What is a cytokine storm?

One of the most dreadful complications that can occur during the course of COVID-19 is the cytokine storm-also known as cytokine release syndrome-a form of systemic inflammatory response syndrome triggered by SARS-CoV-2 infection. The cytokine storm is an activation cascade of auto-amplifying cytokines, which leads to excessive activation of immune cells and generation of pro-inflammatory cytokines. It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, in turn activating even more white blood cells, finally resulting in an exaggerated pro-inflammatory-mediated response and ineffective anti-inflammatory control, leading to tissue damage, multiorgan failure, acute respiratory distress syndrome and death. Although cytokine storm pathogenesis is multifactorial, we hypothesize there is a close association between hypoxemia and cytokine storms in COVID-19, although it is difficult to establish the direction of this relationship. Most probably they coexist and, given enough time, one triggers the other in a chain reaction. Careful analysis of the day-to-day clinical evolution of COVID-19 indicates that there are short and slight periods of hypoxemia (confirmed by pulse oximetry and arterial gasometry), even on the day of the onset of persistent cough and/or shortness of breath. We propose the use of continuous positive airway pressure in early stages of COVID-19, at the onset of respiratory symptoms. This non-invasive ventilation method may be useful in individualized treatments to prevent early hypoxemia in COVID-19 patients and thus avoid triggering a cytokine storm. We believe such an approach is relevant everywhere, and in Cuba in particular, since the country has initiated national production of mechanical ventilation systems, including non-invasive ventilators. Moreover, as Cuba's COVID-19 protocols ensure early patient admission to isolation centers or hospitals, clinicians can prescribe the early use of continuous positive airway pressure as soon as respiratory symptoms begin, averting early hypoxemia and its triggering effect on cytokine storm development, and consequently, avoiding acute respiratory distress syndrome, multi-organ failure, and death.

Abstract Cytokine storm (Hypercytokinemia/Cytokine Release Syndrome) is an acute immune reaction consisting of a positive feedback loop between cytokines and immune cells, resulting in severe inflammation and organ failure. A clinical trial of immunotherapeutic anti-CD28 antibody TGN1412 in 2006 demonstrated the importance of thorough pre-clinical screening and need for more sensitive assays to predict cytokine storm. In that study, 6 healthy volunteers suffered from hypercytokinemia at doses 500-fold less than the lowest dose tested in non-human primates (NHP), showing the failure of standard pre-clinical safety approaches of that time. We have developed an in vitro assay to evaluate antibodies for induction of cytokine storm. Frozen PBMC from humans and NHP are cultured with test articles bound to the cell-culture plate and assayed for cytokine production and cell proliferation. Anti-CD28 superagonist antibodies, which have been shown to stimulate human PBMCs using similar mechanisms as TGN1412, are used as a positive control. Human PBMC produced significantly more IL-2, IL-6, IFN-gamma, TNF-alpha, MIP-1-alpha and several other cytokines compared to isotype control or untreated cells, while PBMC from NHP were non-responsive. The increased production of key pro-inflammatory cytokines in response to stimulation with anti-CD28 antibodies is accompanied by increased PBMC proliferation, while no proliferation increase is detected in isotype-treated or unstimulated human PBMC.

Cytokine storm is an umbrella term that describes an inflammatory syndrome characterized by elevated levels of circulating cytokines and hyperactivation of innate and/or adaptive immune cells. One type of cytokine storm is hemophagocytic lymphohistiocytosis (HLH), which can be either primary or secondary. Severe COVID-19-associated pneumonia and acute respiratory distress syndrome (ARDS) can also lead to cytokine storm/cytokine release syndrome (CS/CRS) and, more rarely, meet criteria for the diagnosis of secondary HLH. Here, we review the immunobiology of primary and secondary HLH and examine whether COVID-19-associated CS/CRS can be discriminated from non-COVID-19 secondary HLH. Finally, we review differences in immunobiology between these different entities, which may inform both clinical diagnosis and treatment of patients.

Cancer patients undergoing immunotherapy may develop cytokine release syndrome (CRS), an inflammatory cytokine storm condition, followed by neurotoxic manifestations and may be life-threatening. The current treatments for CRS successfully reduce the inflammatory response but may limit the anticancer effect of the given immunotherapy and fail to overcome the neurotoxic adverse events. Adenosine, a ubiquitous purine nucleoside, induces a plethora of effects in the body via its binding to four adenosine receptors A1, A2a, A2b, and the A3. Highly selective agonists to the A3 adenosine receptor act as inhibitors of proinflammatory cytokines, possess robust anti-inflammatory and anticancer activity, and concomitantly, induce neuroprotective effects. Piclidenoson and namodenoson belong to this group of compounds, are effective upon oral administration, show an excellent safety profile in human clinical studies, and therefore, may be considered as drug candidates to treat CRS. In this article, the detailed anti-inflammatory characteristics of these compounds and the rationale to use them as drugs to combat CRS are described.

Background: Cytokine release syndrome, also termed "cytokine storm," is the leading cause of morbidity and mortality among patients with various conditions such as sepsis. While cytokine storm is associated with multiple organ damage, acute cardiac and renal injury represents a hallmark of cytokine storm. Since recent reports have suggested that cannabidiol (CBD) may assist in the treatment of inflammatory diseases, our objective was to examine the effect of CBD on cytokine storm-induced cardiac and renal injury using the lipopolysaccharide (LPS)-induced sepsis mouse model. Materials and Methods: At 8 weeks of age, mice were randomly assigned to receive CBD (15 mg/kg) or vehicle one hour before a single injection of either phosphate-buffered saline or LPS (10 mg/kg) for an additional 24 h. Results: Our results show that CBD improves cardiac function and reduces renal injury in a mouse model of cytokine storm. Moreover, our data indicate that CBD significantly reduces systemic and renal inflammation to contribute to the improvements observed in a cytokine storm-model of cardiac and renal injury. Conclusions: Overall, the findings of this study suggest that CBD could be repurposed to reduce morbidity in patients with cytokine storm particularly in severe infections such as sepsis.

Introduction. Novel coronavirus infection (COVID-19) is characterized by systemic hyper-inflammation with elevated inflammatory cytokines referred to cytokine storm. It has been recognized as a leading cause of severe COVID-19 and its progression to multi-organ failure. Objectives. To make a synthesis if the literature sources and to critical appraise “cytokine storm” concept in COVID-19. Results. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory immunomodulation therapy in severe COVID-19. Although a number of studies have been conducted on target immunomodulatory therapy for severe COVID-19, no specific recommendations have been made yet. Moreover, there are some evidence against cytokine storm as pivotal pathogenetic mechanism for clinical deterioration in COVID-19 patients. Conclusion. There are enough evidence supporting cytokine response impairment as one of leading cause of COVID-19 progression to multiorgan failure. However, cytokine response abnormalities couldn’t explain clinical deterioration in some patients, so further studies are needed to find possible alternative pathogenetic mechanisms.

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.

A severe immune response in patients with coronavirus disease 2019 (COVID-19) can cause a potentially lethal unconstrained inflammatory cytokine storm, known as cytokine release syndrome (CRS). The present study provides an overview of the biology underlying CRS and how targeted inhibition of interleukin (IL)-6 signaling may improve outcomes and the survival of patients suffering from COVID-19. Preliminary clinical results have indicated that antagonism of the IL-6 receptor (IL-6R), including with the FDA-approved humanized monoclonal antibody tocilizumab, can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile. The available clinical data support the expansion of clinical trials using IL-6R targeting inhibitors for severe and critical COVID-19 treatment.

The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID‐19, and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T‐cell engagers and chimeric antigen receptor (CAR) T cells. CRS is intimately linked with dysregulated and excessive cytokine release, including IFN‐γ, TNF‐α, IL 1, IL‐6, and IL‐10, resulting in a systemic inflammatory response leading to multiple organ failure. Here, we show that mice intravenously administered the agonistic hamster anti‐mouse CD3ε monoclonal antibody 145‐2C11 develop clinical and laboratory manifestations seen in patients afflicted with CRS, including body weight loss, hepatosplenomegaly, thrombocytopenia, increased vascular permeability, lung inflammation, and hypercytokinemia. Blood cytokine levels and gene expression analysis from lung, liver, and spleen demonstrated a hierarchy of inflammatory cytokine production and infiltrating immune cells with differentiating organ‐dependent kinetics. IL‐2, IFN‐γ, TNF‐α, and IL‐6 up‐regulation preceded clinical signs of CRS. The co‐treatment of mice with a neutralizing anti‐cytokine antibody cocktail transiently improved early clinical and laboratory features of CRS. We discuss the predictive use of this model in the context of new anti‐cytokine strategies to treat human CRS.

Cytokine-release syndrome (CRS) includes overproduction of inflammatory cytokines, termed a “cytokine storm,” which has been observed in a large proportion of critically ill COVID-19 patients. Patients diagnosed with CRS rapidly progress to cardiovascular collapse and multi-organ failure and carry a high mortality rate. Therefore, early detection, treatment, and prevention of cytokine storms are important. Immunomodulators, such as interleukin-6 (IL-6) antagonists, have recently emerged as an alternative therapeutic option for COVID-19 patients with cytokine storms. In preparation for a clinical trial, we searched the PUBMED, EMBASE, and COCHRANE databases to obtain related publications on the use of immunotherapies in CRS and CRS with COVID-19. We also included major review articles and recent guidelines. In our proposal, we aim to evaluate the efficacy and safety of anti-IL-6 alone versus anti-IL-6 and corticosteroid combination in COVID-19 critically ill patients with CRS. Our primary outcomes are duration of mechanical ventilation and 28-day ventilator-free days.