Cytokine Storm Research Articles

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Efficacy and Safety of Tocilizumab with Methylprednisolone versus Methylprednisolone Only as a Treatment for Severe Covid-19 Patients

Abstract Background SARS-CoV-2 was identified as a worldwide fatal pandemic that causes acute respiratory infections. The aim of this work was to compare the effect of Using combined therapy: (tocilizumab with Methylprednisolone) versus using (Methylprednisolone alone) as immuno-modulatory therapy on 28 days mortality mortality, need for mechanical ventilation & adverse effects. Methods This retrospective observational cohort study was carried out on 60 patients diagnosed as having covid 19 infection with cytokine storm and severe acute respiratory syndrome during the period(2020-2021). Patients were divided into 2 groups: (TCZ+MP)group received 2 doses of tocilizumab within 24 hrs (5 mg/kg in each dose) in addition to a dose of methylprednisolone(2mg/kg/day)for7days and(MP)group:received only a dose of methylprednisolone (2 mg\kg\day) for 7days. All patients were subjected to routine laboratory investigations (Complete blood count, liver function tests, kidney function tests, LDH, ferritin, D-dimer, frequent ABGs (P/F ratio), CRP, IL6, procalcitonin& albumin), and radiology investigation (Chest x-ray and CT chest). Results 60 patients with ARDS(both genders) were included in this study, in TCZ+MPgroup, 8(26.67%) of 30 patients died, compared to 17(56,67%) of 30patients in (MP)group, so mortality rate was significantly lower in patients on TCZ+MPgroup than those on (MP)group (P value =0.018). In TCZ+MPgroup, 12(40%) of 30 patients needed mechanical ventilation compared to 22(73.33%) of 30 patients in MP group, so Number of patients who required mechanical ventilation was significantly lower in patients on TCZ+MPgroup than MP group (P value = 0.009). Adverse effects of intervention drugs after 28 days were insignificantly different between both groups (P value = 0.018). Conclusions In patients with severe COVID-19 infection, combination therapy of tocilizumab &methylprednisolone reduced mortality rate and need for mechanical ventilation as compared with the use of methylprednisolone alone.

Network-based Multi-omics Disease–Drug Associations Reveal Drug Repurposing Candidates for Covid-19 Disease Phases

Background The development and rollout of vaccines and the use of various drugs have contributed to controlling the coronavirus disease 2019 (Covid-19) pandemic. Nevertheless, challenges such as the inequitable distribution of vaccines, the influence of emerging viral lineages and immunoevasive variants on vaccine efficacy, and the inadequate immune defense in subgroups of the population continue to motivate the development of new drugs to combat the disease. Aim In this study, we sought to identify, prioritize, and characterize drug repurposing candidates appropriate for treating mild, moderate, or severe Covid-19 using a network-based integrative approach that systematically integrates drug-related data and multi-omics datasets. Methods We leveraged drug data and multi-omics data and used a random walk with restart algorithm to explore an integrated knowledge graph comprising three subgraphs: (i) a Covid-19 knowledge graph, (ii) a drug repurposing knowledge graph, and (iii) a Covid-19 disease state-specific omics graph. Results We prioritized 20 US Food and Drug Administration-approved agents as potential candidate drugs for mild, moderate, and severe Covid-19 disease phases. Specifically, drugs that could stimulate immune cell recruitment and activation including histamine, curcumin, and paclitaxel have potential utility in mild disease states to mitigate disease progression. Drugs like omacetaxine, crizotinib, and vorinostat that exhibit antiviral properties and have the potential to inhibit viral replication can be considered for mild to moderate Covid-19 disease states. Also, given the association between antioxidant deficiency and high inflammatory factors that trigger cytokine storms, antioxidants like glutathione can be considered for moderate disease states. Drugs that exhibit potent anti-inflammatory effects like (i) anti-inflammatory drugs (sarilumab and tocilizumab), (ii) corticosteroids (dexamethasone and hydrocortisone), and (iii) immunosuppressives (sirolimus and cyclosporine) are potential candidates for moderate to severe disease states that trigger a hyperinflammatory cascade of Covid-19. Conclusion Our study demonstrates that the multi-omics data-driven integrative analysis within the drug data enables prioritizing drug candidates for Covid-19 disease phases, offering a comprehensive basis for therapeutic strategies that can be brought to market quickly given their established safety profiles. Importantly, the multi-omics data-driven integrative analysis within the drug data approach implemented here can be used to prioritize drug repurposing candidates appropriate for other diseases.

Pharmacological validation of a novel exopolysaccharide from Streptomyces sp. 139 to effectively inhibit cytokine storms

With the rapid development of immunotherapy in recent years, cytokine storm has been recognized as a common adverse effect of immunotherapy. The emergence of COVID-19 has renewed global attention to it. The cytokine storm's inflammatory response results in infiltration of large amounts of monocytes/macrophages in the lungs, heart, spleen, lymph nodes, and kidneys. This infiltration leads to secondary tissue damage, acute respiratory distress syndrome (ARDS), organismal damage, and even death. However, there is currently no designated treatment for cytokine storm and the resulting ARDS. Consequently, there is a pressing need to identify a pharmaceutical agent that can effectively mitigate cytokine storms. Ebosin is a new exopolysaccharide generated by Streptomyces sp.139 and pharmacological activity for cytokine storm is investigated in vivo. The results show that Ebosin significantly augments the survival rates of mice, and its effectiveness increases with higher doses. It significantly inhibited the expression of cytokines IL-5, IL-6, IL-9 and chemokine Eotaxin in serum and lung tissues. Ebosin can alleviate the pathological damage in the lungs, liver, and spleen caused by LPS. Additionally, it can inhibit the phosphorylation of IKKα/β, Stat3 and NF-κB p65 upon LPS stimulation in vitro. We hypothesized that Ebosin may decrease cytokine release by inhibiting the phosphorylation of IKKα/β, Stat3, and NF-κB p65, neutrophil infiltration in animals. The article preliminarily elucidated the activity and mechanism of Ebosin against cytokine storm, which provides a reference for the study of anti-cytokine storm activity of microbial natural products.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin-18 (IL-18) and interferon gamma (IFNγ). Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-oligonucleotide-induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome or the downstream caspase-1 prevented MAS-mediated upregulation of IL-18 in the plasma but, interestingly, did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore blockade of IL-1 receptor with its antagonist IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that, during the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18 - a key cytokine in clinical cases of MAS - but was not a driving factor in the pathogenesis of CpG-induced MAS.

Unveiling the Correlation between Transferrin Saturation and Critically Ill COVID-19 Patients’ Outcomes: A Multicenter Cohort Study

Abstract Background: Critically ill patients with coronavirus disease 2019 (COVID-19) often have cytokine storms, manifested with elevated levels of proinflammatory biomarkers and hyperferritinemia. Systemic inflammation significantly limits the iron availability for erythropoiesis, which may disturb iron homeostasis and affect clinical outcomes. Thus, this study aimed to evaluate the impact of iron hemostasis on the clinical outcomes of critically ill patients with COVID-19. Materials and Methods: A multicenter, retrospective cohort study was conducted and included critically ill adult COVID-19 patients admitted to the intensive care units (ICUs) from March 2020 to July 2021. Patients were categorized based on transferrin saturation (TSAT) during their ICU stay (TSAT < 20% vs. TSAT ≥ 20%). The primary outcome was the in-hospital mortality, while other outcomes were considered secondary. Results: After propensity score matching (PSM) (1:1 ratio), 46 patients were included in the final analysis. In-hospital mortality was not statistically significantly different between the two groups (OR, 0.91; 95% CI, 0.29–2.87; P = 0.88). Patients with TSAT ≥ 20% had a longer mechanical ventilation duration (beta coefficient 0.11; 95% CI, −0.54–0.76; P = 0.19); however, it did not reach statistical significance. Moreover, the ICU length of stay (LOS) and hospital LOS were not statistically significant in patients with a TSAT ≥ 20%. Conclusion: Our results show no significant differences in clinical outcomes between patients with TSAT levels ≥20% and those with TSAT < 20%. Larger prospective studies are needed to verify these findings and evaluate the effect of iron correction on anemic patients’ outcomes.

Prognostic value of interleukin-6 serum levels in hospitalized COVID-19 patients: A case-control study in Iran.

The coronavirus pandemic (COVID-19) is an infectious disease with a high mortality rate that is challenging to treat. Cytokine storm is a crucial factor leading to acute respiratory distress syndrome in COVID-19 patients. Identifying factors that predict the severity of the disease may be primarily prognostic to guide drug therapy. The objective of this study was to investigate the prognostic role of interleukin 6 (IL-6) in the hospitalized patients infected with COVID-19. This case-control study was conducted from October 2019 to April 2020 at Shahid Faqihi hospital in Iran. Fifty hospitalized COVID-19 patients and 50 healthy individuals were included while controlling demographics and comorbidities. IL-6 serum levels were measured and compared based on demographic characteristics (age, sex) and comorbidities in the case and control groups. Spearman rank correlation coefficient was also used to analyze the correlations between IL-6 levels and lung involvement in COVID-19 patients. Moreover, some laboratory parameters were compared based on the percentage of lung involvement. The level of IL-6 in the case group was significantly higher than the control (p ˂ 0.001). We observed a positive and significant correlation between the level of IL-6 and the severity of lung involvement (r = 0.0.79, p < 0.01). The median level of IL-6 in patients who showed more than 75% lung involvement was 573 (IQR = 320-850). Available evidence suggests that high levels of IL-6 are associated with the severity of COVID-19. According to the results, it could be proposed that inhibition of IL-6 might be a target for therapeutic managements to reduce mortality in the patients with COVID-19.

Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections.

The late 2019 emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, caused profound and unprecedented disruption to the global socio-economic structure, negatively affecting millions of lives worldwide. A typical hallmark of severe COVID-19 is hyper inflammation due to aberrant cytokine release (cytokine storm) by innate immune cells. Recent studies have revealed that SARS-CoV-2, through its spike (S) protein, can activate the body's innate immune cells via Toll-Like Receptors (TLRs), particularly TLR4. In silico studies have demonstrated that the S protein binds with high affinity to TLR4, triggering downstream signaling processes that result in pro-inflammatory cytokine release. Compared to other TLRs, such as TLR2, TLR4 plays a more significant role in initiating and sustaining the inflammatory response associated with severe COVID-19. Furthermore, interactions between the virus and target cells can enhance the cellular expression of TLR4, making cells more susceptible to viral interactions and subsequent inflammation. This increased expression of TLR4 upon viral entry creates a feedback loop, where heightened TLR4 levels lead to amplified inflammatory responses, contributing to the severity of the disease. Additionally, TLR4's potent activation of inflammatory pathways sets it apart from other TLRs, underscoring its pivotal role in the pathogenesis of COVID-19. In this review, we thoroughly explore the multitude of regulatory signaling pathways that SARS-CoV-2 employs to incite inflammation. We specifically focus on the critical impact of TLR4 activation compared to other TLRs, highlighting how TLR4's interactions with the viral S protein can exacerbate the severity of COVID-19. By delving into the mechanisms of TLR4-mediated inflammation, we aim to shed light on potential therapeutic targets that could mitigate the inflammatory damage caused by severe COVID-19. Understanding the unique role of TLR4 in the context of SARS-CoV-2 infection could pave the way for novel treatment strategies that specifically inhibit this receptor's activity, thereby reducing the overall disease burden and improving patient outcomes.

Serum Proteomics Distinguish Subtypes of NMO Spectrum Disorder and MOG Antibody-Associated Disease and Highlight Effects of B-Cell Depletion.

AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons. In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients. In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD. Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.

Differentiation in pyroptosis induction by Burkholderia pseudomallei and Burkholderia thailandensis in primary human monocytes, a possible cause of sepsis in acute melioidosis patients.

Melioidosis caused by Burkholderia pseudomallei is an infectious disease with a high mortality rate. In acute melioidosis, sepsis is a major cause of death among patients. Once the bacterium enters the bloodstream, immune system dysregulation ensues, leading to cytokine storms. In contrast to B. pseudomallei, a closely related but non-virulent strain B. thailandensis has rarely been reported to cause cytokine storms or death in patients. However, the mechanisms in which the virulent B. pseudomallei causes sepsis are not fully elucidated. It is well-documented that monocytes play an essential role in cytokine production in the bloodstream. The present study, therefore, determined whether there is a difference in the innate immune response to B. pseudomallei and B. thailandensis during infection of primary human monocytes and THP-1 monocytic cells by investigating pyroptosis, an inflammatory death pathway known to play a pivotal role in sepsis. Our results showed that although both bacterial species exhibited a similar ability to invade human monocytes, only B. pseudomallei can significantly increase the release of cytosolic enzyme lactate dehydrogenase (LDH) as well as the increases in caspase-1 and gasdermin D activations in both cell types. The results were consistent with the significant increase in IL-1β and IL-18 production, key cytokines involved in pyroptosis. Interestingly, there was no significant difference in other cytokine secretion, such as IL-1RA, IL-10, IL-12p70, IL-15, IL-8, and IL-23 in cells infected by both bacterial species. Furthermore, we also demonstrated that ROS production played a crucial role in controlling pyroptosis activation during B. pseudomallei infection in primary human monocytes. These findings suggested that pyroptosis induced by B. pseudomallei in the human monocytes may contribute to the pathogenesis of sepsis in acute melioidosis patients.

Implications of inflammatory cell death-PANoptosis in health and disease.

Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.

Evaluation of the Effectiveness of Adjunctive N-Acetylcysteine Nebulizer in Critically Ill Patients with COVID-19: A Pre-post Study

Abstract Background: The uncontrolled inflammatory immune response associated with SARS-CoV-2 can lead to cytokine storm and acute respiratory distress syndrome. N-Acetylcysteine (NAC) nebulizer therapy is being considered as a potential treatment option in coronavirus disease 2019 (COVID-19) patients due to its mucolytic, antioxidant, anti-inflammatory, and antiviral properties. However, the use of NAC in critically ill COVID-19 patients has not been extensively studied. Therefore, a study was conducted to evaluate the effectiveness of adjunctive NAC on respiratory function in critically ill patients with COVID-19. Materials and Methods: A pre-post retrospective study included critically ill patients with COVID-19 admitted to the intensive care units and received NAC nebulizers between March 2020 and July 2021. The primary outcome was to assess the PaO2/FiO2 (P/F) ratio differences before and after NAC administration. Other outcomes were considered secondary, such as the positive end-expiratory pressure (PEEP), tidal volume, and invasive mechanical ventilation (MV) status. A paired t test or Wilcoxon signed-rank test was used based on the data distribution. A P value of &lt;0.05 was considered statistically significant. Results: The results revealed that a total of 1081 critically ill patients with COVID-19 were screened during the study period, and only 44 were included. Most of the patients were male (75%) with a median age of 58 years (range = 48.5–76.5 years). Before NAC initiation, the median P/F ratio was 136.55 (with a range of 92.15–207.3), whereas 24 h post-initiation, it increased significantly to a median of 159.7 (with a range of 109.6–270.2; P = 0.02). In contrast, no statistically significant differences were observed in PEEP, tidal volume, and invasive MV status before and after NAC initiation. Conclusion: This study concludes that adjunctive NAC therapy in critically ill patients with COVID-19 was associated with improved P/F ratio 24 h:24-h post-initiation. This improvement occurred without significant differences observed in PEEP, tidal volume, and invasive MV status. However, it is essential to conduct randomized control trials to validate these findings and determine their clinical significance.

Tumor Cell-Derived Exosomal Hybrid Nanosystems Loaded with Rhubarbic Acid and Tanshinone IIA for Sepsis Treatment.

Sepsis continues to exert a significant impact on morbidity and mortality in clinical settings, with immunosuppression, multi-organ failure, and disruptions in gut microbiota being key features. Although rheinic acid and tanshinone IIA show promise in mitigating macrophage apoptosis in sepsis treatment, their precise targeting of macrophages remains limited. Additionally, the evaluation of intestinal flora changes following treatment, which plays a significant role in subsequent cytokine storms, has been overlooked. Leveraging the innate inflammation chemotaxis of tumor cell-derived exosomes allows for their rapid recognition and uptake by activated macrophages, facilitating phenotypic changes and harnessing anti-inflammatory effects. We extracted exosomes from H1299 cells using a precipitation method. Then we developed a tumor cell-derived exosomal hybrid nanosystem loaded with rhubarbic acid and tanshinone IIA (R+T/Lipo/EXO) for sepsis treatment. In vitro studies, we verify the anti-inflammatory effect and the mechanism of inhibiting cell apoptosis of nano drug delivery system. The anti-inflammatory effects, safety, and modulation of intestinal microbiota by the nanoformulations were further validated in the in vivo study. Nanoformulation demonstrated enhanced macrophage internalization, reduced TNF-α expression, inhibited apoptosis, modulated intestinal flora, and alleviated immunosuppression. R+T/Lipo/EXO presents a promising approach using exosomal hybrid nanosystems for treating sepsis.

Early Infantile Hemophagocytic Lymphohistiocytosis Masquerading as Late-onset Sepsis: A Case Report with Review of the Literature

Background: Hemophagocytic lymphohistiocytosis (HLH) is a condition due to uncontrolled overactivation of macrophages, cytotoxic T cells, and natural killer cells creating a cytokine storm, characterized by multiorgan involvement. Familial HLH (fHLH) is due to genetic defects and presents early in life. There are only a few reports of neonatal onset of fHLH. Clinical Description: A 40-days-old male baby, born at 36 weeks of gestation, presented with fever, abdominal distension, poor feeding, lethargy, seizures. He had metabolic acidosis, respiratory failure, hepatosplenomegaly and bicytopenia, with a deranged coagulation profile. Management and Outcome: Treatment was started as per sepsis with meningitis with disseminated coagulation profile. All cultures were sterile, bacterial and fungal polymerase chain reaction were negative, but the baby deteriorated rapidly to shock. As the baby fulfilled the HLH criteria, he was started on intravenous immunoglobulin, methylprednisolone, and immunomodulator anakinra while sending sample for whole-exome sequencing for primary HLH. However, the baby succumbed to the illness. Whole-exome sequencing revealed a perforin-1 gene defect which confirmed primary HLH type 2. Conclusion: This report creates awareness that a primary genetic HLH may mimic early infantile sepsis. The rapidly progressive course in an otherwise healthy, breast-fed baby, with no setting of sepsis, and absence of infective etiology, should raise a suspicion of this underlying potentially fatal condition.

Smoking and vaping alter genes related to mechanisms of SARS-CoV-2 susceptibility and severity: a systematic review and meta-analysis.

Evidence for the impact of smoking on coronavirus disease 2019 (COVID-19) is contradictory, and there is little research on vaping. Here we provide greater clarity on mechanisms perturbed by tobacco cigarette, electronic cigarette and nicotine exposures that may impact the risks of infection and/or disease severity. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the Ovid and Web of Science databases were searched. Study design and exposure-induced gene expression changes were extracted. Each study was quality assessed and higher confidence scores were assigned to genes consistently changed across multiple studies following the same exposure. These genes were used to explore pathways significantly altered following exposure. 125 studies provided data on 480 genes altered by exposure to tobacco cigarettes, e-cigarettes, nicotine or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genes involved in both SARS-CoV-2 viral-entry and inflammation were changed following exposure. Pathway analysis revealed that many of those genes with high confidence scores are involved in common cellular processes relating to hyperinflammatory immune responses. Exposure to tobacco cigarettes, e-cigarettes or nicotine may therefore impact initial host-pathogen interactions and disease severity. Smokers and vapers of e-cigarettes with nicotine could potentially be at increased risk of SARS-CoV-2 infection, associated cytokine storm, and acute respiratory distress syndrome. However, further research is required, particularly on e-cigarettes, to determine the biological mechanisms involved in perturbation of viral-entry genes and host-pathogen interactions and subsequent responses within the respiratory tract. This will improve our physiological understanding of the impact of smoking and vaping on COVID-19, informing public health advice and providing improved guidance for management of SARS-CoV-2 and other respiratory viruses.

Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19.

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

The Behaviour of IL-6 and Its Soluble Receptor Complex during Different Waves of the COVID-19 Pandemic.

In late December 2019, SARS-CoV-2 was identified as the cause of a new pneumonia (COVID-19), leading to a global pandemic declared by the WHO on 11 March 2020, with significant human, economic, and social costs. Although most COVID-19 cases are asymptomatic or mild, 14% progress to severe disease, and 5% develop critical illness with complications such as interstitial pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction syndrome (MODS). SARS-CoV-2 primarily targets the respiratory system but can affect multiple organs due to the widespread presence of angiotensin-converting enzyme 2 (ACE2) receptors, which the virus uses to enter cells. This broad distribution of ACE2 receptors means that SARS-CoV-2 infection can lead to cardiovascular, gastrointestinal, renal, hepatic, central nervous system, and ocular damage. The virus triggers the innate and adaptive immune systems, resulting in a massive cytokine release, known as a "cytokine storm", which is linked to tissue damage and poor outcomes in severe lung disease. Interleukin-6 (IL-6) is particularly important in this cytokine release, with elevated levels serving as a marker of severe COVID-19. IL-6 is a multifunctional cytokine with both anti-inflammatory and pro-inflammatory properties, acting through two main pathways: classical signalling and trans-signalling. Classical signalling involves IL-6 binding to its membrane-bound receptor IL-6R and then to the gp130 protein, while trans-signalling occurs when IL-6 binds to the soluble form of IL-6R (sIL-6R) and then to membrane-bound gp130 on cells that do not express IL-6R. The soluble form of gp130 (sgp130) can inhibit IL-6 trans-signalling by binding to sIL-6R, thereby preventing it from interacting with membrane-bound gp130. Given the central role of IL-6 in COVID-19 inflammation and its association with severe disease, we aimed to analyse the behaviour of IL-6 and its soluble receptor complex during different waves of the pandemic. This analysis could help determine whether IL-6 levels can serve as prognostic markers of disease severity.

Critically Ill Patients with COVID-19 Pneumonia Requiring Continuous Renal Replacement Therapy with oXiris® Membrane in a Third-Level Hospital in Northeast Mexico

Introduction: The coronavirus disease 2019 (COVID-19) pandemic represented a global public health problem with devastating consequences that have challenged conventional medical treatments. Continuous renal replacement therapy (CRRT), based on a spectrum of modalities and dialysis membranes, can modify cytokine storms, and improve the clearance of inflammatory factors. As severe COVID-19 can lead to acute kidney injury (AKI) requiring RRT, most patients require more than one extracorporeal organ support at this point. This is due to complications that lead to organ dysfunction. The aim of our study was to assess renal recovery and survival while use of the oXiris membrane, as well as a decrease in vasopressors and hemodynamic parameters. Methods: This was a retrospective, observational study. The population included adult patients (aged >18 years) with a real-time PCR COVID-19 positive test, admitted to the intensive care unit (ICU) with AKI KDIGO 3, which required CRRT, in a hospital in northern Mexico. The primary outcomes were renal recovery and survival, and the secondary outcomes were a decrease in the vasopressor requirements and changes in the hemodynamic parameters. Results: Thirteen patients were included from January 2020 to August 2021, all of whom met the inclusion criteria. oXiris, an AN69-modified membrane, was used for blood purification and cytokine storm control in all the patients. The primary outcome, renal recovery, and survival were observed in 23% of the patients. The secondary outcome was a decrease of 12% in the use of noradrenaline in the first 24 h of CRRT initiation with oXiris, in addition to a decrease in creatinine and C-reactive protein levels in all patients. Discussion: The use of the oXiris membrane in patients with severe COVID-19 improved hemodynamic parameters, with 23% of the patients achieving renal recovery. The decrease on the requirement of vasopressors in the overall patients in the first 24 h of CRRT with oXiris was achieved. The mean decrease was of 12%, accompanied by a decrease in inflammatory markers. There is literature on the benefit of CRRT with a modified AN69 membrane in Mexico; however, studies in this regard are scarce, and our research provides valuable information on our experience in this field.

Pathogenetic and clinical-neurological features of post-COVID syndrome

Despite the developed methods of treatment and prevention of COVID-19, new strains of the SARS-CoV-2 virus continue to appear. The development of complications from various organs and systems against the background of the coronavirus infection COVID-19 is noted. In patients with three or more chronic diseases, the infection can occur with varying degrees of severity, often leading to the formation of acute vascular accidents. Such patients have an unfavorable rehabilitation prognosis due to the severe course of the disease. The complex of symptoms manifested by various psycho-emotional and functional disorders after the coronavirus infection is called post-COVID syndrome. This syndrome develops 3–4 months after COVID-19 infection. The scientific community has put forward a number of hypotheses describing the pathogenetic features of the post-COVID syndrome. It has been proven that the development of this syndrome is associated with the main pathogenetic mechanisms and course of COVID-19, specifically, a disorder in the hemostasis system and hyperproduction of inflammatory cytokines with the development of a «cytokine storm». Post-COVID syndrome is characterized by a wide range of symptoms, the manifestation of which does not depend on the severity of previous COVID-19. However, there is a more severe manifestation of the post-COVID syndrome, with the risk of developing acute vascular accidents, in patients with chronic pathology of the cardiovascular system. The article presents an analysis of modern literature data on the clinical and neurological features of the development and course of post-COVID syndrome.