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Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage. [Display omitted] • COVID-19 leads to hyperinflammation and endothelial dysfunction, resulting in pulmonary and vascular complications. • NOand H 2 S are endogenous gasotransmitters with antiviral, anti-inflammatory, and anti-thrombotic activity. • Modulation of NO and H 2 S levels may be protective against pulmonary and vascular complications in viral infections. • Further investigation into efficacy, dosage, delivery methods, and timing of therapy is necessary. [ABSTRACT FROM AUTHOR]

• Evidence indicates that a cytokine storm is involved in the pathophysiology of monkeypox. • We hypothesize that purinergic signaling plays a role in the cytokine storm seen in monkeypox. • Modulating purinergic receptors could help mitigate the cytokine storm. • Our findings offer fresh perspectives on the connection between purinergic signaling and human monkeypox. Some evidence has indicated that monkeypox can induce a cytokine storm. Purinergic signaling is a cell pathway related to the cytokine storm. However, the precise mechanisms that lead to cytokine storms in monkeypox infections and the possible involvement of purinergic signaling in the immune response to this virus remain unknown. In this review article, we aimed to highlight a body of scientific evidence that consolidates the role of the cytokine storm in monkeypox infection and proposes a new hypothesis regarding the roles of purinergic signaling in this immune-mediated mechanism. We further suggested some purinergic signaling modulators to mitigate the deleterious and aggravating effects of immune dysregulation in human monkeypox virus infection by inhibiting P2X3, P2X7, P2Y2, and P2Y12, reducing inflammation, and activating A1 and A2A receptors to promote an anti-inflammatory response. [ABSTRACT FROM AUTHOR]

A key component of severe COVID-19 is a "cytokine storm" i.e., the excessive expression of unneeded cytokines. Previous studies suggest that SARS-CoV-2 proteins can induce macrophages to secrete pro-inflammatory cytokines; a process that may involve Toll-like receptors (TLRs). Glycogen synthase kinase-3 (GSK-3) has been implicated in TLR signal transduction and a selective GSK-3 inhibitor, termed COB-187, dramatically attenuates cytokine expression induced by the TLR ligand lipopolysaccharide (LPS). In the present study, we provide evidence that the SARS-CoV-2 spike protein (S) and the S2 subunit (S2) induce production of CXCL10 (a chemokine elevated in severe COVID-19) by a human macrophage cell line. Further, we report that two clinically relevant GSK-3 inhibitors and COB-187 attenuate S and S2 protein-induced CXCL10 production. Combined, our observations provide impetus for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19. • Cytokine storms, the overexpression of unneeded cytokines, are a key aspect of severe COVID-19. • CXCL10, a chemokine, has been shown to be elevated in severe COVID-19. • We provide evidence that the SARS-CoV-2 spike protein induces expression of CXCL10 by a human macrophage cell line. • Two clinically relevant GSK-3 inhibitors, and GSK-3 inhibitor COB-187, attenuate spike protein-induced CXCL10 expression. • These findings provide impetus for exploring GSK-3 inhibitors as potential therapeutics for severe COVID-19. [ABSTRACT FROM AUTHOR]

• Cytokine storm/excessive pro-inflammatory is the major causes of pathology in COVID-19, malaria and other infectious diseases. • Relationship of inflammation, viral infection and the coagulation system is covered. • Targeting an excessive pro-inflammatory response and coagulation could be crucial in COVID-19 and P. falciparum -caused malaria. Infectious diseases are affecting the people worldwide. Mostly, infectious agents activate excessive production of cytokines so called cytokine storm. Among the infectious diseases COVID-19 is one of the deadliest diseases affecting individuals all over the world, moreover, Plasmodium falciparum malaria and HIV are major killers. An excessive pro-inflammatory response is one of the major causes of pathological conditions in these diseases. It is important to investigate the pathophysiology in the infectious diseases such as COVID-19, malaria and HIV as there is no concrete therapy against them so far. Exploration of excessive pro-inflammation could be important for therapeutic intervention. In this article, an attempt has been made to analyze the pathological conditions arise due to excessive inflammatory response in COVID-19, malaria and other infectious diseases. Targeting excessive pro-inflammatory response/cytokine storm in infectious diseases could be a useful strategy. [ABSTRACT FROM AUTHOR]

• Anakinra is an adjuvant treatment in severe COVID-19 by blocking IL-1. • We aimed to summarize the studies that evaluated its the safety and efficacy. • 23 studies and 3179 patients were incorporated in the study. • Anakinra had some promising results in COVID-19 by reducing mortality and need of invasive mechanical ventilation. • Anakinra may be effective in immunocompromised cases. The most important presentation of COVID-19 is hyper inflammatory condition and cytokine storm that occurs due to excessive increase of the inflammatory mediators specially, pro-inflammatory interleukins such as IL-1β, IL-6 and tumor necrosis factor-α which have an important role in the cytokine storm pathway. Up till now there is not a definitive treatment for COVID-19 disease, but according to the pathophysiology of the disease, Anakinra (Interleukin- 1 inhibitor) is an adjuvant treatment option in patients with severe COVID-19 by blocking the effect of IL-1. So, we aimed to summarize the studies that evaluated the safety and efficacy of Anakinra in patients diagnosed with COVID-19. We performed a search in PubMed, Cochrane Library, Scopus, and Web of Science (WOS) databases from inception till 7 Jan 2022. Additionally, we searched randomized and non-randomized clinical trials, cohort, case series, case control, case report more than 3 patients which contain confirmed cases of COVID-19 who received Anakinra (Interleukin- 1 inhibitor) for the management of hyper-inflammatory condition associated with COVID-19 disease. A meta-analysis was conducted using review manager 5.4. We included 44 articles in the systematic review. Ultimately, 23 studies were incorporated in the meta-analysis with a total number of 3179 patients. Our analysis showed statistically significant difference in the following outcomes: duration of ICU stays [MD = −0.65, 95% CI (−1.09, −0.03), p = 0.04], the number of patients who needed invasive mechanical ventilation [RR = 0.57, 95% CI (0.39, 0.84), p = 0.004], and number of deaths [RR = 0.80, 95% CI (0.66, 0.99), p = 0.04]. Our analysis showed no statistically significant difference in the following outcomes: length of hospital stays [MD = −0.16, 95% CI (−0.42, 0.11), p = 0.26], oxygen-free days [MD = −0.81, 95% CI (−3.81, 2.20), p = 0.60], and the number of patients who needed non-invasive mechanical ventilation [RR = 1.09, 95% CI (0.47, 2.52), p = 0.84]. Anakinra showed some promising results in important outcomes related to COVID-19 as it significantly reduced the rate of mortality and the need of invasive mechanical ventilation. It should be used in severe cases more than mild and moderate cases to avoid possible immunosuppression complications. Anakinra use is safe in cases of COVID-19 at dose less than 100 mg. Another important outcome was significant reduction is the D-dimer level. Anakinra may be effective in the treatment of specific immunocompromised cases, but it should be used cautiously. [ABSTRACT FROM AUTHOR]

[Display omitted] • SARS-CoV-2 mediated cytokine storm is associated with the mortality and morbidity of COVID-19 patients. The key cytokines implicated in the onset of disease severity include TNF-α, IFN-γ, IL-6, IL-1β, GM-CSF, and G-CSF. • This review emphasizes the role of GM-CSF and G-CSF in COVID-19. • Emerging therapeutic interventions involve antibodies against TNF-α and IFN-γ, blocking IL-1 production, anti-IL-6 receptor antagonists, JAK-STAT inhibitors, and employment of mesenchymal stem cells and therapeutic plasma exchange. COVID-19 has claimed millions of lives during the last 3 years since initial cases were reported in Wuhan, China, in 2019. Patients with COVID-19 suffer from severe pneumonia, high fever, acute respiratory distress syndrome (ARDS), and multiple-organ dysfunction, which may also result in fatality in extreme cases. Cytokine storm (CS) is hyperactivation of the immune system, wherein the dysregulated production of proinflammatory cytokines could result in excessive immune cell infiltrations in the pulmonary tissues, resulting in tissue damage. The immune cell infiltration could also occur in other tissues and organs and result in multiple organs' dysfunction. The key cytokines implicated in the onset of disease severity include TNF-α, IFN-γ, IL-6, IL-1β, GM-CSF, and G-CSF. Controlling the CS is critical in treating COVID-19 disease. Therefore, different strategies are employed to mitigate the effects of CS. These include using monoclonal antibodies directed against soluble cytokines or the cytokine receptors, combination therapies, mesenchymal stem cell therapy, therapeutic plasma exchange, and some non-conventional treatment methods to improve patient immunity. The current review describes the role/s of critical cytokines in COVID-19-mediated CS and the respective treatment modalities. [ABSTRACT FROM AUTHOR]

[Display omitted] • Etoposide is a 40-year-old anticancer drug targeting topoisomerase II-DNA complexes. • The drug displays immune-modulatory effects useful to reduce the cytokine storm syndrome. • Etoposide is used to treat hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). • The mode of action of etoposide in HLH/MAS is discussed. For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced small-cell lung cancer and in various chemotherapy regimen for autologous stem cell transplantation, and other anticancer protocols. Etoposide is a potent topoisomerase II poison, causing double-stranded DNA breaks which lead to cell death if they are not repaired. It is also a genotoxic compound, responsible for severe side effects and secondary leukemia occasionally. Beyond its well-recognized function as an inducer of cancer cell death (a "killer on the road"), etoposide is also useful to treat immune-mediated inflammatory diseases associated with a cytokine storm syndrome. The drug is essential to the treatment of hemophagocytic lymphohistiocytosis (HLH) and the macrophage activation syndrome (MAS), in combination with a corticosteroid and other drugs. The use of etoposide to treat HLH, either familial or secondary to a viral or parasitic infection, or treatment-induced HLH and MAS is reviewed here. Etoposide dampens inflammation in HLH patients via an inhibition of the production of pro-inflammatory mediators, such as IL-6, IL-10, IL-18, IFN-γ and TNF-α, and reduction of the secretion of the alarmin HMGB1. The modulation of cytokines production by etoposide contributes to deactivate T cells and to dampen the immune stimulation associated to the cytokine storm. This review discussed the clinical benefits and mechanism of action of etoposide (a "rider on the storm") in the context of immune-mediated inflammatory diseases, notably life-threatening HLH and MAS. The question arises as to whether the two faces of etoposide action can apply to other topoisomerase II inhibitors. [ABSTRACT FROM AUTHOR]

The emergence of Coronavirus disease 2019 (Covid-19) is a global problem nowadays, causing health difficulty with increasing mortality rates, which doesn't have a verified treatment. SARS-CoV-2 infection has various pathological and epidemiological characteristics, one of them is increased amounts of cytokine production, which in order activate an abnormal unrestricted response called "cytokine storm". This event contributes to severe acute respiratory distress syndrome (ARDS), which results in respiratory failure and pneumonia and is the great cause of death associated with Covid-19. Endotoxemia and the release of bacterial lipopolysaccharides (endotoxins) from the lumen into the bloodstream enhance proinflammatory cytokines. SARS-CoV-2 can straightly interplay with endotoxins via its S protein, leading to the extremely elevating release of cytokines and consequently increase the harshness of Covid-19. In this review, we will discuss the possible role of viral-bacterial interaction that occurs through the transfer of bacterial products such as lipopolysaccharide (LPS) from the intestine into the bloodstream, exacerbating the severity of Covid-19 and cytokine storms. • SARS-CoV-2 infection can increased amounts of cytokine production. • Interaction between viral and bacterial can be transfer bacterial products into the bloodstream. • SARS-CoV-2 infection can be activated an abnormal unrestricted response called "cytokine storm. [ABSTRACT FROM AUTHOR]

[Display omitted] • The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml, and 5.5 pg/ml in healthy persons. • Pooled estimate means for IL-1β and IFN-γ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. • A TNF-α cutoff level ≥14.7 pg/mL separated sepsis patients from healthy persons with a sensitivity of 82.6%, and a specificity of 91.7% • Elevated TNFα concentrations associated with increased 28-day sepsis mortality but not with sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. • As causative of sepsis pathogenesis, elevated pro-inflammatory cytokine levels need to be revisited. Sepsis is a global health challenge associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to excessive inflammation or a "cytokine storm." However, anti-inflammation therapies have failed to lower sepsis mortality. We aim to characterize levels of key inflammatory cytokines in patients with sepsis and compare levels with those in healthy individuals and relate tumor necrosis factor (TNF) α levels to patient characteristics and outcomes. We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched between 1985 and May 2020. Analysis was restricted to studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy individuals. The Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800). We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8–85.8 pg/ml), and in healthy individuals was 5.5 pg/ml (95% CI 3.8–8.0 pg/ml). Pooled estimate means for IL-1β and IFN-γ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNFα concentrations associated with increased 28-day sepsis mortality (p = 0.001). In subgroup analyses, we did not detect an association between TNFα levels and sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. A TNF-α cutoff level ≥14.7 pg/ml separated sepsis patients from healthy individuals with a sensitivity of 82.6%, a specificity of 91.7%, and a likelihood ratio of 9.9. Sepsis mean TNFα concentration is increased approximately 10-fold compared to mean concentration in healthy individuals, and TNFα associated with sepsis mortality but not sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data. None. [ABSTRACT FROM AUTHOR]

Patients with SARS-CoV-2 infection, exhibit various clinical manifestations and severity including respiratory and enteric involvements. One of the main reasons for death among covid-19 patients is excessive immune responses directed toward cytokine storm with a low chance of recovery. Since the balanced gut microbiota could prepare health benefits by protecting against pathogens and regulating immune homeostasis, dysbiosis or disruption of gut microbiota could promote severe complications including autoimmune disorders; we surveyed the association between the imbalanced gut bacteria and the development of cytokine storm among COVID-19 patients, also the impact of probiotics and bacteriophages on the gut bacteria community to alleviate cytokine storm in COVID-19 patients. In present review, we will scrutinize the mechanism of immunological signaling pathways which may trigger a cytokine storm in SARS-CoV2 infections. Moreover, we are explaining in detail the possible immunological signaling pathway-directing by the gut bacterial community. Consequently, the specific manipulation of gut bacteria by using probiotics and bacteriophages for alleviation of the cytokine storm will be investigated. The tripartite mutualistic cooperation of gut bacteria, probiotics, and phages as a candidate prophylactic or therapeutic approach in SARS-CoV-2 cytokine storm episodes will be discussed at last. • The gut microbiota regulates multiple host functions, including immune homeostasis. • The imbalanced gut microbiota could act as one of the main factors in formation of cytokine storm in COVID-19. • Some probiotics and phages could potentially prevent the formation of cytokine storms. • The targeted manipulation of gut microbiome could potentially decrease the risk of development of cytokine storm in COVID-19. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) infection evokes severe proinflammatory storm and pulmonary infection with the number of confirmed cases (more than 200 million) and mortality (5 million) continue to surge globally. A number of vaccines (e.g., Moderna, Pfizer, Johnson/Janssen and AstraZeneca vaccines) have been developed over the past two years to restrain the rapid spread of COVID-19. However, without much of effective drug therapies, COVID-19 continues to cause multiple irreversible organ injuries and is drawing intensive attention for cell therapy in the management of organ damage in this devastating COVID-19 pandemic. For example, mesenchymal stem cells (MSCs) have exhibited promising results in COVID-19 patients. Preclinical and clinical findings have favored the utility of stem cells in the management of COVID-19-induced adverse outcomes via inhibition of cytokine storm and hyperinflammatory syndrome with coinstantaneous tissue regeneration capacity. In this review, we will discuss the existing data with regards to application of stem cells for COVID-19. Proposed mechanisms for MSCs function in severe COVID-19 patients. [Display omitted] [ABSTRACT FROM AUTHOR]

• Cytokine storms of different diseases including COVID-19 have shared abnormalities. • Elevated levels of TNF-α, IL-6, IL-1β, NFκB are common immune abnormalities. • Inflammasome activation and release of DAMPs is common to COVID-19, H1N1, and MAS. • Anakinra may adjust the biochemical and immune abnormalities reported in COVID-19. An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1β, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended. [ABSTRACT FROM AUTHOR]

• High number of deaths due to COVID-19 have been found in Mexican patients. • IL-6 can be used as biomarker of mortality in COVID-19 patients form Mexico. • IL-6 is correlated to high levels of CRP, LDH, procaciltonin and lymphopenia. The first case of SARS-CoV-2 in Mexico was reported in February 2020, since then, high rates of mortality due to COVID-19 have been found. Cytokine storm is linked to the severity and decreasing the survival among infected patients by COVID-19. The serum levels of Interleukin 6 (IL-6) have been correlated to mortality in COVID-19 cases and could be used as indicator of mortality in COVID-19 cases. The aim of this study was to determine levels of IL-6 and assess its usefulness as indicator of mortality among COVID-19 patients from Mexico. A cohort study among 38 adults (28 men, 10 women) was carried out in the Regional High Specialty Hospital of the Yucatan Peninsula in Merida, Yucatan, Mexico. Demographic and clinical biochemistry data were collected. The serum levels of IL-6 were measured in each patient by specific immunoassays. High frequency of mortality (36.84%) was found in the sample. The average age of individuals that non-survive was significantly higher (59.71 ± 13.83 years) than the survival group (43.29 ± 11.80 years). Serum levels of IL-6 were significantly higher in patients that did not survive. A correlation between IL-6 levels with lymphocyte count, LDH, CRP and procaciltonin was found. The optimal cutoff value of IL-6 was 30.95 pg/mL with high sensitivity and specificity. Our findings demonstrate that level of IL-6 is an indicator of mortality among hospitalized COVID-19 patients in Mexico. [ABSTRACT FROM AUTHOR]