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.

Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

Nivolumab-Induced Cytokine Release Syndrome: A Case Report and Literature Review.

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

Endoplasmic reticulum-associated SARS-CoV-2 ORF3a elicits heightened cytopathic effects despite robust ER-associated degradation.

IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tragically claimed millions of lives through coronavirus disease 2019 (COVID-19), and there remains a critical gap in our understanding of the precise molecular mechanisms responsible for the associated fatality. One key viral factor of interest is the SARS-CoV-2 ORF3a protein, which has been identified as a potent inducer of host cellular proinflammatory responses capable of triggering the catastrophic cytokine storm, a primary contributor to COVID-19-related deaths. Moreover, ORF3a, much like the spike protein, exhibits a propensity for frequent mutations, with certain variants linked to the severity of COVID-19. Our previous research unveiled two distinct types of ORF3a mutant proteins, categorized by their subcellular localizations, setting the stage for a comparative investigation into the functional and mechanistic disparities between these two types of ORF3a variants. Given the clinical significance and functional implications of the natural ORF3a mutations, the findings of this study promise to provide invaluable insights into the potential roles undertaken by these mutant ORF3a proteins in the pathogenesis of COVID-19.

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Impaired cell-cell communication and axon guidance because of pulmonary hypoperfusion during postnatal alveolar development.

BACKGROUND: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. METHODS AND RESULTS: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell-cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. CONCLUSIONS: This study suggested that promoting cell-cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion-induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion.

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.

Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19.

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed. RESULTS: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg. CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.

AKR1B10, One of the Triggers of Cytokine Storm in SARS-CoV2 Severe Acute Respiratory Syndrome.

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.

Castleman disease and TAFRO syndrome.

Although Castleman disease was first described in 1956, this disease includes various conditions, including unicentric Castleman disease with hyaline vascular histology, human herpesvirus-8 (HHV-8) related multicentric Castleman disease, idiopathic multicentric Castleman disease, and mimics of Castleman disease associated with other conditions. To date, Castleman disease remains incompletely understood due to its rareness and difficulties in clinical and pathological diagnosis. TAFRO syndrome was reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease. Clinically, however, these conditions differ markedly. Although elevated interleukin-6 (IL-6) expression is characteristic of Castleman disease, increased expression of IL-6 may occur in patients with other diseases, making elevated IL-6 unsuitable for differential diagnosis. Further understanding of these disorders requires the identification of novel disease-specific biomarkers. This review article therefore outlines the characteristics of Castleman disease and TAFRO syndrome.

Lipopolysaccharide induces acute lung injury and alveolar haemorrhage in association with the cytokine storm, coagulopathy and AT1R/JAK/STAT augmentation in a rat model that mimics moderate and severe Covid-19 pathology.

Progress in the study of Covid-19 disease in rodents has been hampered by the lack of angiotensin-converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid-19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)-like effect was observed in the model group as demonstrated by the development of a "cytokine storm" (>2.7 fold increase in blood levels of IL-6, IL-17A, GM-CSF, and TNF-α), high blood ferritin, demonstrable coagulopathy, including elevated D-dimer (approximately 10-fold increase), PAI-1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)-JAK-STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid-19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT-mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid-19 disease noted in humans.

Cytokine storm in COVID-19: from viral infection to immune responses, diagnosis and therapy.

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.

Impact of cytokine storm on severity of COVID-19 disease in a private hospital in West Jakarta prior to vaccination.

BACKGROUND AND AIM: Coronavirus Disease 2019 (COVID-19) has become a worldwide pandemic and is a threat to global health. Patients who experienced cytokine storms tend to have a high mortality rate. However, to date, no study has investigated the impact of cytokine storms. MATERIALS AND METHODS: This retrospective cohort study included only COVID-19 positive patients hospitalized in a Private Hospital in West Jakarta between March and September 2020. All patients were not vaccinated during this period and treatment was based on the guidelines by the Ministry of Health Indonesia. A convenience sampling method was used and all patients who met the inclusion criteria were enrolled. RESULTS: The clinical outcome of COVID-19 patients following medical therapy was either cured (85.7%) or died (14.3%), with 14.3% patients reported to have cytokine storm, from which 23.1% led to fatalities. A plasma immunoglobulin (Gammaraas®) and/or tocilizumab (interleukin-6 receptor antagonist; Actemra®) injection was utilised to treat the cytokine storm while remdesivir and oseltamivir were administered to ameliorate COVID-19. Most (61.5%) patients who experienced the cytokine storm were male; mean age 60 years. Interestingly, all patients who experienced the cytokine storm had hypertension or/ and diabetes complication (100%). Fever, cough and shortness of breath were also the common symptoms (100.0%). Almost all (92.3%) patients with cytokine storm had to be treated in the intensive care unit (ICU). Most (76.9%) patients who had cytokine storm received hydroxychloroquine and all had antibiotics [1) azithromycin + levofloxacin or 2) meropenam for critically ill patients] and vitamins such as vitamins C and B-complex as well as mineral. Unfortunately, from this group, 23.1% patients died while the remaining 70% of patients recovered. A significant (p<0.05) correlation was established between cytokine storms and age, the presence of comorbidity, diabetes, hypertension, fever, shortness of breath, having oxygen saturation (SPO2) less than 93%, cold, fatigue, ward of admission, the severity of COVID-19 disease, duration of treatment as well as the use of remdesivir, Actemra® and Gammaraas®. Most patients recovered after receiving a combination treatment (oseltamivir + remdesivir + Antibiotics + Vitamin/Mineral) for approximately 11 days with a 90% survival rate. On the contrary, patients who received oseltamivir + hydroxychloroquine + Gammaraas® + antibiotics +Vitamin/Mineral, had a 83% survival rate after being admitted to the hospital for about ten days. CONCLUSION: Factors influencing the development of a cytokine storm include age, duration of treatment, comorbidity, symptoms, type of admission ward and severity of infection. Most patients (76.92%) with cytokine storm who received Gammaraas®/Actemra®, survived although they were in the severe and critical levels (87.17%). Overall, based on the treatment duration and survival rate, the most effective therapy was a combination of oseltamivir + favipiravir + hydroxychloroquine + antibiotics + vitamins/minerals.

Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury.

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.

Pericardial Cytokine "Storm" in a COVID-19 Patient: the Confirmation of a Hypothesis.

Novel Coronavirus Disease in most cases produces mild symptoms which resolve after a few days. Some authors hypothesized that SARS-CoV-2 infection could trigger excessive cytokine production leading to a severe multi-organ disease requiring intensive care admission. Respiratory and neurological symptoms are the most frequently reported manifestation of the disease. Indeed, cardiac involvement is reported mostly as a part of a systemic disease. Few isolated cardiac manifestations of COVID-19 infection have been described. We report herein a case of SARS-CoV-2 related severe isolated pericardial involvement requiring ICU admission due to cardiac tamponade needing urgent drainage. Analysis of pericardial fluid from drainage demonstrated a higher cytokine concentration than blood values. Other causes of pericardial disease, such as autoimmunity, bacterial or other than COVID-19 infection, neoplasms or acute myocardial infarction were also evaluated, but all tests confirmed negative results. The suspicion of isolated involvement of the pericardium was therefore demonstrated by the analysis of cytokines which strongly support our hypothesis.

Heterogeneous expression of ACE2 and TMPRRS2 in mesenchymal stromal cells.

The outbreak of COVID-19 has become a serious public health emergency. The virus targets cells by binding the ACE2 receptor. After infection, the virus triggers in some humans an immune storm containing the release of proinflammatory cytokines and chemokines followed by multiple organ failure. Several vaccines are enrolled, but an effective treatment is still missing. Mesenchymal stem cells (MSCs) have shown to secrete immunomodulatory factors that suppress this cytokine storm. Therefore, MSCs have been suggested as a potential treatment option for COVID-19. We report here that the ACE2 expression is minimal or nonexistent in MSC derived from three different human tissue sources (adipose tissue, umbilical cord Wharton`s jelly and bone marrow). In contrast, TMPRSS2 that is implicated in SARS-CoV-2 entry has been detected in all MSC samples. These results are of particular importance for future MSC-based cell therapies to treat severe cases after COVID-19 infection.

COVID-19 immunopathology with emphasis on Th17 response and cell-based immunomodulation therapy: Potential targets and challenges.

The role of the immune system against coronavirus disease 2019 (COVID-19) is unknown in many aspects, and the protective or pathologic mechanisms of the immune response are poorly understood. Pro-inflammatory cytokine release and a consequent cytokine storm can lead to acute respiratory distress syndrome (ARDS) and result in multi-organ failure. There are many T cell subsets during anti-viral immunity. The Th17-associated response, as a pro-inflammatory pathway, and its consequent outcomes in many autoimmune disorders play a fundamental role in progression of systemic hyper-inflammation during COVID-19. Therapeutic strategies based on immunomodulation therapy could be helpful for targeting hyper-inflammatory immune responses in COVID-19, especially Th17-related inflammation and hyper-cytokinemia. Cell-based immunotherapeutic approaches including mesenchymal stem cells (MSCs), tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs) seem to be promising strategies as orchestrators of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we highlight Th17-related immunopathology of SARS-CoV-2 infection and discuss cell-based immunomodulatory strategies and their mechanisms for regulation of the hyper-inflammation during COVID-19.

Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective.

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1ß levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.

Basic Predictive Risk Factors for Cytokine Storms in COVID-19 Patients.

Objective: A critical role in coronavirus disease 2019 (COVID-19) pathogenesis is played by immune dysregulation that leads to a generalized uncontrolled multisystem inflammatory response, caused by overproduction of proinflammatory cytokines, known as "a cytokine storm" (CS), strongly associated with a severe course of disease. The aim of this study is to identify prognostic biomarkers for CS development in COVID-19 patients and integrate them into a prognostic score for CS-associated risk applicable to routine clinical practice. Materials and Methods: The authors performed a review of 458 medical records from COVID-19 patients (241 men and 217 women aged 60.0 ± 10.0) who received treatment in the St. Petersburg State Budgetary Institution of Healthcare City Hospital 40 (City Hospital 40, St. Petersburg), from Apr. 18, 2020 to Nov. 21, 2020. The patients were split in two groups: one group included 100 patients with moderate disease symptoms; the other group included 358 patients with progressive moderately severe, severe, and extremely severe disease. The National Early Warning Score (NEWS) score was used alongside with clinical assessment, chest computed tomographic (CT) scans, electrocardiography (ECG), and lab tests, like ferritin, C-reactive protein (CRP), interleukin (IL)-6, lactate dehydrogenase (LDH), and D-dimer. Results: The basic risk factors for cytokine storms in COVID-19 patients are male gender, age over 40 years, positive test result for replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, absolute lymphocyte count, dynamics in the NEWS score, as well as LDH, D-dimer, ferritin, and IL-6 levels. These clinical and instrumental findings can be also used as laboratory biomarkers for diagnosis and dynamic monitoring of cytokine storms. The suggested prognostic scale (including the NEWS score dynamics; serum IL-6 greater than 23 pg/ml; serum CRP 50 mg/L or greater; absolute lymphocyte count less than 0.72 × 109/L; positive test result for replicative coronavirus (SARS-CoV-2) RNA; age 40 years and over) is a useful tool to identify patients at a high risk for cytokine storm, requiring an early onset of anti-inflammatory therapy.