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• 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]

• Proteins released by activated endothelial cells due to SARS-CoV2 infections are implicated COVID-19 severity. • The levels of BK, KLK, SERPIN A, IL-18, and ACE2 are directly linked to D-dimer, ferritin, CTSS, and the WHO clinical progression score. • Increased shedding of study proteins, along with D-dimer and ferritin, could be beneficial indicator of COVID-19 pathogenesis. • Machine model analysis demonstrated that SERPIN A could serve as a robust prognostic biomarker for COVID-19 disease severity. • The study supports the idea that COVID-19 is a vascular disease that involves endothelial impairment due to bradykinin/cytokine storm. Host proteins released by the activated endothelial cells during SARS-CoV-2 infection are implicated to be involved in coagulation and endothelial dysfunction. However, the underlying mechanism that governs the vascular dysfunction and disease severity in COVID-19 remains obscure. The study evaluated the serum levels of Bradykinin, Kallikrein, SERPIN A, and IL-18 in COVID-19 (N-42 with 20 moderate and 22 severe) patients compared to healthy controls (HC: N-10) using ELISA at the day of admission (DOA) and day 7 post-admission. The efficacy of the protein levels in predicting disease severity was further determined using machine learning models. The levels of bradykinins and SERPIN A were higher (P ≤ 0.001) in both severe and moderate cases on day 7 post-admission compared to DOA. All the soluble proteins studied were found to elevated (P ≤ 0.01) in severe compared to moderate in day 7 and were positively correlated (P ≤ 0.001) with D-dimer, a marker for coagulation. ROC analysis identified that SERPIN A, IL-18, and bradykinin could predict the clinical condition of COVID-19 with AUC values of 1, 0.979, and 1, respectively. Among the models trained using univariate model analysis, SERPIN A emerged as a strong prognostic biomarker for COVID-19 disease severity. The serum levels of SERPIN A in conjunction with the coagulation marker D-dimer, serve as a predictive indicator for COVID-19 clinical outcomes. However, studies are required to ascertain the role of these markers in disease virulence. [ABSTRACT FROM AUTHOR]

• COVID-19 asymptomatic patients had high levels of IL-8. • IL-12, IL-2, IL-13, IL-17 and GM-CSF were undetectable in COVID-19 asymptomatic patients. • IL-6, IL-10, MIP-1α, MCP-1 and IP-10 are associated with COVID-19 disease progression. • IL-4 tends to decrease with COVID-19 disease progression. • SARS-CoV-2 is associated with the cytokine storm. COVID-19 is a viral infection that disturbs the host's immune system and causes an overproduction of cytokines leading to a cytokine storm. The present study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with COVID-19 disease severity. The serum levels of 89 patients with different degrees of COVID-19 disease severity [asymptomatic (n = 14), moderate (n = 14), severe (n = 30), and critical (n = 31)] and 14 healthy individuals were tested for a panel of 27 cytokines and chemokines using Luminex assay (27 Bio‑Plex Pro Human Cytokine, Bio-rad™). IL-12, IL-2 and IL-13, as well as IL-17 and GM-CSF were clearly undetectable in asymptomatic patients. IL-8 levels were higher in asymptomatic compared with other groups. Very high levels of IL-6, IL-10 and the chemokines MIP-1α, MCP-1 and IP10 were associated with disease progression, while IL-4 tends to decrease with disease severity. Our study provides more evidence that excessive cytokine synthesis is linked to the disease progression. [ABSTRACT FROM AUTHOR]

• Intraperitoneal injection of ZY can induce sterile sepsis model in rats that is dose-dependent. • Preemptive application of eLIR can establish focal inflammatory sites on the body surface, thus shifting the pro-inflammatory to anti-inflammatory milieu. This modulation is instrumental in diminishing the risk of cytokine storm and subsequent mortality by influencing the levels of inflammatory cytokines at critical junctures of in vivo inflammation exacerbation. • Notably, compared to being implemented immediately after the onset of inflammation, this strategy proved more efficacious when implemented prior to the acute phase of inflammation, underscoring the significance of intervention timing. • The anti-inflammatory process should be dynamically analyzed on the time axis. The emergence of severe sepsis is contingent upon the occurrence of a cytokine storm (CS), a multifaceted process intricately entwined with the temporal dimension, thereby rendering the infection response remarkably intricate. Consequently, it becomes imperative to discern and accurately identify the optimal timing for interventions, predicated upon the dynamic timeline of inflammatory changes. Moreover, the administration of exogenous low-dose pro-inflammatory agents has exhibited the potential to impede the relentless progression of the inflammatory cascade. Hence, the present study aims to scrutinize the impact of exogenous Local Inflammatory Response (eLIR) on the body surface in the context of the inflammatory cascade during sepsis, within a temporal framework, with a particular emphasis on the point of exacerbation of inflammation. Rats were induced sterile sepsis by intraperitoneal injection of zymosan (ZY) at an appropriate dosage. The temporal progression of inflammatory changes and eLIR effects were described based on the trend of serum crucial inflammatory cytokines, tring to quest time-point of inflammatory aggravation in sepsis. Then, the varying degrees of surface inflammation caused by eLIR on this time point leading to the final effects on the inflammatory cascade response were explored. In addition, given the authentic pathological progression of sepsis, further observation was conducted on the impact of another intervention timing of eLIR on the inflammatory cascade. The survival rate was measured. Serum and organ related inflammatory cytokines were detected, and organ histopathology was investigated. In present study, a dosage of 600 mg/kg ZY was found to be optimal for the sterile sepsis model. Initiating eLIR 6 h prior to ZY injection, the maximum effect point of eLIR could be precisely align with the inflammatory aggravation point of sterile sepsis. Initiating eLIR at this time, 3 sessions of eLIR were found to be more effective than 1 or 2 sessions in mitigating inflammatory responses during the initial stage of inflammation and the peak of inflammation. Notably, the findings also suggested that this intervention improve survival rate. In addition, the anti-inflammatory efficacy has been substantially diminished by the prompt initiation of 3 sessions of eLIR immediately after ZY injection at the onset of sepsis. Similarly, the current findings did not demonstrate a statistically significant enhancement in survival rates with eLIR at this time point. Compared with the initial stage of inflammation, low-scale inflammation caused by a certain intensity of eLIR (3 sessions) on the body surface can more effectively pry the inflammation aggravation time-point, thereby shifting the pro-inflammatory to anti-inflammatory milieu, impeding the disproportionate cytokines release in inflammatory diseases, slowing down the inflammatory cascade, and improving the survival rate of sepsis. [ABSTRACT FROM AUTHOR]

• In CHF, damaged myocardium sends a signal to stimulate the immune system. In continuous, cytokine storm is initiated and causes the probability of CHF and persistent inflammation causes remodeling. • CRT is an effective treatment for CHF and can be beneficial to management of heart failure. Congestive heart failure (CHF) is a complex multistage syndrome that has a great financial burden on human societies. It was known that the damaged myocardium sends a signal to stimulate the immune system and proliferation of leukocytes. In continuous, cytokine storm can be initiated and causes the probability of CHF. Persistent inflammation by increasing the levels of pro-inflammatory cytokines, plays an important role in the pathogenesis of CHF and causes remodeling, which is a progressive processs. Although treatment by drugs can reduce mortality and partially control the symptoms of heart failure patients, but complications and mortality are still high. Therefore, other treatment options such as Cardiac Resynchronization Therapy (CRT) are necessary. Today, it is known that CRT can be an effective treatment for many patients with heart failure. CRT is novel, non-pharmacological, and device-based therapy that would be beneficial to know more about its performance in the management of heart failure. In this study, we have reviewed the immunological processes involved in heart failure and the effect of CRT in controlling of the cytokine storm. [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]

[Display omitted] • An update on lymphocytopenia induced by severe SARS-CoV disease and influenza A infections. • Apoptosis and sequestration are reportedly amongst two principal modes of CD4+/CD8+ leukodepletion. • A novel "Index Severity Score" of infection was classified in conjunction with depleted T -cell counts. • A total T -cell threshold of <=560 cell/uL, a predictor of advanced infection, escalated mortality; and a tool guiding clinical trials of new therapeutics. • Future research in progress to identify quantifiable relationships between T -cell counts, cytokines, inflammatory and coagulation markers in conjunction with disease severity. We proposed T -cell lymphocytopenia as a strategic predictor of serious coronavirus and influenza infections. Our preeminent goal was to determine whether a degree of T -cell lymphopenia would identify a distinct threshold cell count to differentiate between severe and non-severe infections. We codified an Index Severity Score to exploit an association between T -cell cytopenia and the grade of disease activity. A T -cell count of 560 cells/uL or below signified a trend towards advanced disease. (1.) The T -cell threshold > 560 cells/uL discriminated 85.7 % specificity of the lesser viral infections and <=560 cells/uL identified 100 % sensitivity of severe infections or death. (2.) The positive predictive value of this threshold test was 92.9 %. (3.) T -cell apoptosis and sequestration are two of the primary mechanisms of T -cell lymphodepletion. (4.) There is potential for the T -cell threshold at <=560 cells/uL to become a standard to differentiate disease severity. (5.) The T-cell threshold should be tested further against flow cytometry of CD4+, CD8+ counts of individual patients. (6.) Future research should explore correlations between the T -cell threshold, medical outcomes of treatment, Cytokine Release Syndromes, cytokine levels, inflammatory and coagulation markers. [ABSTRACT FROM AUTHOR]

In October 2013, the International Life Sciences Institute - Health and Environmental Sciences Institute Immunotoxicology Technical Committee (ILSI-HESI ITC) held a one-day workshop entitled, “Workshop on Cytokine Release: State-of-the-Science, Current Challenges and Future Directions”. The workshop brought together scientists from pharmaceutical, academic, health authority, and contract research organizations to discuss novel approaches and current challenges for the use of in vitro cytokine release assays (CRAs) for the identification of cytokine release syndrome (CRS) potential of novel monoclonal antibody (mAb) therapeutics. Topics presented encompassed a regulatory perspective on cytokine release and assessment, case studies regarding the translatability of preclinical cytokine data to the clinic, and the latest state of the science of CRAs, including comparisons between mAb therapeutics within one platform and across several assay platforms, a novel physiological assay platform, and assay optimization approaches such as determination of FcR expression profiles and use of statistical tests. The data and approaches presented confirmed that multiple CRA platforms are in use for identification of CRS potential and that the choice of a particular CRA platform is highly dependent on the availability of resources for individual laboratories (e.g. positive and negative controls, number of human blood donors), the assay through-put required, and the mechanism-of-action of the therapeutic candidate to be tested. Workshop participants agreed that more data on the predictive performance of CRA platforms is needed, and current efforts to compare in vitro assay results with clinical cytokine assessments were discussed. In summary, many laboratories continue to focus research efforts on the improvement of the translatability of current CRA platforms as well explore novel approaches which may lead to more accurate, and potentially patient-specific, CRS prediction in the future. [ABSTRACT FROM AUTHOR]

• Meta-summary highlights potential conserved COVID-19 severity biomarkers. • FGG, SERPINA3, IL10, CRP and d -dimer are increased in three severe COVID-19 studies. • IGFBP3 is decreased in three severe COVID-19 studies. • IL6 is a master regulator of COVID-19 severity biomarkers. • Drugs that manipulate these proteins may modulate COVID-19 disease severity. With the rising demand for improved COVID-19 disease monitoring and prognostic markers, studies have aimed to identify biomarkers using a range of screening methods. However, the selection of biomarkers for validation from large datasets may result in potentially important biomarkers being overlooked when datasets are considered in isolation. Here, we have utilized a meta -summary approach to investigate COVID-19 biomarker datasets to identify conserved biomarkers of COVID-19 severity. This approach identified a panel of 17 proteins that showed a consistent direction of change across two or more datasets. Furthermore, bioinformatics analysis of these proteins highlighted a range of enriched biological processes that include inflammatory responses and compromised integrity of physiological systems including cardiovascular, neurological, and metabolic. A panel of upstream regulators of the COVID-19 severity biomarkers were identified, including chemical compounds currently under investigation for COVID-19 treatment. One of the upstream regulators, interleukin 6 (IL6), was identified as a "master regulator" of the severity biomarkers. COVID-19 disease severity is intensified due to the extreme viral immunological reaction that results in increased inflammatory biomarkers and cytokine storm. Since IL6 is the primary stimulator of cytokines, it could be used independently as a biomarker in determining COVID-19 disease progression, in addition to a potential therapeutic approach targeting IL6. The array of upstream regulators of the severity biomarkers identified here serve as attractive candidates for the development of new therapeutic approaches to treating COVID-19. In addition, the findings from this study highlight COVID-19 severity biomarkers which represent promising, robust biomarkers for future validation studies for their use in defining and monitoring disease severity and patient prognosis. [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]

• IL-6 might be a target of specific intervention in severe COVID-19. • Hemoperfusion and anti IL-6 drugs use have been reported in COVID-19 patients. • vv-ECMO support might worsen COVID-19-related cytokine release syndrome. • HA-380 hemoperfusion filter reduces IL-6 concentration. • Hemodynamic, renal and chest X ray improvement might be related to cytokines removal. [ABSTRACT FROM AUTHOR]

A synergistic impact of virulence capacity of dengue viruses and host immune response contributes to the pathogenesis of dengue virus infection (DENV). Elevation of hepatic enzyme and cytokine storm is the major contributory factor producing severity. IL-2 and IL-18 both play a critical role in generating immunogenicity during viral infection. The goal of the study was to evaluate the correlation between alterations in IL-2 and IL-18 levels with alterations in hepatic enzymes in dengue-infected patients. Accordingly, a total of 91 NS1/IgM confirmed DENV infected patients were selected for the IL-2 and IL-18 evaluation using a standard ELISA assay. Biochemical, haematological parameters were recorded at the time of admission. Interestingly, raised levels of IL-2 (p < 0.0001) and IL-18 (p < 0.0001) was obtained in severe dengue as compared to non-severe dengue patients. A significant positive correlation was observed between IL and 2 levels and SGOT (r = 0.3168 with p = 0.002), SGPT (r = 0.569 with p < 0.0001). Similarly IL-18 was also highly associated with SGOT (r = 0.387 with p = 0.0002) and SGPT (r = 0.407 with p < 0.0001) in dengue infected patient.Our data reveal that a rising amount of IL-2 and IL-18 in initial stage of the disease could be predictors for developing severe form of dengue infection. [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]

• Anti-IL-1 drugs may offer an important and safe treatment option in hyperinflammatory COVID-19. • Case reportsand clinicaltrials of anti-IL-1 drugs as anti-inflammation agent in severely COVID-19 so far. • The summary of registered clinical trials of anakinra for COVID-19 so far. The overproduction of proinflammatory cytokines, resulting in what has been described as a cytokine storm or cytokine release syndrome (CRS), may be the key factor in the pathology of severe coronavirus disease 2019 (COVID-19) and is also a crucial cause of death from COVID-19. With the purpose of finding effective and low-toxicity drugs to mitigate CRS, IL-1 blockade agents, which are one of the safest ways to stop this overwhelming innate immune response, are already available in several preliminary reports or are under observational trials and may offer an important treatment option in hyperinflammatory COVID-19. In this review, we described the key information in both case reports and clinical studies on the potential beneficial features of IL-1 inhibitors in COVID-19 patients. [ABSTRACT FROM AUTHOR]

• Severe COVID-19 is associated with increased plasma concentrations of IL-6. • Tocilizumab, an interleukin-6 inhibitor, might alleviate the cytokine storm. • Tocilizumab treated group has better clinical outcome, laboratory results, and swab conversion. • The benefit from tocilizumab is more significant in severe COVID-19 patients. • Therefore, tocilizumab might be one of the promising therapies for severe COVID-19. COVID-19 is a public health emergency of international concern with millions confirmed cases globally including in Indonesia with more than two hundred thousand confirmed cases to date COVID-19. (1) COVID-19 has wide clinical manifestation ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitates mechanical ventilation and support in an ICU, to MODS. (2) Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease. (3)–(5) Severe COVID-19 is associated with increased plasma concentrations of IL-6, resulting in cytokine storm. (6) Tocilizumab, an interleukin-6 inhibitor, might alleviates the cytokine storm, prevents significant lungs and organs damage, thus improving clinical outcomes. (7) Therefore, tocilizumab, might be one of the promising therapies for severe COVID-19. (8) However there were limited studies regarding the efficacy in COVID-19 patients, especially with control group. We would like to report our experience in using tocilizumab as treatment in severe COVID-19 patients in Indonesia, which is the first in Indonesia to the best of our knowledge. [ABSTRACT FROM AUTHOR]

• COVID-19 can have CNS and PNS neurological manifestations. • Headache and hyposmia are common neurological symptoms. • COVID-19 could trigger cytokine storm. • COVID-19 neurological sequalae may be due to viral neuroinvasion and cytokine storm. • Cytokine storm-targeting therapies may help manage COVID-19 neurological symptoms. The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19. [ABSTRACT FROM AUTHOR]

• Fifteen cytokines were increased at ICU admission in Covid-19 patients. • A relatively moderate increase in cytokine concentrations was observed. • IL-1ra, IL-6 and IP-10 correlated with respiratory failure and acute kidney injury. • IL-8 may be a future biomarker due to its correlation with 30-day mortality. The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients. 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality. A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality. The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission. [ABSTRACT FROM AUTHOR]

• The early and late plasma levels of IL-6, IL-8 and IL-5 elevated significantly in deceased patients. • IL-6, IL-8 and IL-5 located at the center of an inter-correlated cytokine network. • The early plasma levels of IFN-a and IL-2 positively correlated with the length of disease course. The hyper-inflammatory response is thought to be a major cause of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Although multiple cytokines are reportedly associated with disease severity, the key mediators of SARS-CoV-2 induced cytokine storm and their predictive values have not been fully elucidated. The present study analyzed maximal and early (within 10 days after disease onset) concentrations of 12-plex cytokines in plasma. We found consistently elevated plasma levels of IL-6, IL-8 and IL-5 in patients who were deceased compared with those who had mild/moderate or severe disease. The early plasma concentrations of IFN-a and IL-2 positively correlated with the length of the disease course. Moreover, correlation network analysis showed that IL-6, IL-8, and IL-5 located at the center of an inter-correlated cytokine network. These findings suggested that IL-8, IL-6, IL-5 might play central roles in cytokine storms associated with COVID-19 and that the early detection of multiple plasma cytokines might help to predict the prognosis of this disease. [ABSTRACT FROM AUTHOR]

• Highest cytokine and chemokine levels were noted in the first 24 h in HSES. • GDF-15 levels were significantly higher in patients with HSES in the first 24 h. • The levels of IL-2 and IL-4 did not differ between HSES patients and controls. Patients with hemorrhagic shock and encephalopathy syndrome (HSES) have a high early mortality rate, which may be caused by a 'cytokine storm'. However, there is little information on how cytokines and chemokines change over time in these patients. We aimed to describe the characteristics of HSES by examining changes in serum biomarker levels over time. Six patients with HSES were included. We retrospectively evaluated their clinical course and imaging/laboratory data. We measured serum levels of multiple cytokines [interleukin 1β (IL-1β), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma, and tumor necrosis factor alpha], chemokines (IL-8, monocyte chemoattractant protein-1, interferon-inducible protein-10), and growth and differentiation factor (GDF)-15. The highest cytokine and chemokine levels were noted in the first 24 h, and decreased thereafter. The GDF-15 level was markedly high. Cytokine, chemokine, and GDF-15 levels were significantly higher in patients with HSES than in controls in the first 24 h, except for IL-2 and IL-4. Patients with HSES have high inflammatory cytokine and chemokine levels, a high GDF-15 level in the first 24 h, and high lactate levels. Our study provides new insights on the pathophysiology of HSES, a detailed clinical picture of patients with HSES, and potential biomarkers. [ABSTRACT FROM AUTHOR]

• Inhibition of IL-6 trans-signaling is crucial to rescue from cytokine storm. • sgp130Fc selectively inhibit IL-6 trans-signaling. • ADAM17/TACE prodomain inhibitor (TPD) effectively stop ADAM17 shedding activity. • Combination of sgp130Fc and TPD have potentiality to reduce cytokine storm in COVID-19. • Future trial may consider combination of sgp130Fc, TPD, anti-coagulant and antivirals for severe cases. The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations. [ABSTRACT FROM AUTHOR]

• Increased activity of the RAAS system occurs in the COVID-19 induced cytokine storm. • The COVID-19 induced cytokine storm is accompanied with attenuation of MasR activity. • The SARS-CoV-2 associated ACE2 induces DABK and BKB1R hyper-activation. • The COVID-19 induced cytokine storm leads to hyperactivity of the complement system. Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]