The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

In 2019–2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.     

Sulforaphane inhibits the expression of interleukin-6 and interleukin-8 induced in bronchial epithelial IB3-1 cells by exposure to the SARS-CoV-2 Spike protein

BackgroundA key clinical feature of COVID-19 is a deep inflammatory state known as “cytokine storm” and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs.PurposeThe objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm".MethodsThe effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis.ResultsIn our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm".ConclusionThe control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.     

The NLRP3 inflammasome and COVID-19: Activation,pathogenesis and therapeutic strategies

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called “cytokine storm”. Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.     

Inflammatory stress in SARS-COV-2 associated Acute Kidney Injury

Increasing clinical evidence shows that acute kidney injury (AKI) is a common and severe complication in critically ill COVID-19 patients. The older age, the severity of COVID-19 infection, the ethnicity, and the history of smoking, diabetes, hypertension, and cardiovascular disease are the risk factor for AKI in COVID-19 patients. Of them, inflammation may be a key player in the pathogenesis of AKI in patients with COVID-19. It is highly possible that SARS-COV-2 infection may trigger the activation of multiple inflammatory pathways including angiotensin II, cytokine storm such as interleukin-6 (IL-6), C-reactive protein (CRP), TGF-β signaling, complement activation, and lung-kidney crosstalk to cause AKI. Thus, treatments by targeting these inflammatory molecules and pathways with a monoclonal antibody against IL-6 (Tocilizumab), C3 inhibitor AMY-101, anti-C5 antibody, anti-TGF-β OT-101, and the use of CRRT in critically ill patients may represent as novel and specific therapies for AKI in COVID-19 patients.     

Mesenchymal stem/stromal cells as adjuvant therapy in COVID-19-associated acute lung injury and cytokine storm: Importance of cell identification

Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvant therapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lung injury and cytokine storm. Several published studies, which used MSCs to alleviate COVID-19-associated acute lung injury and cytokine storm, reported promising results. However, the evidence came from a case report, case series, and clinical trials with a limited number of participants. Therefore, more studies are needed to get robust proof of MSC beneficial effects.     

A Comparative Assessment of Effects of Major Mediators of Acute Phase Response (IL-1, TNF-α, IL-6) on Breathing Pattern and Survival Rate in Rats with Acute Progressive Hypoxia

Journal of Evolutionary Biochemistry and Physiology - A pressing issue of the day is the identification of therapeutic targets to suppress the “cytokine storm” in COVID-19 complicated...     

Cytokine storm intervention in the early stages of COVID-19 pneumonia

Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30^th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.     

Is COVID-19-associated cytokine storm distinct from non-COVID-19 secondary hemophagocytic lymphohistiocytosis?

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.     

Clinical progress in MSC-based therapies for the management of severe COVID-19

Considering the high impact that severe Coronavirus disease 2019 (COVID-19) cases still pose on public health and their complex pharmacological management, the search for new therapeutic alternatives is essential. Mesenchymal stromal cells (MSCs) could be promising candidates as they present important immunomodulatory and anti-inflammatory properties that can combat the acute severe respiratory distress syndrome (ARDS) and the cytokine storm occurring in COVID-19, two processes that are mainly driven by an immunological misbalance. In this review, we provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation that occurs in COVID-19, discussing the potential that the cytokines and growth factors that constitute the MSC-derived secretome present to treat the disease. Moreover, we revise the latest clinical progress made in the field, discussing the most important findings of the clinical trials conducted to date, which follow 2 different approaches: MSC-based cell therapy or the administration of the secretome by itself, as a cell-free therapy.     

A clinical trial of IL-15 and IL-21 combination therapy for COVID-19 is warranted

Previous studies of SARS-CoV-2 viral infection suggest that both the humoral and cytotoxic arms of the immune system are weak in patients with severe COVID-19 disease when compared to mild disease. A cytokine storm is also induced in severe disease. IL-15 has been shown to support the cytotoxic arm of the immune response. IL-21 has been shown to support both the cytotoxic and humoral arms of the immune response. In addition, in some settings, Il-21 has been shown to actually decrease IL-6 and TNF-alpha production, reducing the inflammatory proteins involved in the cytokine storm. Furthermore, in other settings, the combination of IL-15 and IL-21 has been shown to be more effective than either interleukin alone in promoting an effective immune response. Therefore, a clinical trial that examines the use of the combination of IL-15 and IL-21 for COVID-19 patients is warranted.     

微量元素硒在对抗COVID-19中的作用研究进展

自新型冠状病毒肺炎（corona virus disease 2019，COVID-19）疫情爆发以来，严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome-coronavirus 2， SARS-CoV-2）引起的各类临床表现和后续并发症受到了广泛关注。有研究发现，COVID-19死亡率具有地域差异性，中度或重度缺硒地区感染人群常常具有更高的死亡率，因此硒可能在对抗COVID-19中具有一定的作用。总结了硒缺乏COVID-19患者的临床表现、硒对抗COVID-19的临床效应、以及硒对抗COVID-19的作用机制等方面的研究进展。从目前的研究结果来看，硒在应对感染SARS-CoV-2以及避免过激免疫反应导致的细胞因子风暴过程中具有积极作用，但仍然缺乏临床试验研究证据。     

COVID-19, leprosy,and neutrophils

Coronavirus Disease 2019 (COVID-19), a disease caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has only recently emerged, while Mycobacterium leprae, the etiological agent of leprosy, has endured for more than 2,000 years. As soon as the initial reports of COVID-19 became public, several entities, including the Brazilian Leprosy Society, warned about the possible impact of COVID-19 on leprosy patients. It has been verified that COVID-19 carriers can be either asymptomatic or present varying degrees of severe respiratory failure in association with cytokine storm and death, among other diseases. Severe COVID-19 patients show increased numbers of neutrophils and serum neutrophil extracellular trap (NET) markers, in addition to alterations in the neutrophil-to-lymphocyte ratio (NLR). The absence of antiviral drugs and the speed of COVID-19 transmission have had a major impact on public health systems worldwide, leading to the almost total collapse of many national and local healthcare services. Leprosy, an infectious neurological and dermatological illness, is widely considered to be the most frequent cause of physical disabilities globally. The chronic clinical course of the disease may be interrupted by acute inflammatory episodes, named leprosy reactions. These serious immunological complications, characterized by cytokine storms, are responsible for amplifying peripheral nerve damage. From 30% to 40% of all multibacillary leprosy (MB) patients experience erythema nodosum leprosum (ENL), a neutrophilic immune-mediated condition. ENL patients often present these same COVID-19-like symptoms, including high levels of serum NET markers, altered NLR, and neutrophilia. Moreover, the consequences of a M. leprae–SARS-CoV-2 coinfection have yet to be fully investigated. The goal of the present viewpoint is to describe some of the similarities that may be found between COVID-19 and leprosy disease in the context of neutrophilic biology.     

Considerations for Gut Microbiota and Probiotics in Patients with Diabetes Amidst the Covid-19 Pandemic: A Narrative Review

Objective: To review data implicating microbiota influences on Coronavirus Disease 2019 (COVID-19) in patients with diabetes.Methods: Primary literature review included topics: “COVID-19,” “SARS,” “MERS,” “gut micro-biota,” “probiotics,” “immune system,” “ACE2,” and “metformin.”Results: Diabetes was prevalent (~11%) among COVID-19 patients and associated with increased mortality (about 3-fold) compared to patients without diabetes. COVID-19 could be associated with worsening diabetes control and new diabetes diagnosis that could be linked to high expression of angiotensin-converting enzyme 2 (ACE2) receptors (coronavirus point of entry into the host) in the endocrine pancreas. A pre-existing gut microbiota imbalance (dysbiosis) could contribute to COVID-19–related complications in patients with diabetes. The COVID-19 virus was found in fecal samples (~55%), persisted for about 5 weeks, and could be associated with diarrhea, suggesting a role for gut dysbiosis. ACE2 expressed on enterocytes and colonocytes could serve as an alternative route for acquiring COVID-19. Experimental models proposed some probiotics, including Lactobacillus casei, L. plantarum, and L. salivarius, as vectors for delivering or enhancing efficacy of anti-coronavirus vaccines. These Lactobacillus probiotics were also beneficial for diabetes. The potential mechanisms for interconnections between coronavirus, diabetes, and gut microbiota could be related to the immune system, ACE2 pathway, and metformin treatment. There were suggestions but no proof supporting probiotics benefits for COVID-19 infection.Conclusion: The data suggested that the host environment including the gut microbiota could play a role for COVID-19 in patients with diabetes. It is a challenge to the scientific community to investigate the beneficial potential of the gut microbiota for strengthening host defense against coronavirus in patients with diabetes.     

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.     

SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.     

BioEssays 12/2020

The outbreak of a new, potentially fatal virus, SARS-COV-2, which started in December 2019 in Wuhan, China, and since developed into a pandemic has stimulated research for an effective treatment and vaccine. For this research to be successful, it is necessary to understand the pathology of the virus. So far, we know that this virus can harm different organs of the body. Although the exact mechanisms are still unknown, this phenomenon may result from the body's secretion of prostaglandin E2 (PGE2), which is involved in several inflammation and immunity pathways. Noticeably, the expression of this molecule can lead to a cytokine storm causing a variety of side effects. In this paper, we discuss those side effects in SARS-COV-2 infection separately to determine whether PGE2 is, indeed, an important causative factor. Lastly, we propose a mechanism by which PGE2 production increases in response to COVID-19 disease and suggest the possible direct relation between PGE2 levels and the severity of this disease. Also see the video abstract here: https://youtu.be/SnPFAcjxxKw.     

COVID-19: Pathogenesis,cytokine storm and therapeutic potential of interferons

The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).     

Glucocorticoid-Induced Hyperglycemia Including Dexamethasone-Associated Hyperglycemia in COVID-19 Infection: A Systematic Review

ObjectiveOptimal glucocorticoid-induced hyperglycemia (GCIH) management is unclear. The COVID-19 pandemic has made this issue more prominent because dexamethasone became the standard of care in patients needing respiratory support. This systematic review aimed to describe the management of GCIH and summarize available management strategies for dexamethasone-associated hyperglycemia in patients with COVID-19.MethodsA systematic review was conducted using the PubMed/MEDLINE, Cochrane Library, Embase, and Web of Science databases with results from 2011 through January 2022. Keywords included synonyms for “steroid-induced diabetes” or “steroid-induced hyperglycemia.” Randomized controlled trials (RCTs) were included for review of GCIH management. All studies focusing on dexamethasone-associated hyperglycemia in COVID-19 were included regardless of study quality.ResultsInitial search for non-COVID GCIH identified 1230 references. After screening and review, 33 articles were included in the non-COVID section of this systematic review. Initial search for COVID-19–related management of dexamethasone-associated hyperglycemia in COVID-19 identified 63 references, whereas 7 of these were included in the COVID-19 section. RCTs of management strategies were scarce, did not use standard definitions for hyperglycemia, evaluated a variety of treatment strategies with varying primary end points, and were generally not found to be effective except for Neutral Protamine Hagedorn insulin added to basal-bolus regimens.ConclusionFew RCTs are available evaluating GCIH management. Further studies are needed to support the formulation of clinical guidelines for GCIH especially given the widespread use of dexamethasone during the COVID-19 pandemic.     

AntagomiRs: A novel therapeutic strategy for challenging COVID-19 cytokine storm

Is it possible to develop a reliable, safe treatment for the widespread COVID-19 pandemic shortly? COVID-19 is characterized by a disruptive cytokine storm, quickly and often irreversibly damaging the patient’s lungs, as its main target organ, leading to lung failure and death. Actual experimental therapies are trying to reduce the activation of some specific cytokines, such as IL-6, somewhat reducing the burden for the patient. However, they are often unable to block the whole storm occurring at the cytokine level. In presence of the cytokine storm, especially in severe patients, antagomiRs, already demonstrated to be efficient and secure in cardiovascular disease, could represent a useful alternative to such treatment, customizable upon the disease specificities and applicable to other coronaviruses possibly associated with such clinical manifestations, while a reliable, efficient vaccine is being distributed.