Polymorphisms in the inter leukin-1 beta gene (rs16944 and rs1143627) as a risk factor for SARS-COV2 infection

Despite evidence of cytokine gene variation in SARS-CoV-2 sickness is few, understanding the function of genetic polymorphisms in the course of respiratory infections may aid in the identification of possible andidates for future inquiry in SARS-CoV-2 patients. As a result, the study raises crucial issues about how cytokine gene polymorphisms may have a role in the severity of COVID-19 sickness. ARMS-PCR was used to detect genotype frequency data for the IL-1B SNP (rs 16944), (rs1143627). All data statistical analyses were performed using the Statistical Package for Social Science (SPSS 26).. shows the genotype distributions (frequencies) of the chosen IL-1B SNPs, rs16944 A/G and rs1143627 G/A, as well as their relationships with SARS-COV2 risk. Significant relationships between the rs16944 A/G and SARS-COV2 risk were found in the samples, The AG variant genotype (AG vs. AA) showed an adjusted OR of 1.0 (95 percent CI = 1.770 (0.935-0.353), P = 0.078*) when compared to the rs16944 AA genotype. There were no statistical differences in rs1143627 polymorphism between the two groups, and there was no evidence that rs1143627 may be associated with an increased risk of acquiring SARS-COV2 based on the results of the p value G (P = 0.167), G/A (P = 0.22), and G/G (P = 0.22). This was the first study to look at the rs1143627 polymorphism in relation to SARS-COV 2, therefore no previous research was published.first, second, and third level headings (first level heading). © 2023 Author(s).

Pro- and Anti-Inflammatory Prostaglandins and Cytokines in Humans: A Mini Review.

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFß families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation.

Significance of Measuring the Proinflammatory Response Biomarkers in Covid-19 Patients

Objectives: In the management of COVID-19, bio-inflammatory cytokines (IL-6 and others) can be measured as inflammatory markers to detect conditions in response to treatment, risk assessment, monitoring disease progression, prognosis determination and treatment selection. The purpose of this study is to identify changes in inflammation markers of COVID-19 patients and to determine whether it should be used as a prognosis marker. Materials-Methods: Three groups of the patients consisting of 138 patients (12 non-survived, 35 severe and 91 mild/moderate) aged 16 to 86 years who were diagnosed with COVID-19 by real-time polymerase chain reaction were included in the study. Acute phase serum levels such as CRP, D-Dimer, Ferritin, IL-1B and IL-6 were measured and compared in serum samples taken from these patients. It was examined whether these parameters can be a biomarker that can be monitored for the course of the disease. IL-6 and ferritin were measured with CLIA, D-dimer immunassay, CRP with photometry and IL1-B was measured with flow cytometry methods. Result(s): It has been observed that all parameters, except for ferritin (P=0.94), increase significantly during the transition from mild to severe form of the disease. (CRP P:0.005, D-Dimer P<0.0001, IL-1B P:0.03, IL-6 P:0.002). A significant difference was observed in the levels of CRP, IL-6 and D-Dimer in the patient survival. (P=0.003, P=0.03, P:0,0001). According to our results, the use of IL-1B in the prognosis monitoring of patients with severe forms was not found to be significant (P:0.48). ROC curve analysis showed that the area under the ROC curve (AUC) of CRP, D-Dimer and IL-6 was 0.645 (0,559 to 0,725), 0.637 (0,551 to 0,717) and 0.663 (0,577 to 0,741) respectively, and the cutoff values were >3.77 (sensitivity, 72.3%;specificity, 55%), >0.48 (sensitivity 68.1%;specificity, 57.1%) and <14.9 (sensitivity, 65,9%;specificity, 62.6%), respectively. Conclusion(s): Our results confirmed that the dynamic change in IL-6, CRP, D-Dimer can be used as a marker for disease monitoring in patients with severe COVID-19.

Association between IL-6 rs1800795 and IL-1β rs 16944 gene polymorphisms with clinical severity of COVID-19 patients in Surakarta, Central Java, Indonesia

Background: Cytokine plays a pivotal role in the pathogenesis of coronavirus disease 2019 (COVID-19). Cytokine storm is characterized by rapid elevation of an inflammatory circulating cytokine such as interleukin-6 (IL-6) and IL-1. However, according to evidence, genetic variables may affect the development and course of infectious diseases. Multiple genetic polymorphisms, mostly single-nucleotide polymorphisms (SNPs), have been linked to this setting's predisposition to viral infections. This study aimed to determine the frequency distribution of IL-6 SNPs rs1800795 and IL-1β SNPs rs16944 and rs1143627 gene polymorphisms and their association with the clinical severity of COVID-19 patients in Surakarta, Indonesia. This study aims to determine the association between IL-6 rs1800795 and IL-1β rs16944 with COVID-19 clinical severity. Methods: This study used a cross sectional design conducted at Universitas Sebelas Maret Hospital and centralized isolation of the Donohudan Hajj Dormitory from May to November 2021. A total of 120 COVID-19 patients were divided into 3 groups: asymptomatic, mild-moderate, and severe-critical. The detection of IL-6 SNPs rs1800795 and IL-1β SNPs rs16944 was carried out by quantitative PCR (qPCR) examination, and IL-6 and IL-1β were determined by the ELISA method. Result: There was no significant association between IL-6 SNPs rs1800795 (p=1.000) and IL-1β SNPs rs16944 (p=0.119) with clinical severity. In IL-1β SNPs rs16944 gene polymorphisms, the GG genotype was more commonly found in the asymptomatic group. AG genotype was commonly found in the symptomatic group (mild to critical). There was a significant association between IL-1β levels and clinical severity (p=0.03), whereas the association between IL-6 levels and clinical severity is not significant (p=0.103). Conclusion: There was a correlation between IL-1β levels with clinical severity. In IL-1β SNPs rs16944, the GG genotype may act as a protective factor, whereas the AG genotype may act as a factor that increases the clinical severity of COVID-19. © 2023, Sanglah General Hospital. All rights reserved.

Inflammasome signaling proteins as biomarkers of COVID-19.

Introduction: One of the main characteristics of COVID-19 is an exacerbated inflammatory response that results in cardiometabolic complications and dysfunction in the nervous system. Moreover, these complications may extend beyond the period of active SARS-CoV2 infection and even extend over a year. Thus, it is important to better understand the contribution of the inflammatory responses in COVID-19 patients, not just in the acute phase but also after the infection has subsided. Methods: We measured the protein levels of inflammasome signaling proteins using Simple Plex microfluidics technology in patients with an active SARS-CoV2 infection and in recovered patients to determine their potential use as biomarkers of COVID-19. We carried out statistical analyses to identify which proteins were increased in COVID-19 patients with active infection and in recovered patients. The receiver operating characteristics (ROC) were calculated for each analyte to determine their potential fit as biomarkers. Results: The inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-1ß and IL-18 were elevated in the plasma of patients with active infection and remained elevated after the infection was resolved for approximately 2 months after. Levels of caspase-1 and ASC continued to increase long after patients had recovered from the infection. Furthermore, when measuring biomarkers of inflammation during active infection, analyses with area under the curve (AUC) values above 0.75 indicated that caspase-1, ASC, IL-1ß and IL-18 are reliable biomarkers of the inflammatory response during active COVID-19 infection. Moreover, when measuring biomarkers of inflammation after recovery from active infection, caspase-1 and ASC presented AUC values above 0.9. Discussion: These findings indicate that inflammasome signaling proteins can be used to reliably monitor the inflammatory innate immune response in COVID-19 patients.

Metabolic Biological Markers for Diagnosing and Monitoring the Course of Tuberculosis

The international biomedical community has been currently facing a need to find a simple and most accessible type of analysis that helps to diagnose tuberculosis ( TB) with the maximum reliability even before the onset of clinical manifestations. Tuberculosis results in more deaths than any other pathogen, second only to pneumonia caused by the SARS-CoV-2 virus, but the majority of infected people remain asymptomatic. In addition, it is important to develop methods to distinguish various forms of tuberculosis infection course at early stages and to reliably stratify patients into appropriate groups (persons with a rapidly progressing infection, chronic course, latent infection carriers). Immunometabolism investigates a relationship between bioenergetic pathways and specific functions of immune cells that has recently become increasingly important in scientific research. The host anti-mycobacteria immune response in tuberculosis is regu lated by a number of metabolic networks that can interact both cooperatively and antagonistically, influencing an outcome of the disease. The balance between inflammatory and immune reactions limits the spread of mycobacteria in vivo and protects from developing tuberculosis. Cytokines are essential for host defense, but if uncontrolled, some mediators may contribute to developing disease and pathology. Differences in plasma levels of metabolites between individuals with advanced infection, LTBI and healthy individuals can be detected long before the onset of the major related clinical signs. Changes in amino acid and cortisol level may be detected as early as 12 months before the onset of the disease and become more prominent at verifying clinical diagnosis. Assessing serum level of certain amino acids and their ratios may be used as additional diagnostic markers of active pulmonary TB. Metabolites, including serum fatty acids, amino acids and lipids may contribute to detecting active TB. Metabolic profiles indicate about increased indolamine 2.3-dioxygenase 1 (IDO1) activity, decreased phospholipase activity, increased adenosine metabolite level, and fibrous lesions in active vs. latent infection. TB treatment can be adjusted based on individual patient metabolism and biomarker profiles. Thus, exploring immunometabolism in tuberculosis is necessary for development of new therapeutic strategies.

Anakinra as a potential treatment for COVID-19.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

Cytokines in Innate Immunity

The IL-1 family: Members of the IL-1 family of cytokines are similar in structure and function. The functions include agonistic (pro-inflammatory) and antagonistic (anti-inflammatory) activities. The IL-1 family of cytokines can signal damage of tissue integrity, distress, and danger to the organism, ultimately alarming innate and adaptive immunity to fight pathogens. TNF and LT: TNF and LT are trimeric proteins belonging to a structurally related TNF superfamily of cytokines. They are pleiotropic cytokines capable of signaling an array of pro- and anti-inflammatory activities. TNF-α has soluble (sTNF) and membrane (mTNF) forms. Both forms can bind to two TNF receptors (TNF-R1 and TNF-R2), but mTNF can alter the structure of the TNF-R2 such that it binds to sTNF with a lower affinity. Thus, sTNF primarily binds to TNF-R1 and plays an important role in the inflammatory immune response, whereas mTNF-α interacts preferentially with TNF-R2 and promotes cellular proliferation and survival and some other biological effects. IL-6: The IL-6 family of cytokines is structurally characterized by four α-helical bundle structure that signals via the JAK-STAT pathway. IL-6 has a major role in innate and adaptive immunity. IL-6 classic signaling is implicated in acute-phase responses, whereas IL-6 trans-signaling (and trans-presentation/cluster-signaling) characteristically initiates pro-inflammatory pathways with a major impact on adaptive immunity, including plasma cell development and antibody production, and T-cell helper 17 response. Interferons: Interferons are classified into three types. Type I (IFN-α, −β) and type III (IFN-λ) are strong antivirals that can stimulate both innate and adaptive immune responses. Type II interferon (IFN-γ) has a weak antiviral ability, as its major role is in regulating adaptive immunity, particularly in Th1 responses. Cytokine storm and COVID-19: Cytokine storm is a hyperinflammatory state due to overactivity of major pro-inflammatory cytokines like IL-1, IL-6, and TNF. It is a major obstacle for the treatment of severe COVID-19. IL-6 is a potential biomarker for the severity of the disease. Anti-IL-6R (tocilizumab) and anti-virotic "remdesivir” are promising treatments of severe disease. Prevention measures are in place with many auspicious novel vaccines. © 2022 Elsevier Inc. All rights reserved.

A Prospective Cohort Study of COVID-19: Evaluation of the Early Role of IL-1 and IL-6 Antagonists in Improving the Outcome of the Illness and Reduction in the Risk of Death.

The COVID-19 pandemic had a profound impact on global health, economies, and social systems. The crucial factor that determines the success of COVID-19 treatments is preventing the need for mechanical ventilation and intensive care admission. In the context of COVID-19, several treatments have been found to play a role in the disease's progression and severity. Interleukins (ILs) have been identified as key mediators of the cytokine storm that can occur in severe cases of COVID-19, leading to respiratory failure and other complications. For instance, IL-1 antagonist (anakinra) and IL-6 antagonist (tocilizumab) are supposed to be promising treatments as well as cortisones for COVID-19. This prospective study aims to evaluate the effectiveness of anakinra or tocilizumab in addition to cortisone in preventing the progression of mild to moderate COVID-19 cases to severe intensive care admission. Biochemical and hematological parameters, such as D-dimer, ferritin, LDH, CRP, and white blood cells (WBCs), were measured after treatment with either anakinra or tocilizumab in addition to cortisone or cortisone alone. The study also recorded the number of deaths and patients admitted to intensive care. The results indicate that anakinra significantly improved outcomes and decreased the number of intensive care admissions compared to tocilizumab or cortisone alone. Therefore, anakinra may play a vital role in controlling the progression of COVID-19, and its use in mild to moderate cases may prevent the worsening of the disease to severe stages.

The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical).

Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021-2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.

COVID-19 and Pain

SARS-CoV-2 causes COVID-19, which includes acute respiratory tract infections with a variety of manifestations such as pneumonia and bronchiolitis which are accompanied by other symptoms such as wheezing, cough, respiratory distress, and pain. The novel Coronavirus has caused millions of deaths and increasing challenges for healthcare professionals globally. When the virus enters our organism through nasal mucosa it is identified by the innate immune system such as macrophages and mast cells, therefore producing pro-inflammatory cytokines including IL-1beta, IL-6, and TNF. The production of cytokines mediates fever, malaise, depression, anxiety, loss of appetite, hyperalgesia, and pain. Here in this paper, we report the interrelationship between COVID-19 and pain.Copyright © by BIOLIFE.

Autoantibodies neutralizing antiinflammatory mediators in the context of SARS-CoV-2 infection and COVID-19

Breakdown of peripheral immune tolerance can be triggered by environmental factors or excessive inflammation. These can induce atypically posttranslational modified isoforms of self-proteins, which—in context of permissive HLA-alleles—can trigger autoimmune phenomena including the formation of autoantibodies. Various self-reactive antibody responses have been reported in context of the hyperinflammation associated with SARS-CoV-2 infection. Here we describe unique autoantibodies targeting the antiinflammatory mediators progranulin and the interleukin one receptor antagonist (IL-1-Ra), both arising frequently in the course of critical COVID-19 in adults or exclusively (anti-IL-1Ra-Ab) in multisystem inflammatory syndrome in children (MIS-C). These antibodies are triggered by hyperphosphorylated, transiently occurring isoforms of PGRN and of IL-1-Ra. Anti-PGRN- and anti-IL1-Ra-autoantibodies deplete their endogenous antigens from patients' plasma and impair their antiinflammatory bioactivity. Collectively, these antibodies can contribute to imbalanced inflammatory signaling in context of SARS-CoV-2 infection-associated hyperinflammation and potentially exacerbate disease. © 2023 Elsevier Inc. All rights reserved.

Treatment with COLchicine in hospitalized patients affected by COVID-19: The COLVID-19 trial.

OBJECTIVE: To evaluate whether the addition of colchicine to standard of care (SOC) results in better outcomes in hospitalized patients with COVID-19. DESIGN: This interventional, multicenter, randomized, phase 2 study, evaluated colchicine 1.5 mg/day added to SOC in hospitalized COVID-19 patients (COLVID-19 trial) and 227 patients were recruited. The primary outcome was the rate of critical disease in 30 days defined as need of mechanical ventilation, intensive care unit (ICU), or death. RESULTS: 152 non-anti-SARS-CoV-2-vaccinated patients (colchicine vs controls: 77vs75, mean age 69.1±13.1 vs 67.9±15 years, 39% vs 33.3% females, respectively) were analyzed. There was no difference in co-primary end-points between patients treated with colchicine compared to controls (mechanical ventilation 5.2% vs 4%, ICU 1.3% vs 5.3%, death 9.1% vs 6.7%, overall 11 (14.3%) vs 10 (13.3%) patients, P=ns, respectively). Mean time to discharge was similar (colchicine vs controls 14.1±10.4 vs 14.7±8.1 days). Older age (>60 years, P=0.025), P/F<275 mmHg (P=0.005), AST>40 U/L (P<0.001), pre-existent heart (P=0.02), lung (P=0.003), upper-gastrointestinal (P=0.014), lower-gastrointestinal diseases (P=0.009) and cancer (P=0.008) were predictive of achieving the primary outcome. Diarrhoea (9.1% vs 0%, p=0.0031) and increased levels of AST at 6 days (76.9±91.8 vs 33.5±20.7 U/l, P=0.016) were more frequent in the colchicine group. CONCLUSION: Colchicine did not reduce the rate and the time to the critical stage. Colchicine was relatively safe although adverse hepatic effects require caution. We confirm that older (>60 years) patients with comorbidities are characterized by worse outcome.

Investigation of the potential of leukoreduction filters in the creation of anti-inflammatory compound.

BACKGROUND: Some viruses such as SARS, SARS-CoV-2, and MERS cause an imbalance in immune responses and leads to an acute inflammatory reaction named cytokine storm. In this situation, an anti-inflammatory component can modulate the immune system and decrease mortality. The aim of this study was investigate the potential of leukoreduction filters (LRFs) in creating an anti-inflammatory compound. MATERIALS AND METHODS: In this experimental study, firstly optimal dose of the anti-inflammatory drug was obtained through LRFs treatment with 0.1 mg, 0.4 mg, 0.6 mg of Betamethasone. Then inflammatory and anti-inflammatory cytokine in gene and protein level was evaluated. In the next step, LRFs were categorized into treatment 1, treatment 2, control assay, and control groups and treated with the optimal dose of the drug. Finally, the obtained compound was investigated for the concentration of IL1, IL6, and TNF-α as inflammatory and IL4, IL1Ra, and IL10 as anti-inflammatory cytokines. RESULTS: The results of the current study showed that the concentration of 0.4 mg of Betamethasone lead to a significant increase of anti-inflammatory cytokine in gene and protein levels. The results also showed that the Betamethasone treated groups (treatment1) causes a significant increase in the secretion of anti-inflammatory cytokine compares to the control while inflammatory cytokine remained at the control level. CONCLUSION: The results showed that under influence of anti-inflammatory drug treatments the production and secretion of anti-inflammatory cytokines can be induced in LRFs.

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination.

The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis.

The field of inflammatory disease of the heart or "cardio-immunology" is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

Inhibition of IL-1/IL-6 Pathway Reduces Mortality in Patients with SARS-CoV-2

Background: Novel 2019 Coronavirus (covid-19) or SARS-CoV-2 disease is spreading quickly throughout the globe and threatening public health. Severe acute respiratory syndrome SARS-CoV-2 may precipitate "cytokine” storm, immune system dysregulation, and hyper-coagulation that are responsible for several organ failure, morbidity, and mortality. The severity of infection symptoms is extremely variable from mild symptoms to acute respiratory distress syndrome. Overproduction of inflammatory cytokines and interplay between the immune system response and dysregulation of coagulation system are hypothesized to play a critical role in the pathological mechanism of seriously ill patients with covid-19 infection via the IL-1/IL-6 central pathway. Methods: The role of SARS-CoV-2 virus in covid-19 disease through cytokine storm and coagulopathy has been discussed in the present brief review. The electronic databases Pubmed, Google Scholar, and SCOPUS were searched to retrieve related English-language articles published between the years 2019 and 2021. Results: The interplay between immune system responses and coagulation pathway was observed in pathological condition of coronavirus patients, leading to abnormal condition of clot formation and increasing incidence of strokes. Indeed, in non-survivor patients, the levels of IL-6, IL-1, and D-dimer were higher than survivor coronavirus patients. Conclusion: Severe SARS-CoV-2 patients with higher level of IL-1/IL-6 and coagulation abnormality confirm this hypothesis that anticytokine drugs are effective for managing cytokine storm, preventing the risk of strokes, and reducing hospitalization and mortality in covid-19 patients. © 2022 The authors.

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19.

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3-4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions.

Intravenous anakinra to curb cytokine storm in adult-onset Still's disease and in macrophage activation syndrome: A case series.

OBJECTIVE: Adult-onset Still's disease (AOSD) is an auto-inflammatory polygenic disorder, for which the diagnosis is essentially clinical. The exclusion of mimickers [such as common bacterial and viral infections, hematologic malignancies, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] is necessary to confirm the diagnosis. Anti-interleukin (IL)-1 therapy is considered a treatment milestone for AOSD. Herein, we present a short series of newly-diagnosed AOSD or upcoming macrophage activation syndrome (MAS) cases who received intravenous (IV) anakinra, an IL-1 receptor blocker. METHODS: Four patients with newly-diagnosed AOSD or upcoming MAS were treated with IV anakinra at the Rheumatology Unit of Padova University Hospital, Italy. We obtained informed consent from the patients for use of their cases and medical images for publication purposes. RESULTS: All patients presented with AOSD or MAS during the COVID-19 pandemic, making diagnosis challenging due to similar immunological and clinical characteristics across both pathologies. All patients presented with hyperpyrexia and elevated inflammatory markers; two patients had a skin rash typically seen in AOSD. IV anakinra slowed down AOSD progression in all patients, prevented severe outcomes and mitigated the risk of multiorgan failure. All cases improved within 24hours of anakinra administration. CONCLUSION: We found that administration of anakinra in patients with newly-diagnosed AOSD and/or upcoming MAS reduced hyperinflammation and prevented life-threatening complications. The IV route appears to be preferable in the hospital setting, where comorbidities such as coagulopathies and thrombocytopenia can complicate the use of other routes of administration.