Hyperinflammatory Conditions Research Articles

Occurrence and clinical correlates of SARS-CoV-2 viremia in two German patient cohorts

Viremia defined as detectable SARS-CoV-2 RNA in the blood is a potential marker of disease severity and prognosis in COVID-19 patients. Here, we determined the frequency of viremia in serum of two independent COVID-19 patient cohorts within the German National Pandemic Cohort Network (German: Nationales Pandemie Kohorten Netzwerk, NAPKON) with diagnostic RT-PCR against SARS-CoV-2. A cross-sectional cohort with 1,122 COVID-19 patients (German: S ektorenuebergreifende Platform, SUEP) and 299 patients recruited in a high-resolution platform with patients at high risk to develop severe courses (German: H ochaufloesende Plattform, HAP) were tested for viremia. Our study also involved a comprehensive analysis and association of serological, diagnostic and clinical parameters of the NAPKON medical dataset. Prevalence of viremia at the recruitment visit was 12,8% (SUEP) and 13% (HAP) respectively. Serological analysis revealed that viremic patients had lower levels of SARS-CoV-2 specific antibodies as well as lower neutralizing antibodies compared to aviremic patients. Viremia was associated with severity (<0.0001 SUEP; 0.002 HAP) and mortality of COVID-19 (both cohorts <0.0001) compared to aviremic patients. While rare, viremia was also detected in patients with mild disease (0.7%). In patients of the SUEP cohort with acute kidney disease (p = 0.0099) and hematooncological conditions (p = 0.0091), viremia was detected more frequently. Compared to the aviremic group, treatment with immunomodulating drugs as well as elevated levels of inflammatory markers in the blood was more frequent in the viremic group. In conclusion, our analysis revealed that detectable viremia correlates with hyperinflammatory conditions and higher risk for severe COVID-19 disease.

Non-coding RNA Networks in Infection.

In the face of global health challenges posed by infectious diseases and the emergence of drug-resistant pathogens, the exploration of cellular non-coding RNA (ncRNA) networks has unveiled new dimensions in infection research. Particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as instrumental players in ensuring a balance between protection against hyper-inflammatory conditions and the effective elimination of pathogens. Specifically, ncRNAs, such as the miRNA miR-155 or the lncRNAs MaIL1 (macrophage interferon-regulatory lncRNA 1), and LUCAT1 (lung cancer-associated transcript 1) have been recurrently linked to infectious and inflammatory diseases. Together with other ncRNAs, discussed in this chapter, they form a complex regulatory network shaping the host response to pathogens. Additionally, some pathogens exploit these ncRNAs to establish and sustain infections, underscoring their dual roles in host protection and colonization. Despite the substantial progress made, the vast majority of ncRNA loci remains unexplored, with ongoing research likely to reveal novel ncRNA categories and expand our understanding of their roles in infections. This chapter consolidates current insights into ncRNA-mediated regulatory networks, highlighting their contributions to severe diseases and their potential as targets and biomarkers for innovative therapeutic strategies.

Prognostic Impact of Aetiology in Adult Hemophagocytic Lymphohistiocytosis: Insights from an Intensive Care Unit Experience.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome marked by excessive immune activation. It can be triggered by various factors, including infections, malignancies, and autoimmune diseases, making the diagnosis challenging due to its overlap with other severe conditions. We discuss two intensive care unit (ICU) cases illustrating the diverse manifestations of HLH and the critical importance of early recognition and treatment. The first case involves natural killer-cell leukaemia, and the second, a suspected viral trigger. Both highlight the necessity of a multidisciplinary approach in diagnosis and management, emphasizing the complexity of HLH in ICU settings. High mortality rates, particularly in malignancy-associated HLH, underscore the importance of tailored treatment strategies based on the underlying aetiology. Hemophagocytic lymphohistiocytosis (HLH) in adults can arise from a variety of triggers, including infections and malignancies, each influencing disease progression and prognosis differently. Recognizing these underlying aetiologies is crucial for tailoring management strategies and anticipating clinical outcomes.Due to its life-threatening nature, HLH requires prompt diagnosis and a coordinated, multidisciplinary approach. Early intervention, incorporating immunosuppressive therapies and supportive care, is essential to improve patient outcomes, particularly in intensive care unit settings where disease severity is often pronounced.Utilizing diagnostic tools such as the HScore and HLH-2004 criteria can facilitate early identification of HLH in critically ill patients with unexplained inflammatory symptoms. These tools, along with a high index of suspicion, help distinguish HLH from other hyperinflammatory conditions, enabling timely and appropriate therapeutic interventions.

Safety, acceptability, and feasibility of acquiring endothelial cells from guidewires in patients having major surgery or with acute critical illness

Abstract Background Endothelial cells (EC) play a key role in vascular homeostasis, and endothelial dysfunction has been linked to the development of cardiovascular disease. While most EC research relies on indirect assessment of EC function in humans, in vitro systems and in vivo animal models, the development of a safe protocol to isolate EC from patients would provide a new window into EC function. Purpose To assess (a) the feasibility of isolating EC from discarded guidewires used as part of the standard of care (SOC) in surgical patients and patients admitted to intensive care (ICU) and (b) to compare EC phenotypes in the patient cohorts. Methods Discarded guidewires were collected from arterial lines and central venous catheters (CVC) from 15 patients before abdominal surgery and 16 patients admitted to ICU requiring organ support. Additionally, J-wires were inserted into forearm veins using an proven technique for EC biopsy (ECBx) in all surgical patients. ECs were dissociated from guidewires, stained for CD31, CD144, CD202b, and nuclear integrity then analysed using flow-cytometry. EC were characterised based on surface marker expression and granularity. Blood biomarkers and clinical information was collected. Organ function was assessed using sequential organ failure assessment (SOFA). Tolerability and adverse event (AE) data was also collected using structured interviews to support the analysis. Results From the surgical cohort 6 arterial lines, 14 CVC and 15 ECBx were collected. From the ICU patients, 8 arterial lines and 9 CVC were collected. EC were identified as live and triple positive for CD31, CD144, CD202b. A median of 536 (IQR 160-796 ) EC were obtained from arterial lines, 622 (IQR 329-1045) from CVCs and 768 (IQR 210-1001) from ECBx with no significant difference between method of collection (Kruskal-Wallis p&amp;gt;0.05). Median granularity showed a significant increase in granularity in EC collected from ICU patients compared to the surgical patients. This could be attributed to internalisation of cell surface proteins or apoptosis caused by the hyperinflammatory conditions in ICU patients (SOFA 7, IQR 5-8.25, CRP 118, IQR 66.2-298) when compared to the surgical patients (SOFA 1, IQR 0-2, CRP &amp;lt;4mg/l). Median fluorescent intensity analysis of all three markers did not show a significant difference between patient groups. AEs to ECBx reported only 4 patients experienced light bruising. High tolerability was reported for ECBx by structured interview, with patients agreeing that they theoretically would tolerate up to 3 ECBx. Conclusion(s) It is feasible to isolate ECs from patients during SOC using discarded guidewires. As an isolated procedure, ECBx from forearm veins is well tolerated and carries low risk. This enables the characterisation of EC phenotypes and obtain unique insight in their roles in health and disease.

The Correlation between Interleukin-6 and D-dimer in Severe and Critical COVID-19 Patients

Severe and critical COVID-19 patients are known to experience hyperinflammatory conditions and endothelial damage primarily characterized by increased levels of IL-6 and D-dimer. This group of patients is also considered at risk of experiencing hemostasis disorders including decreased platelet counts, prolonged PT and APTT, as well as increased fibrinogen. Therefore, this study aimed to determine the correlation between IL-6 and D-dimer in severe and critical COVID-19 patients. The relationship between IL-6 and other hemostasis parameters such as platelet count, PT, APTT, and fibrinogen were also analyzed. A descriptive-correlative observational design was used with a retrospective cross-sectional approach. The subjects were severe and critical COVID-19 patients at Hasan Sadikin Hospital, Bandung treated between January to December 2021 and met the inclusion and exclusion criteria. Secondary data were taken from medical records and the Laboratory Information System (LIS). Correlation analysis between IL-6 and D-dimer as well as hemostasis parameters was carried out using the Spearman test. The results showed that among the total 167 subjects, the median age was 60 years. The number of male subjects was 110 (65.86%), while the most common comorbidity was hypertension (45.51%). The analysis showed a very weak and insignificant correlation between IL-6 and platelets (r= -0.044; p=0.571), IL-6 and PT (r=0.115; p=0.137), IL-6 and APTT (r=0.109; p=0.159), as well as IL-6 and fibrinogen (r= -0.087; p=0.264). However, the correlation between IL-6 and D-dimer was significant (r= 0.199; p=0.010). Interleukin-6 did not correlate with hemostasis parameters but correlated with D-dimer. This means that IL-6 and D-dimer may provide information about the inflammatory response in COVID-19 patients and help monitor disease progression.

Extracorporeal Elimination of Pro- and Anti-inflammatory Modulators by the Cytokine Adsorber CytoSorb® in Patients with Hyperinflammation: A Prospective Study.

The release of pro-inflammatory cytokines in critically ill patients with sepsis leads to endothelial dysfunction resulting in cardiocirculatory insufficiency. Their extracorporeal elimination using the cytokine adsorber CytoSorb® (CS) (adsorption of especially hydrophobic molecules < 60kDa) might be promising, but data about the adsorption capacity as well as a potential harmful adsorption of anti-inflammatory cytokines are missing so far. The prospective Cyto-SOLVE-study included 15 patients with sepsis or other hyperinflammatory conditions (interleukin 6 > 500pg/ml), continuous kidney replacement therapy, and the application of CS. Various cytokines and chemokines were measured pre- and post-CS as well as in patients' blood at predefined timepoints. Significant changes in the concentrations were detected with the Wilcoxon test with associated samples. Clearance of the adsorber (ml/min) was calculated with: RESULTS: Most of the inflammatory mediators showed a high initial extracorporeal clearance of 70-100ml/min after CS installation, which dropped quickly to 10-30ml/min after 6h of treatment. No difference in clearance was observed between pro- and anti-inflammatory cytokines. Despite extracorporeal adsorption, a significant (p < 0.05) decrease in the blood concentration after 6h was only observed for the pro-inflammatory cytokines tumor necrosis factorα (TNF-α) (median 284 vs. 230pg/ml), vascular endothelial growth factor (VEGF) (median 294 vs. 252pg/ml), macrophage inflammatory protein 1a (MIP-1a) (median 11.1 vs. 9.0pg/ml), and regulated upon activation, normal T cell expressed and secreted (RANTES) (median 811 vs. 487pg/ml) as well as the anti-inflammatory cytokines interleukin 4 (median 9.3 vs. 6.4pg/ml), interleukin 10 (median 88 vs. 56pg/ml), and platelet-derived growth factor (PDGF) (median 177 vs. 104pg/ml). A significant (p < 0.05) decrease in patients' blood after 12h was only detected for interleukin 10. CS can adsorb pro- as well as anti-inflammatory mediators with no relevant difference regarding the adsorption rate. A fast saturation of the adsorber resulted in a rapid decrease of the clearance. The potential clinical benefit or harm of this unspecific cytokine adsorption needs to be evaluated in the future. ClinicalTrials.gov NCT04913298, registration date June 4, 2021.

Migraine Causality in Alpha-1 Antitrypsin Deficiency

Alpha1-antitrypsin (A1AT) is an anti-inflammatory mediator with antiprotease activity associated with anti-inflammatory and immunomodulatory effects in various inflammatory conditions. A1AT deficiency (A1ATD) has been associated with various hyperinflammatory diseases, such as lung disease (emphysema and bronchiectasis), liver disease (chronic hepatitis, cirrhosis, and hepatoma), and skin diseases (panniculitis). Migraine with aura is one of the common migraine subtypes associated with neuroimmunologic activation and neuroinflammation which is associated with cortical spreading depression and glial hyperinflammation in etioradiopathogenesis, and the main mechanisms explained so far are hyperinflammation of pro-inflammatory mediators, sensitivity of trigeminal nerve fibers and pain-conjugated glial cells activation. In this case report, a causative perspective of migraine with aura and A1ATD was presented through etioradiopathogenetics mechanisms that show the central reflections of systemic hyperinflammatory processes, and the importance of peripheral hyperinflammatory conditions in migraine etiology was examined.

Blinatumomab-induced macrophage activating syndrome (MAS) in adult with B-cell acute lymphoblastic leukemia (B-ALL)

Blinatumomab as a single agent has demonstrated superiority over salvage chemotherapy in patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), with manageable safety and efficacy. Though known to have anticipated drug toxicities including cytokine release syndrome (CRS) and neurotoxicity, there is only one prior report of macrophage activating syndrome (MAS) due to blinatumomab. Case Presentation: We report the first case of blinatumomab-induced MAS in an adult. The patient presented with fever, cough, and weakness on the second cycle of blinatumomab. Complete blood count was notable for severe leukopenia, with comprehensive metabolic panel notable for elevated alkaline phosphatase, AST, ALT, LDH, and hyperferritinemia consistent with MAS. The patient was already in MRD-negative remission at presentation with MAS. She responded rapidly to withholding the drug and administration of both tocilizumab and dexamethasone. She was able to restart therapy with blinatumomab dosed at 9 mcg/day with no recurrence of symptoms. Though MAS is not an expected association with blinatumomab, the risk for CRS is. Secondary MAS in this case likely shares a mechanism with other hyperinflammatory conditions. Management includes holding the offending agent, like blinatumomab, and administering tocilizumab and dexamethasone. Future research will be needed to predict which patients are at highest risk to develop MAS after similar T-cell therapies.

Proteomic mapping identifies serum marker signatures associated with MIS-C specific hyperinflammation and cardiovascular manifestation

Multisystem inflammatory syndrome in children (MIS-C) shares several clinical and immunological features with Kawasaki Disease (KD) and pediatric hyperinflammation, but the immuno-phenotypic overlap among these clinical mimics is still incompletely understood. Here we analyzed serum samples from treatment-naïve patients with MIS-C (n = 31) and KD (n = 11), pediatric hyperinflammation (n = 13) and healthy controls (HC, n = 10) by proximity extension assay (PEA) to profile 184 blood biomarkers. Collectively, immunophenotypic overlap between MIS-C and hyperinflammation exceeds overlap with KD. Overexpression of IL-17A in MIS-C and KD could best separate these conditions from hyperinflammatory conditions, while those were hallmarked by overabundance of adenosin deaminase and IL-18. Depletion in serum TNF-related subfamily member 9 (TNFRSF9) and apoptosis inducing ligand (TRAIL) linked with cardiovascular manifestations and myocarditis in MIS-C. Altogether, our analysis highlights important differences in molecular marker signatures also across different MIS-C and KD cohorts and suggests several previously unidentified molecular associations in context of cardiovascular inflammation.

Not just for lymphoid cells: the role of the noncanonical NF-κB signaling pathway in early and late myelopoiesis with a focus on hypereosinophilic disorders.

The noncanonical NF-κB pathway is involved in lymphoid organ development, B-cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis, are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease, including acute and chronic myeloid leukemias, preleukemic processes such as myelodysplastic syndrome, or hyperinflammatory conditions like hypereosinophilic syndrome. In this review, we discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, and how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on hypereosinophilic syndrome. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients with leukemia or idiopathic hypereosinophilic syndrome. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients with such complex and overlapping hematopoietic diseases.

P018 A review of the use of anakinra in hyperinflammatory conditions at a large central London teaching hospital

Abstract Background/Aims The interleukin-1 receptor antagonist, anakinra, is increasingly used to treat inflammatory disorders. We recognized a need to provide patients with accurate information regarding the trajectory of their treatment. In this service evaluation project, we collected data on patients prescribed anakinra at a London teaching hospital over a 4-year period. Methods Patients included were started on anakinra to manage an inflammatory disorder between April 2019 and Feb 2023. Patients were identified by searching a high-cost drugs system. Data on indication for the drug, start and stop date(s) of treatment and any adverse effects were then collected using electronic patient records. Results 74 patients met inclusion criteria, 43 females and 31 males. Median age 38.5 years. 56 patients were treated for haemophagocytic lymphohisticytosis (HLH), 5 for Juvenile Idiopathic Arthritis (JIA) and 13 for Adult Onset Still’s Disease (AOSD). Median time on anakinra was 140.5 days (IQR 563.5), 1487.5 days (IQR 861) and 673 days (IQR 1017) for HLH, JIA and AOSD respectively. Of those treated for HLH, drivers and median duration of anakinra treatment for each respective driver were: infection (seven patients, 31 days), rheumatological (six patients, 785 days), haematological (26 patients, 36.5 days), iatrogenic (1 patient, 89 days), primary HLH (2 patients, 89 days), underlying rheumatological condition with infective/drug trigger (3 patients, 345 days), unknown (11 patients, 191 days). 9/56 patients with HLH remained on treatment at data collection - 4 with an unknown driver, two with AOSD, one with underlying Sjogren’s and a drug trigger, one with a haematological driver and one with primary HLH. 12/56 patients with HLH had died. Of those who died, eight had a haematological malignancy driving their condition, three had an infective driver and one an unknown driver. Five patients in our study had HLH driven by AOSD. Of these, 2/5 successfully stopped anakinra during the study period. Five patients (8.9%) with HLH required multiple courses of treatment with anakinra; three had lymphoma associated HLH, one primary HLH and one idiopathic HLH. Three patients were unable to continue with therapy due to side effects: neutropenia(1), rash (1), problems self-injecting (1). Conclusion From this data set we can begin to formulate answers to many commonly encountered questions regarding anakinra therapy. The length of time someone can expect to receive treatment with anakinra is significantly impacted by the indication for prescribing. Those with a haematological malignancy driving their HLH receive anakinra for the shortest time of all groups, usually while awaiting definitive treatment for their cancer, or before transition to palliative management. Some patients with AOSD driven HLH can safely stop treatment. Some patients may require multiple courses of treatment with anakinra for disease relapse. Adverse effects requiring treatment cessation are low in all groups. Disclosure I. Munro: None. R. Allen: None. A. Jones: None. J. Manson: None.

JAK Inhibitors in Cytokine Storm Syndromes.

Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&amp;5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&amp;7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&amp;5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&amp;7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Dyslipidemia in rheumatoid arthritis: the possible mechanisms

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called “lipid paradox”. The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

A narrative review on tofacitinib: The properties, function, and usefulness to treat coronavirus disease 2019.

In coronavirus disease 2019 (COVID-19), the formation of cytokine storm may have a role in worsening of the disease. By attaching the cytokines like interleukin-6 to the cytokine receptors on a cell surface, Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway will be activated in the cytoplasm lead to hyperinflammatory conditions and acute respiratory distress syndrome. Inhibition of JAK/STAT pathway may be useful to prevent the formation of cytokine storm. Tofacitinib is a pan inhibitor of JAKs. In this review, the main characteristics of tofacitinib and its usefulness against COVID-19 pneumonia were reviewed. Tofacitinib may be a hopeful therapeutic candidate against COVID-19 respiratory injury since it inhibits a range of inflammatory pathways. Hence, the agent may be considered a potential therapeutic against the post-COVID-19 respiratory damage. Compared to other JAK inhibitors (JAKi), the administration of tofacitinib in COVID-19 patients may be safer and more effective. Other JAKi such as baricitinib are related to severe adverse events such as thrombotic events compared to more common side effects of tofacitinib.

Literature Review: Hubungan Kadar D-Dimer dengan Tingkat Keparahan Pasien Covid-19

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes Corona Virus Disease-19 (COVID-19). D-dimer is one of the hemostasis tests performed on patients infected with the disease, it is a product of fibrin degradation and a biomarker of platelet disorders. With the development of COVID-19 as a pandemic, D-dimer has become an indicator for prognosis in COVID-19 patients. Based on symptoms, the severity of COVID-19 patients consists of mild, moderate, and severe symptoms. The author conducted a literature review regarding the correlation between D-dimer levels and the severity of COVID-19 patients. Data and theory were taken from ten references from several databases: Google Scholar, PubMed, Semantic Scholar, Science Direct, Garuda, and Neliti. The references taken were from the 2020-2022 range. In all of these references, statistical test results were obtained with a significant value below 0.05, so it can be concluded that there is a correlation between D-dimer levels and the severity of COVID-19. In COVID-19 infections with severe symptoms, immunothrombosis can occur due to hyperinflammatory conditions and cytokine storms. Immunothrombosis occurs as a result of the body's defense against viral infections. Damage to lung tissue in COVID-19 patients triggers a procoagulant response associated with inflammatory cytokines in blood vessel tissue.

The Effect of CytoSorb on Inflammatory Markers in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effectiveness of CytoSorb at removing inflammatory mediators in critically ill patients is controversial. Electronic databases were searched from inception to May 2023. Randomized controlled trials reporting the effects of CytoSorb therapy on inflammatory parameters in critically ill patients with hyperinflammatory conditions were included. Two authors screened articles for eligibility, extracted data, and assessed the risk of bias, conflicts of interest, and certainty of evidence (CoE). The primary outcome was interleukin (IL)-6 at 1 day after initiation of the therapy. Secondary outcomes included various inflammatory markers at 1, 2, 3, and 5 days and mortality. Data were pooled if at least three trials reported the outcome of interest. We conducted meta-analyses of the data using a random-effects model. Seventeen trials ( n = 855) were included. Fourteen trials were judged to have notable concern about conflicts of interest. Seven trials were performed in medical ICU patients with hyperinflammatory conditions and 10 in complex cardiovascular surgery under cardiopulmonary bypass. Hemoadsorption with CytoSorb was not associated with lower IL-6 at 1 day (mean difference -5.98 [95% CI, -30.44 to 18.48] pg/mL), 2 days, 3 days, or 5 days after initiation of the treatment, as well as the concentration of procalcitionin. The levels of C-reactive protein were not lower with CytoSorb at 1, 2, and 3 days. The use of CytoSorb was associated with higher mortality at latest follow-up (relative risk = 1.22 [95% CI, 1.02-1.45]) and at 30 days. CoE ranged from low to very low. The use of CytoSorb hemoadsorption in a mixed population of critically ill patients with hyperinflammatory conditions does not exhibit a consistent decrease in IL-6 and other inflammatory parameters within the first 5 days of treatment. The significant uncertainty surrounding these findings highlights the need for further investigations.

Phorbol-12-myristate-13-acetate is a potent enhancer of B cells with a granzyme B+ regulatory phenotype.

The infusion of ex-vivo-generated regulatory B cells may represent a promising novel therapeutic approach for a variety of autoimmune and hyperinflammatory conditions including graft-versus-host disease. Previously, we developed a protocol for the generation of a novel population of regulatory B cells, which are characterized by secretion of enzymatically active granzyme B (GraB cells). This protocol uses recombinant interleukin 21 (IL-21) and goat-derived F(ab)'2 fragments against the human B cell receptor (anti-BCR). Generally, the use of xenogeneic material for the manufacturing of advanced therapy medicinal products should be avoided to prevent adverse immune reactions as well as potential transmission of so far unknown diseases. In the present work we demonstrated that phorbol-12-myristate-13-acetate (PMA/TPA), a phorbol ester with a particular analogy to the second messenger diacylglycerol (DAG), is a potent enhancer of IL-21-induced differentiation of pre-activated B cells into GraB cells. The percentage of GraB cells after stimulation of pre-activated B cells with IL-21 and PMA/TPA was not significantly lower compared to stimulation with IL-21 and anti-BCR. Given that PMA/TPA has already undergone encouraging clinical testing in patients with certain haematological diseases, our results suggest that PMA/TPA may be a safe and feasible alternative for ex-vivo manufacturing of GraB cells.

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.

The Techniques of Blood Purification in the Treatment of Sepsis and Other Hyperinflammatory Conditions

Even in the absence of strong indications deriving from clinical studies, the removal of mediators is increasingly used in septic shock and in other clinical conditions characterized by a hyperinflammatory response. Despite the different underlying mechanisms of action, they are collectively indicated as blood purification techniques. Their main categories include blood- and plasma processing procedures, which can run in a stand-alone mode or, more commonly, in association with a renal replacement treatment. The different techniques and principles of function, the clinical evidence derived from multiple clinical investigations, and the possible side effects are reviewed and discussed along with the persisting uncertainties about their precise role in the therapeutic armamentarium of these syndromes.