-4, and HO-1. Immunohistochemical analysis of caspase-3 expression in lung tissue section showed low caspase-3 expression in cholecalciferol and low dose gamma radiation treated group. Histopathological examinations were performed in both lung and liver tissues which also emphasis the biochemical findings. Our results exhibit the importance of cholecalciferol and low dose gamma radiation in improving liver function and providing anti-inflammatory response in diseases causing cytokine storm.

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

A body-brain circuit that regulates body inflammatory responses.

The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

Laboratory indicators of inflammation in the development of cytokine storm in patients with COVID-19

Laboratory indicators of inflammation in the development of cytokine storm in patients with COVID-19