Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications.

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.

Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Effects of ß-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.

Cytokine Release Syndrome after Treatment of Anti-CD19 CAR-T Therapy with IL-6 Knocking Down in Patients with Central Nervous System B-cell Acute Lymphocytic Leukemia.

OBJECTIVE: To investigate the cytokine release syndrome (CRS) condition for central nervous system B-cell acute lymphocytic leukemia (CNS B-ALL) patients after CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) infusion. METHODS: This prospective observational research included a total of 12 cases of patients with CNS B-ALL from March 2017 to February 2020. ssCART-19 infusions (5×106 cells/kg) were given to patients for 3 consecutive days. After infusion, the temperature of all patients was detected constantly and the CRS was carefully monitored within 1 month after treatment. The serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, CRP and IL-17A were tested by enzyme-linked immunosorbent assay (ELISA) within 10 days after infusion. RESULTS: All 12 CNS B-ALL patients showed CRS with 100% incidence rate, with 3 cases (25.00%) of CRS stage I and 9 cases (75.00%) with CRS stage II. No CRS stage III~V was observed. The overall response rate was 91.67% (11/12), with 10 patients (83.33%) showed CR and 1 case (8.33%) of PR. In 9 patients with CRS stage II, the temperature increased persistently, ranging from 4 days to 14 days after infusion, and decreased gradually after 14 days of nursing treatment. The hyperthermia condition started from 1 day after infusion and returned to baseline at the following 2-10 days of nursing treatment. The levels of the inflammatory factors increased markedly after ssCAR-T19s infusion for 2-3 days compared to the baseline, and gradually returned to the baseline after treatment. After 10 days of infusion, all inflammatory factors returned to normal levels. CONCLUSION: ssCART-19s infusion induced short-term slight CRS with increased temperature and inflammatory factors, and no severe CRS was observed.

Nonclinical safety assessment of engineered T cell therapies.

Over the last decade, immunotherapy has established itself as an important novel approach in the treatment of cancer, resulting in a growing importance in oncology. Engineered T cell therapies, namely chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cell therapies, are platform technologies that have enabled the development of products with remarkable efficacy in several hematological malignancies and are thus the focus of intense research and development activity. While engineered T cell therapies offer promise in addressing currently intractable cancers, they also present unique challenges, including their nonclinical safety assessment. A workshop organized by HESI and the US Food and Drug Administration (FDA) was held to provide an interdisciplinary forum for representatives of industry, academia and regulatory authorities to share information and debate on current practices for the nonclinical safety evaluation of engineered T cell therapies. This manuscript leverages what was discussed at this workshop to provide an overview of the current important nonclinical safety assessment considerations for the development of these therapeutic modalities (cytokine release syndrome, neurotoxicity, on-target/off-tumor toxicities, off-target effects, gene editing or vector integration-associated genomic injury). The manuscript also discusses approaches used for hazard identification or risk assessment and provides a regulatory perspective on such aspects.

The Mechanism behind Influenza Virus Cytokine Storm.

Influenza viruses are still a serious threat to human health. Cytokines are essential for cell-to-cell communication and viral clearance in the immune system, but excessive cytokines can cause serious immune pathology. Deaths caused by severe influenza are usually related to cytokine storms. The recent literature has described the mechanism behind the cytokine-storm network and how it can exacerbate host pathological damage. Biological factors such as sex, age, and obesity may cause biological differences between different individuals, which affects cytokine storms induced by the influenza virus. In this review, we summarize the mechanism behind influenza virus cytokine storms and the differences in cytokine storms of different ages and sexes, and in obesity.

Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2.

ABSTRACT: Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome.

Shedding light on vitamin D: the shared mechanistic and pathophysiological role between hypovitaminosis D and COVID-19 risk factors and complications.

Severe acute respiratory syndrome coronavirus (SARS-COV-2) is the culprit of the Coronavirus Disease (COVID-19), which has infected approximately 173 million people and killed more than 3.73 million. At risk groups including diabetic and obese patients are more vulnerable to COVID-19-related complications and poor outcomes. Substantial evidence points to hypovitaminosis D as a risk factor for severe disease, the need for ICU, and mortality. 1,25(OH)D, a key regulator of calcium homeostasis, is believed to have various immune-regulatory roles including; promoting anti-inflammatory cytokines, down regulating pro-inflammatory cytokines, dampening entry and replication of SARS-COV-2, and the production of antimicrobial peptides. In addition, there are strong connections which suggest that dysregulated 1,25(OH)D levels play a mechanistic and pathophysiologic role in several disease processes that are shared with COVID-19 including: diabetes, obesity, acute respiratory distress syndrome (ARDS), cytokine storm, and even hypercoagulable states. With evidence continuing to grow for the case that low vitamin D status is a risk factor for COVID-19 disease and poor outcomes, there is a need now to address the public health efforts set in place to minimize infection, such as lock down orders, which may have inadvertently increased hypovitaminosis D in the general population and those already at risk (elderly, obese, and disabled). Moreover, there is a need to address the implications of this evidence and how we may apply the use of cheaply available supplementation, which has yet to overcome the near global concern of hypovitaminosis D. In our review, we exhaustively scope these shared pathophysiologic connections between COVID-19 and hypovitaminosis D.

Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration.

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing major threat to global health and has posed significant challenges for the treatment of severely ill COVID-19 patients. Several studies have reported that cytokine storms are an important cause of disease deterioration and death in COVID-19 patients. Consequently, it is important to understand the specific pathophysiological processes underlying how cytokine storms promote the deterioration of COVID-19. Here, we outline the pathophysiological processes through which cytokine storms contribute to the deterioration of SARS-CoV-2 infection and describe the interaction between SARS-CoV-2 and the immune system, as well as the pathophysiology of immune response dysfunction that leads to acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS), and coagulation impairment. Treatments based on inhibiting cytokine storm-induced deterioration and occurrence are also described.

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection.

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor ß (TGF-ß) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients.IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

Efficacy and Effect of Inhaled Adenosine Treatment in Hospitalized COVID-19 Patients.

Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.

Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence.

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

SARS-CoV-2, recurrent ischemic strokes and carotid macrothrombosis: the other face of the cytokine storm (a case report).

Since December 2019, the world has experienced the emergence in China of a new infection called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This infection quickly has progressed to a global pandemic since March 2020, with very high human-to-human transmission rate. Besides lung injury, COVID-19 is also associated with cardio and neurovascular complications. Herein, we report the case of a 77-year-old female who presented with non-severe COVID-19 and multiple ischemic strokes secondary to an extensive carotid thrombosis. The ischemic stroke was supposed to have been caused by the cytokine storm related to COVID-19. The possibility of hemorrhagic transformation, based on the assessment of bleeding score, limited the use of anticoagulation, and probably explained the stroke recurrence and poor outcome in our patient. The pathogenic mechanism and the management of this complex situation are still lacking and further studies are needed.

Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy.

OBJECTIVE: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS: Narrative literature review. RESULTS: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.

The Brain on COVID-19.

In March 2020 -still the early days of the U.K.'s COVID-19 crisis-Rhys Thomas, a neurologist at Newcastle University, got a call at home from a concerned colleague. The colleague's cousin was hospitalized, critically ill with COVID-19, and had developed brainstem encephalitis, a severe inflammatory condition of the brain causing a suite of symptoms, from eye problems to balance problems and drowsiness. He wanted to know if Thomas knew anything about these conditions. At the time, the research coming out of Wuhan, China, only suggested a mild whiff of neurological symptoms-headache, dizziness, and the loss of taste and smell. Clearly the virus could affect the brain in some ways, but it wasn't, Thomas thought then, anything serious. But this report sounded much more concerning. Symptoms like this patient's would mean the virus was accessing more of the nervous system than scientists originally thought.

COVID-19 and inflammatory bowel disease: A pathophysiological assessment.

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD.

Promising Therapy for Heart Failure in Patients with Severe COVID-19: Calming the Cytokine Storm.

The coronavirus disease 19 (COVID-19) pandemic poses a serious global threat to human health and the economy. Based on accumulating evidence, its continuous progression involves not only pulmonary injury but also damage to the cardiovascular system due to intertwined pathophysiological risks. As a point of convergence in the pathophysiologic process between COVID-19 and heart failure (HF), cytokine storm induces the progression of COVID-19 in patients presenting pre-existing or new onset myocardial damage and even HF. Cytokine storm, as a trigger of the progression of HF in patients with COVID-19, has become a novel focus to explore therapies for target populations. In this review, we briefly introduce the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illuminate the mechanism and links among COVID-19, cytokine storm, and HF. Furthermore, we discuss drugs and therapeutic targets for patients with COVID-19 and HF.

Haemophagocytic syndrome and COVID-19.

Primary and secondary haemophagocytic lymphohistiocytosis (HLH) are hyperferritinaemic hyperinflammatory syndromes with a common terminal pathway triggered by different etiopathogenetic factors. HLH is characterised by a decreased capacity of interferon gamma production with an activated NK phenotype profile similar to other hyperinflammatory syndromes. Viruses are closely linked to the development of HLH as infectious triggers, and the break of tolerance to self-antigens is considered a critical mechanism involved in the development of immune-mediated conditions triggered by viral infections. Emerging studies in patients with COVID-19 are suggesting a key role of monocytes/macrophages in the pathogenesis of this viral infection, and there is a significant overlap between several features reported in severe COVID-19 and the features included in the HLH-2004 diagnostic criteria. Therefore, SARS-Cov-2, as other respiratory viruses, may also be considered a potential etiological trigger of HLH. The frequency of HLH in adult patients with severe COVID-19 is lower than 5%, although this figure could be underestimated considering that most reported cases lacked information about some specific criteria (mainly the histopathological criteria and the measurement of NK cell function and sCD25 levels). Because HLH is a multi-organ syndrome, the diagnostic approach in a patient with severe COVID-19 in whom HLH is suspected must be carried out in a syndromic and holistic way, and not in the light of isolated clinical or laboratory features. In COVID-19 patients presenting with persistent high fever, progressive pancytopenia, and hepatosplenic involvement, together with the characteristic triad of laboratory abnormalities (hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia), the suspicion of HLH is high, and the diagnostic workup must be completed with specific immunological and histopathological studies.