Storm In Patients Research Articles

Common for COVID-19 cytokine storm in patients with SARS-CoV-2 infection and CLL (chronic lymphocytic leukemia)

Common for COVID-19 cytokine storm in patients with SARS-CoV-2 infection and CLL (chronic lymphocytic leukemia)

Laboratory indicators of inflammation in the development of cytokine storm in patients with COVID-19

Laboratory indicators of inflammation in the development of cytokine storm in patients with COVID-19

Cytokines in influenza in children (literature review)

This literature review was compiled according to the data of search engines PubMed, eLIBRARY.RU, Google Scholar using key words influenza, cytokines, children. The article highlights the participation of pro-inflammatory and antiinflammatory cytokines in the pathogenesis of influenza, compares the cytokine profile in different strains of the virus, with concomitant pathology, as well as attempts to find an answer to the question: “Why are young children more susceptible to this infection?” The article contains information about the creation of express systems for diagnosing cytokine storm in patients with influenza and other acute respiratory viral infections, taking into account a complex of clinical and laboratory data that comes to the aid of a practicing physician. It should be noted that there are different opinions among authors regarding the early markers of severe and complicated influenza in childhood. This information makes the topic of studying the significance of cytokines in influenza in children relevant, but it requires continuation and clarification of knowledge on this issue.

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease.

Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear. Here, we conducted single-cell transcriptome analyses of 212 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls. KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4+ T, CD8+ T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B (tumor necrosis factor superfamily member 13b), CXCL16 (C-X-C motif chemokine ligand 16), TNFSF10 (tumor necrosis factor superfamily member 10), and IL1RN (interleukin 1 receptor antagonist), mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD. Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.

Clinical characteristics of electrical storm in patients with early repolarization syndrome

BackgroundEarly repolarization syndrome (ERS) is an idiopathic ventricular fibrillation (VF) associated with inferolateral J waves. While electrical storm (ES) in ERS is not rare, their characteristics and risk factors are not fully understood. ObjectiveThis study aimed to clarify the significance of ES in ERS. MethodsWe evaluated 44 patients with ERS who experienced VF/sudden cardiac death or arrhythmic syncope. We assessed clinical characteristics to identify the risk factors for ES. ResultsIn total, 13 patients (30%) experienced ES (ES group). Of these, 11 patients (85%) experienced ES during the acute phase of initial VF episodes and 2 patients (2%) experienced ES during follow-up. VF associated with ES occurred during therapeutic hypothermia in 6 of 13 patients (46%). The J-wave voltage during therapeutic hypothermia was higher in the ES group than that in the patients without ES. Isoproterenol was used in 5 patients (38%), which decreased J-wave voltage and relieved ES. Among the clinical markers, shorter QT and QTp intervals (the interval from QRS onset to the peak of T wave), pilsicainide-induced ST elevation, and high scores on the Shanghai Score System were associated with ES. Although pilsicainide induced ST elevation in 6 of 34 patients (18%), spontaneous Brugada electrocardiographic patterns did not appear to be associated with VF. Therapeutic hypothermia was also a risk factor for acute phase ES. ConclusionPatients with ERS in the ES group frequently had short QT and QTp intervals, pilsicainide-induced ST elevations, and high Shanghai Score System scores. Therapeutic hypothermia was also associated with acute phase ES.

Mid-Regional Proadrenomedullin in COVID-19—May It Act as a Predictor of Prolonged Cardiovascular Complications?

The rising prevalence of cardiovascular disease (CVD) and the impact of the SARS-CoV-2 pandemic have both led to increased mortality rates, affecting public health and the global economy. Therefore, it is essential to find accessible, non-invasive prognostic markers capable of identifying patients at high risk. One encouraging avenue of exploration is the potential of mid-regional proadrenomedullin (MR-proADM) as a biomarker in various health conditions, especially in the context of CVD and COVID-19. MR-proADM presents the ability to predict mortality, heart failure, and adverse outcomes in CVD, offering promise for improved risk assessment and treatment strategies. On the other hand, an elevated MR-proADM level is associated with disease severity and cytokine storms in patients with COVID-19, making it a predictive indicator for intensive care unit admissions and mortality rates. Moreover, MR-proADM may have relevance in long COVID, aiding in the risk assessment, triage, and monitoring of individuals at increased risk of developing prolonged cardiac issues. Our review explores the potential of MR-proADM as a predictor of enduring cardiovascular complications following COVID-19 infection.

Single-cell transcriptomic analysis reveals a systemic immune dysregulation in COVID-19-associated pediatric encephalopathy

Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments. Here, we utilized single-cell transcriptomic analysis and integrated clinical observations and laboratory examination to dissect the host immune responses and reveal pathological mechanisms in COVID-19-associated pediatric encephalopathy. We found that lymphopenia was a prominent characteristic of immune perturbation in COVID-19 patients with encephalopathy, especially those with acute necrotizing encephalopathy (AE). This was characterized a marked reduction of various lymphocytes (e.g., CD8+ T and CD4+ T cells) and significant increases in other inflammatory cells (e.g., monocytes). Further analysis revealed activation of multiple cell apoptosis pathways (e.g., granzyme/perforin-, FAS- and TNF-induced apoptosis) may be responsible for lymphopenia. A systemic S100A12 upregulation, primarily from classical monocytes, may have contributed to cytokine storms in patients with AE. A dysregulated type I interferon (IFN) response was observed which may have further exacerbated the S100A12-driven inflammation in patients with AE. In COVID-19 patients with AE, myeloid cells (e.g., monocytic myeloid-derived suppressor cells) were the likely contributors to immune paralysis. Finally, the immune landscape in COVID-19 patients with encephalopathy, especially for AE, were also characterized by NK and T cells with widespread exhaustion, higher cytotoxic scores and inflammatory response as well as a dysregulated B cell-mediated humoral immune response. Taken together, this comprehensive data provides a detailed resource for elucidating immunopathogenesis and will aid development of effective COVID-19-associated pediatric encephalopathy treatments, especially for those with AE.

Probable Neuropsychological and Cognitive Complications Due to Cytokine Storm in Patients With COVID-19.

COVID-19 (coronavirus disease 2019) was first identified in China in December 2019 and is rapidly spreading worldwide as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this context have focused on pathogenesis primarily in the respiratory system. However, evidence shows that the central nervous system (CNS) may also be affected by COVID-19. Since COVID-19 is spreading, it is necessary to study its possible cognitive effects on COVID-19 patients and their recovery. The articles used in this study were searched by keywords, such as cytokine storm and COVID-19, COVID-19 and executive dysfunction, cognitive disorder, and COVID-19, central nervous system (CNS) and COVID-19, coronavirus, neuroinvasion in Science Direct, Scopus, PubMed, Embase, and Web of Science databases based on preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The study evaluates all observational studies published between December 2019 and April 2021 in peer-reviewed journals, including cross-sectional, cohort, case-control studies, case reports, and case series. The search result was 106 articles, of which 73 articles related to COVID-19, the stages of infection by this virus, its effect on the nervous system and neurological symptoms, the cytokine storm caused by this infection, and the possible cognitive consequences caused by this virus in patients, has been reviewed. Other articles were not checked due to their limited relevance to the topic under discussion. Studies showed that neurons may be directly affected by severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and SARS-CoV-2. Furthermore, various studies indicated that systemic inflammation (so-called "cytokine storm") is also responsible for brain damage induced by infection with SARS-CoV-1 and SARS-CoV-2. In such a way that these patients showed elevated levels of interleukin (IL-), 6, 8, and 10 and of tumor necrosis factor-alpha (TNF-α) in their blood. Various cognitive defects have been observed following an increased level of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, 8. Therefore, due to the increased level of these pro-inflammatory factors in the brains of these patients, cognitive deficits can be expected, which need further investigation.

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.

Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4-5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

Use of Plasmapheresis in the Treatment of Thyrotoxicosis Secondary to Graves' Disease at the National Medical Center 20 de Noviembre ISSSTE: Case Report

Thyrotoxicosis refers to the clinical syndrome secondary to excess of circulating thyroid hormones, thyroid storm is an extreme manifestation of thyrotoxicosis, and which can reach 10-30% mortality with treatment depending on the series. This rare but serious complication occurs mainly in patients with Graves' disease (GD) who account for 60% to 80% of cases of hyperthyroidism. Both plasmapheresis/therapeutic plasma exchange (TPE) and emergency surgery have been used to treat thyroid storm in patients who respond poorly to first-line therapeutic measures. We present the case report of three patients with severe disease (GD) managed at the National Medical Center 20 de Noviembre ISSSTE using TPE as a bridge treatment to thyroidectomy, of which the indication for two patients was intolerance to antithyroid drugs and one with intolerance to antithyroid drugs in addition to impending thyroid storm. Between 4-5 sessions of TPE were performed in which there was a decrease in T4L and anti-TSH receptor antibodies (TSH-R-Ab), in addition to significant clinical improvement, which allowed us to perform thyroidectomy safely. Therefore, we consider that TPE is a fast, safe, and effective bridge treatment to surgery, which should be considered in patients with no response or intolerance to thionamide treatment, in centers where TPE and immediate surgery are available.

The inhibitory potential of chemical constituents of Ficus carica targeting interleukin-6 (IL-6) mediated inflammation.

Inflammation is an innate reaction of the body of an individual when subjected to the noxious factors repeatedly. Pharmacological approaches focused at disrupting cytokine signaling networks have become significant therapeutic alternatives for the treatment of inflammatory illnesses, cancer and autoimmune disorders. High levels of inflammatory mediators, particularly interleukin IL-1, IL-6, IL-18, IL-12, and tumor necrosis factor alpha leads to a cytokine storm in the body. Among all the released cytokines in a patient suffering from inflammatory disorder, IL-6 mediator has a pivotal role in this inflammatory cascade which progresses to a cytokine storm. Therefore, the blockage of the IL-6 inflammatory mediator could be a promising treatment option for the patients with hyper inflammatory conditions. The phytochemicals could provide the new lead compounds against the IL-6 mediator. Ficus carica has been the ideal plant of research and investigation due to its commercial, economic and medical importance. The anti-inflammatory properties of F. carica were further investigated by in silico and in vivo approaches. The docking scores of Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin are -9.231, -8.921, -8.840, and -8.335 Kcal/mole respectively. The free energy of binding and stability of the docked complexes of these top four phytochemicals with the IL-6 were further analyzed by Molecular Mechanics-Generalized Born Surface Area and Molecular Dynamic simulations, respectively. The in vivo anti-inflammatory carrageenan-induced rat paw edema model was used for the validation of in silico results. The maximum percentage paw edema inhibition with petroleum ether and ethyl acetate was 70.32% and 45.05%, respectively. The in vivo anti-inflammatory activity confirms the anti-inflammatory potential of F. carica. Therefore, it is predicted that Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin have the potential to inhibit the IL-6 mediator which will aid in mitigating the cytokine storm in patients with acute inflammations.

Prognosis of patients undergoing catheter ablation of arrhythmic storm in patients with and without history of previous ICD interventions

Abstract Funding Acknowledgements Type of funding sources: None. Background Catheter ablation (CA) improves prognosis in patients with electrical storm (ES). However, its effectiveness and timing in patients with ventricular tachycardia and appropriate ICD therapies remain a matter of debate. Purpose Our aim was to investigate whether patients with history of discrete ventricular tachycardia episodes had different clinical features and outcome compared to patients with ES as first arrhythmic occurrence. Methods We enrolled 57 consecutive patients undergoing CA for ES and collected clinical, echocardiographic and electroanatomic mapping data. The primary end point was a composite of death from any cause and recurrences of sustained VT or ventricular fibrillation, appropriate ICD therapy, or ES. Results During a median follow up of 39 months, 28 patients (49%) met the primary end point of arrhythmic recurrence or death from any cause. There were no significant differences between clinical, electrocardiographic and echocardiographic parameters in the two groups. Regarding ICD therapies, patients with who met the primary end point had a higher number of ATP/shock episodes preceding the ES event: 15 (52%) vs 25 (89%), p=0.002. At Cox regression analysis, NIDCM, previous ATP and/or shock and ≥3 ATP were associated with arrhythmic recurrences and/or death. At multivariate analysis, ≥3 ATP was the only predictor that met statistical significance for the primary end point: HR was 30.41, CI 4.42 – 209.12, p=0.001. When dividing our population in patients and without ventricular arrhythmias (VAs) with appropriate device intervention before ES, thoses with VAs arrhythmias before ES had a higher percentage of presence of late potentials (80% vs 55%, p=0.041) and a greater unipolar scar (59.2±41.6 vs 30.2±21.6, p=0.001). At univariate analysis the presence of late potentials was associated with ventricular arrhythmias before ES (OR 3.33, CI 1.03-10.84, p=0.045). Conclusions CA in patients with a long arrhythmia history, recurrent ICD therapies and presence of late potentials at electroanatomic mapping, may yield worse outcomes and therefore our results support an early referral for CA of VT to improve prognosis in these subjects.

Impact of cardiac sympathetic denervation on electrical storms in patients with cardiomyopathies

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac Sympathetic Denervation (CSD) has been recently proposed for the treatment of refractory ventricular arrhythmias (VAs) in patients with cardiomyopathy (CMP). A multicentric American case series suggested a greater efficacy of the bilateral (BCSD), compared to the left-side only procedure (LCSD), albeit with a potential impact on chronotropism. The impact of CSD on the risk of electrical storms (ES) in CMP has never been evaluated. Purpose To describe our multicenter experience with CSD in CMP patients with refractory VAs, with a specific focus on ES incidence. Methods Thirty patients with CMP and refractory VAs underwent either LCSD or BCSD between April 2016 and June 2022. Among them, one patient received first LCSD and then right-side CSD due to ES recurrence after LCSD: to properly assess the risk of ES after LCSD and BCSD he was included in both groups, leading to 5 cases of LCSD and 26 cases of BCSD. All patients had a Video-Assisted Thoracoscopic Surgery, in 8 cases with the robotic technique. The main reason (3/5 cases, 60%) to perform LCSD instead of BCSD since the beginning was sinus bradycardia in single ICD lead recipients. Results 87% of pts were male, mean age was 56 ± 16 yrs and mean LVEF 31± 12%; most (n=26, 85%) suffered non-ischemic CMP and 37% were in NYHA class ≥3. Main indications for CSD were refractory polymorphic/fast VAs in 60% of pts and refractory monomorphic VAs in the rest. Except for 5 patients (17%) with previous thyrotoxicosis, the majority were either on amiodarone (n=19, 63%) or on sotalol (n=3, 10%) and 53% had previously undergone ≥1 catheter ablation for VAs. The median follow-up (FU) after CSD was 16 months (IQR 6-42 months). No major complications occurred. Eleven patients (37%) either died during FU (n=8, 27%), mostly due to end-stage heart failure, or underwent heart transplant (n=3, 10%). After CSD, the percentage of patients with ES decreased from 77% to 40% (p&amp;lt;0.01), while patients with appropriate shocks decreased from 100% to 60%. The figure shows the significant impact of CSD on VT burden. The antiarrhythmic benefit was more pronounced after BCSD: ES incidence decreased from 85% to 39% (p&amp;lt;0.01), ICD shock incidence from 100% to 54% (p&amp;lt;0.01), while no significant changes in ES and ICD shock incidence were observed after the few LCSD procedures (n=5). Survival free from ICD shock at 1 year was better among patients with a NYHA class &amp;lt;3 (73% versus 15%, p&amp;lt;0.001). Conclusions Our case series of CSD in CMP represents the largest reported in Europe and the first one to evaluate the impact of CSD on electrical storms. The occurrence of electrical storms was more than halved by BCSD confirming the powerful protective effect also on this ominous phenomenon. The greater antiarrhythmic benefit observed among patients with better functional class suggests the opportunity to perform this procedure earlier on in the trajectory of patients with progressive heart failure.

Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury

Pneumonia is an acute inflammation of the lungs induced by pathogenic microorganisms, immune damage, physical and chemical factors, and other factors, and the latest outbreak of novel coronavirus pneumonia is also an acute lung injury (ALI) induced by viral infection. However, there are currently no effective treatments for inflammatory cytokine storms in patients with ALI/acute respiratory distress syndrome (ARDS). Protein kinase D (PKD) is a highly active kinase that has been shown to be associated with the production of inflammatory cytokines. Therefore, small-molecule compounds that inhibit PKD may be potential drugs for the treatment of ALI/ARDS. In the present study, we evaluated the ability of the small-molecule inhibitor CRT0066101 to attenuate lipopolysaccharide (LPS)-induced inflammatory cytokine production through in vitro cell experiments and a mouse pneumonia model. We found that CRT0066101 significantly reduced the protein and mRNA levels of LPS-induced cytokines (e.g., IL-6, TNF-α, and IL-1β). CRT0066101 inhibited MyD88 and TLR4 expression and reduced NF-κB, ERK, and JNK phosphorylation. CRT0066101 also reduced NLRP3 activation, inhibited the assembly of the inflammasome complex, and attenuated inflammatory cell infiltration and lung tissue damage. Taken together, our data indicate that CRT0066101 exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway, suggesting that CRT0066101 may have therapeutic value in acute lung injury and other MyD88-dependent inflammatory diseases.

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1-2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16-0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26-0·57; p<0·0001, compared with the VIR-N1-Storm group). The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood. Instituto de Salud Carlos III, Canadian Institutes of Health Research, Li Ka-Shing Foundation, Research Nova Scotia, and European Society of Clinical Microbiology and Infectious Diseases. For the Spanish translation of the abstract see Supplementary Materials section.

Evaluating the Effectiveness of Intravenous Ozonated Normal Saline in the Treatment of Severe COVID-19 Disease: A randomized control trial

Background: There is still no specific treatment strategy for COVID-19 other than supportive management. The potential biological benefits of ozone therapy include reduced tissue hypoxia, decreased hypercoagulability, modulated immune function by inhibiting inflammatory mediators, improved phagocytic function, and impaired viral replication. This study aimed to evaluate the effect of intravenous ozonated normal saline on patients with severe COVID-19 disease. Methods: In this study, a single centralized randomized clinical trial was conducted on 80 hospitalized patients with severe COVID-19. The patients were selected by random allocation method and divided into two groups A and B. In group A (control group), patients were given standard drug treatment, and in group B (intervention group), patients received ozonated normal saline in addition to the standard drug treatment. In the intervention group, 400 mL of normal saline was weighed by 40 μg/ kg of body weight and was injected into patients within 15 to 30 minutes (80 to 120 drops per minute). This process was done daily every morning for a week. Primary and secondary outcomes of the disease included changes in the following items: length of hospital stay, inflammatory markers including C-reactive protein (CRP), clinical recovery, arterial blood oxygen status, improvement of blood disorders such as leukopenia and leukocytosis, duration of ventilator attachment, and rapid clearance of lung lesions on CT scans. The need for intensive care unit (ICU) hospitalization, the length of ICU stay, and the mortality rate in patients of the two groups was compared. Results: According to the results of the initial outcome variable analysis, the probability of discharge of patients who received the normal ozonated saline intervention was 33% higher than patients who did not receive this intervention; however, this relationship was not statistically significant (HR=0.67, 95%, CI=0.42-1.06, P value=0.089). The chance of ICU hospitalization in patients of the intervention group was three times more than that of the comparison group, but this relationship was not significant (odds ratio=4.4 95% CI=1.32-14.50, P value=0.016). The use of ozonated normal saline was found to increase the risk of death by 1.5 times but this relationship was not statistically significant (odds ratio=1.5, 95% CI=.24-9.75, P value=0.646). Ozonated normal saline had a significant effect on changes in respiration rate (in the intervention group the number of breaths was decreased) and the erythrocyte sedimentation rate (in the intervention group the erythrocyte sedimentation rate was increased); however, it had no significant effect on other indicators. Conclusion: The present study showed that ozone therapy in hospitalized patients with severe COVID-19 could help improve some primary and secondary outcomes of the disease. Governments and health policymakers should make ozone therapy an available care service so that the need for advanced treatment facilities decreases; consequently, this measure may improve patient safety, prevent lung tissue destruction, and control cytokine storms in patients. Additionally, health decision-makers need to aim for the effective clinical improvement of patients, especially severe ones, and the reduction of their mortality. However, further large-scale multicenter studies with larger sample sizes considering drug side effects and other variables influencing the clinical course of COVID-19 can provide more information on the effectiveness and importance of ozone therapy.

Tocilizumab-coated solid lipid nanoparticles loaded with cannabidiol as a novel drug delivery strategy for treating COVID-19: A review.

Commonly used clinical strategies against coronavirus disease 19 (COVID-19), including the potential role of monoclonal antibodies for site-specific targeted drug delivery, are discussed here. Solid lipid nanoparticles (SLN) tailored with tocilizumab (TCZ) and loading cannabidiol (CBD) are proposed for the treatment of COVID-19 by oral route. TCZ, as a humanized IgG1 monoclonal antibody and an interleukin-6 (IL-6) receptor agonist, can attenuate cytokine storm in patients infected with SARS-CoV-2. CBD (an anti-inflammatory cannabinoid and TCZ agonist) alleviates anxiety, schizophrenia, and depression. CBD, obtained from Cannabis sativa L., is known to modulate gene expression and inflammation and also shows anti-cancer and anti-inflammatory properties. It has also been recognized to modulate angiotensin-converting enzyme II (ACE2) expression in SARS-CoV-2 target tissues. It has already been proven that immunosuppressive drugs targeting the IL-6 receptor may ameliorate lethal inflammatory responses in COVID-19 patients. TCZ, as an immunosuppressive drug, is mainly used to treat rheumatoid arthritis, although several attempts have been made to use it in the active hyperinflammatory phase of COVID-19, with promising outcomes. TCZ is currently administered intravenously. It this review, we discuss the potential advances on the use of SLN for oral administration of TCZ-tailored CBD-loaded SLN, as an innovative platform for managing SARS-CoV-2 and related infections.

The use of mesenchymal stem cells in the treatment of severe forms of new coronavirus infection COVID-19: a prospective observational study

INTRODUCTION: One of the promising treatments for COVID-19 aimed at correcting the immune response and reducing the level of pro-inflammatory cytokines is the use of mesenchymal stem cells (MSCs). There is evidence that MSCs, due to various mechanisms, are able to suppress the cytokine storm in patients with COVID-19. Thus, the use of MSCs can contribute to the suppression of inflammation and the regulation of immune homeostasis in patients with severe COVID-19. OBJECTIVE: Evaluation of the effect of mesenchymal stem cell (MSC) therapy on the course of severe forms of novel coronavirus infection, accompanied by “cytokine storm”. MATERIALS AND METHODS: A prospective single-center study included 39 patients treated for coronavirus infection on the basis of the intensive care unit and, after randomization, randomly divided into control (n = 16) and study groups (n = 23). An assessment of clinical, laboratory parameters in both groups and a cytokine profile in the study group was carried out. Outcomes were compared, the incidence of complications and clinical and laboratory parameters in both groups, and the cytokine profile in the study group. RESULTS: The use of MSCs in patients with severe forms of COVID-19 affected the outcomes of the disease, the duration of stay on mechanical ventilation, the course of acute respiratory distress syndrome (ARDS) (an increase in the oxygenation index in patients of the study group by 5, 7 days from administration in comparison with the control group). CONCLUSIONS: In patients treated with MSCs, there was a significant decrease in a number of pro-inflammatory cytokines.

Prediction of Mortality Following Cytokine Storm in Patients with Hematological Malignancies and COVID-19 Infections

Background: Cytokine Storm (CS) is characterized by profound inflammation and multi-organ dysfunction. In a subset of COVID-19 patients with CS (COVID-CS), this has been shown to cause increased morbidity and mortality. There is, however, insufficient data to fully understand the precise role and scope of dysregulated cytokine responses in COVID-19 patients with hematological malignancies. We investigated the prognostic significance of pro-inflammatory cytokines with the overall outcome of patients with myeloid and lymphoid malignancies developing SARS-CoV-2 infection. Methods: A retrospective study was conducted among 9,790 patients diagnosed or admitted with COVID-19 at MD Anderson Cancer Center between March 2020 and June 2022. The Palantir Foundry platform was used to collect and curate PHI via the D3CODE (Data Driven Determinants for COVID 19 Oncology Discovery Efforts) Initiative, through which baseline demographic, clinical, and biochemical characteristics of patients were collected. We used a combination of higher than laboratory cutoff values of C-reactive protein (CRP), interleukin 6 (IL-6) and ferritin measured within 14 days of COVID or malignancy as CS defining criteria. In order to distinguish CS due to COVID and CS due to underlying disease/treatment, two groups were identified as COVID-CS (C-CS+) and Non-COVID-CS (NC-CS+). The clinical features, diagnosis, and pathogenesis of C-CS+ were compared to those of NC-CS+ due to malignancy associated secondary hemophagocytic lymphohistiocytosis (sHLH) and chimeric antigen receptor (CAR-T) cell therapy associated Cytokine Release Syndrome (CRS). Finally, we compared these two cohorts with patients infected with SARS-CoV-2 without any clinical or laboratory evidence of CS, labelled as COVID without CS (CVD+CS-). The prognostic significance of these markers was examined in these three cohorts. Fit models and ROC curves were developed for comparing C-CS+, NC-CS+ and CVD+CS- groups. We recorded overall survival (OS) at last follow-up. Results: We studied 366 patients in total: 40 were C-CS+, 127 were NC-CS+, and 199 were CVD+CS-. 113 patients had Leukemia (33%), 97 had Aggressive Lymphomas (30%), 71 had Indolent Lymphomas (19%), and 30 patients had Plasma Cell and Other Myelomas (8.2%). 168 patients (46%) received B-cell depleting therapy, 28 patients (8%) received CAR-T therapy, and 92 patients (25%) received chemotherapy. 36 patients (92%) in the C-CS+ group and 72 pts in the CVD+CS- (36%) and 105 pts (93%) in the NC-CS+ group were admitted. Length of stay (LOS) for the three groups C-CS+, CVD+CS-, NC-CS+ were 10 (R=4,20), 2 (R=0,5), 22 (R=11,30) (p<0.001). ICU admissions for the three groups C-CS+, CVD+CS-, NC-CS+ were 8 (21%), 4 (5.6%), 28 (25%) (p=0.002). Ferritin (p <0.001), IL-6 (p=0.01) and CRP (p <0.001) were higher for both CS+ groups vs. CS-, but had similar distributions between C-CS+ and NC-CS+. On univariate modeling, features with good predictive performance (AUC>8) included ferritin, albumin, Hgb, platelet count. ROC curve for multivariate model for all features had an AUC of 0.92. Multivariate analysis showed that CRP (OR-0.99, 95% CI 0.99-1, p=0.015), sodium (OR-1.13, 95% CI 1.02-1.26, p=0.022), and albumin (OR-3.04, 95% CI (1.41, 6.82), p=0.005) were associated with a higher mortality risk. Patients with C-CS+ had a lower OS compared to NC-CS+ and CVD+CS- (p=0.001). OS from both CS cohorts was better if they received prior vaccination (p=0.03). Finally, there was a striking OS in NC-CS+ patients when they received tocilizumab (p=0.005), while no difference in OS in C-CS+ in response to tocilizumab (p=0.81). Conclusion: With the ongoing surge in COVID, patients with hematological malignancies are at higher risk particularly associated with CS. The results show that myeloid and lymphoid C-CS+ and NC-CS+ patients with higher levels of inflammatory markers are more likely to be admitted with ICU support and tend to have worse outcomes. Additionally, C-CS+ patients do not respond to cytokine targeted therapies. A consensus definition of COVID-CS may enable us to identify patients with CS who may benefit most from timely immune modulating therapies. Furthermore, lessons learned from both COVID and hematologic associated CS syndromes may provide insight into the pathologic immune dysregulation underlying CS, expedite rapid identification and implementation of therapeutic strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Secreted Sars-Cov-2 Encoded ORF8 Protein Stimulates Pro-Inflammatory Cytokines and Predicts Severe Clinical Outcome

Introduction: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in a cytokine storm that is associated with poor patient outcomes. Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the inflammatory response remains unidentified. We hypothesized that one or more of these proteins is secreted to the bloodstream to induce a systematic inflammatory cytokine response leading to the cytokine storm in patients. We demonstrate that SARS-CoV-2 encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein into culture supernatant in vitro and into the bloodstream in patients with COVID-19. Glycosylated ORF8 stimulates monocytes to produce a set of pro-inflammatory cytokines through an NOD-like receptor family pyrin domain-containing 3 (NLPR3)-mediated inflammasome response, which can be inhibited by select NLRP3 inhibitors. Methods: Following institutional review board approval, serum samples were collected from Mayo Clinic COVID-19 infected patients. Lentiviral constructs expressing SARS-CoV-2 proteins were used to express SARS-CoV-2 proteins in HEK293 cells. Polymerase chain reaction and Luminex multiplex assays were used to detect cytokines induced by COVID-19 proteins. Single-cell RNA sequencing (scRNA-Seq) and flow cytometry were used to identify specific leukocyte populations responsible for cytokine release upon ORF8 stimulation. Immunoblotting, mass spectroscopy, and immunofluorescence microscopy were used to quantify and localize proteins of interest. Results: We transduced HEK293 cells with lentiviral constructs that express each SARS-CoV-2 protein and identified ORF8 as abundantly secreted. We treated human peripheral blood mononuclear cells (PBMCs) from healthy donors in vitro with conditioned media (CM) containing major secreted non-structural proteins (NSP) or secreted ORF8 followed by an assessment of cytokine mRNA expression. We found that none of the secreted NSP proteins induced cytokine expression while ORF8-containing CM (ORF8-CM) induced the mRNA expression of IL1b, IL6, IL8, and CCL2 up to 5-fold in PBMCs from select donors. scRNA-Seq on PBMCs treated with ORF8-CM showed that treatment with ORF8 induced IL1b, IL8, and CCL2 expression in CD14, CD16, CD68, and HLA-DR positive activated monocytes. Flow cytometry analysis of PBMCs stimulated with purified ORF8 showed significant increases of IL1β protein expression only in classical (CD14+/CD16-) and intermediate (CD14+/CD16-) monocyte subsets while no significant changes to cells of other types. scRNA-Seq and Western analyses demonstrated that ORF8 activates NOD-like receptor family pyrin domain-containing 3 (NLPR3) leading to the production of IL1b protein. Furthermore, ORF8-mediated IL1β cytokine induction was abolished in NLPR3 knockdown THP1 cells, demonstrating the NLRP3 dependency of ORF8-mediated cytokine response in human monocytes. We then examined the correlation between blood ORF8 levels and patients’ survival outcome in 25 patients with COVID-19 infection (Figure 1a). After 120 days of follow-up, all seven fatalities were exclusively associated with the ORF8-high group while all patients in ORF8-low group had minimal morbidity and without any events of death (Figure 1b). Importantly, the ORF8-initiated NLPR3-mediated inflammasome pathway can be effectively inhibited by the NLRP3 inhibitor MCC950 at a nanomolar dose range, demonstrating that targeting ORF8/NLRP3 is a promising strategy for treating patients with symptomatic COVID-19. Conclusion: We demonstrate that the virus-encoded ORF8 protein is abundantly secreted as a glycoprotein in vitro and in patients with COVID-19. ORF8 specifically targets CD14 + monocytes to produce pro-inflammatory cytokines through NLRP3 mediated inflammasomal activation. Importantly, ORF8 protein level in the blood of patients correlates with severity and disease-specific mortality in with acute SARS-CoV-2 infection. The ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment for severe COVID-19 infection. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal