OBJECTIVE: The IL-6 receptor inhibitor tocilizumab reduces mortality and morbidity in severe cases of COVID-19 through its effects on hyperinflammation and was approved as adjuvant therapy. Since tocilizumab changes the levels of inflammatory markers, we aimed to describe these changes in patients treated with tocilizumab, analyse their value in predicting death and bacterial superinfection and determine their influence on mortality rates.
METHODS: A retrospective analysis of 76 patients who were treated with tocilizumab for severe COVID-19 in 2020 and 2021 was conducted. Inflammatory markers (IL-6, C-reactive protein (CRP), procalcitonin) were documented before and up to seven days after tocilizumab administration.
RESULTS: The overall mortality was 25% and 53.8% in patients who required invasive respiratory support. Deceased patients had higher baseline IL-6 (p = 0.026) and peak IL-6 levels after tocilizumab vs those who survived (p < 0.0001). A peak IL-6 value > 1000 pg/dl after tocilizumab administration was a good predictor of mortality (AUC = 0.812). Of the deceased patients 41.1% had a renewed CRP increase after an initial decrease following tocilizumab administration, compared to 7.1% of the surviving patients (p = 0.0011). Documented bacterial superinfections were observed in 35.5% (27/76) of patients, of whom 48.1% (13/27) died.
CONCLUSIONS: CRP-decline and IL-6 increase after tocilizumab treatment occurs regularly. An increase of IL-6 levels exceeding tenfold of baseline IL-6 levels, an absolute peak of 1000 pg/ml or a renewed increase of CRP are associated with higher mortality. Suppressed CRP synthesis can impede the diagnosis of bacterial superinfections, thus increasing the risk for complications.

BACKGROUND: 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 < 60 kDa) might be promising, but data about the adsorption capacity as well as a potential harmful adsorption of anti-inflammatory cytokines are missing so far.
METHODS: The prospective Cyto-SOLVE-study included 15 patients with sepsis or other hyperinflammatory conditions (interleukin 6 > 500 pg/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: b l o o d f l o w ∗ c o n c e n t r a t i o n p r e - p o s t c o n c e n t r a t i o n pre . RESULTS: Most of the inflammatory mediators showed a high initial extracorporeal clearance of 70-100 ml/min after CS installation, which dropped quickly to 10-30 ml/min after 6 h 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 6 h was only observed for the pro-inflammatory cytokines tumor necrosis factorα (TNF-α) (median 284 vs. 230 pg/ml), vascular endothelial growth factor (VEGF) (median 294 vs. 252 pg/ml), macrophage inflammatory protein 1a (MIP-1a) (median 11.1 vs. 9.0 pg/ml), and regulated upon activation, normal T cell expressed and secreted (RANTES) (median 811 vs. 487 pg/ml) as well as the anti-inflammatory cytokines interleukin 4 (median 9.3 vs. 6.4 pg/ml), interleukin 10 (median 88 vs. 56 pg/ml), and platelet-derived growth factor (PDGF) (median 177 vs. 104 pg/ml). A significant (p < 0.05) decrease in patients\' blood after 12 h was only detected for interleukin 10.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov NCT04913298, registration date June 4, 2021.

Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. KD predominantly affects young children and shares clinical features and immunobiology with other hyperinflammation syndromes including systemic juvenile idiopathic arthritis (sJIA) and multisystem inflammatory syndrome in children (MIS-C). Cytokine storm syndrome (CSS) is an acute complication in ~2% of KD patients; however, the incidence is likely underestimated as many clinical and laboratory features of both diseases overlap. CSS should be entertained when a child with KD is unresponsive to IVIG therapy with recalcitrant fever. Early recognition and prompt institution of immunomodulatory treatment can substantially reduce the mortality and morbidity of CSS in KD. Given the known pathogenetic role of IL-1β in both syndromes, the early use of IL-1 blockers in refractory KD with CSS deserves consideration.

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.

Sepsis, a condition characterized by life-threatening organ dysfunction due to a dysregulated host response to infection, significantly impacts global health, with mortality rates varying widely across regions. Traditional therapeutic strategies that target hyperinflammation and immunosuppression have largely failed to improve outcomes, underscoring the need for innovative approaches. This review examines the development of therapeutic agents for sepsis, with a focus on clinical trials addressing hyperinflammation and immunosuppression. It highlights the frequent failures of these trials, explores the underlying reasons, and outlines current research efforts aimed at bridging the gap between theoretical advancements and clinical applications. Although personalized medicine and phenotypic categorization present promising directions, this review emphasizes the importance of understanding the complex pathogenesis of sepsis and developing targeted, effective therapies to enhance patient outcomes. By addressing the multifaceted nature of sepsis, future research can pave the way for more precise and individualized treatment strategies, ultimately improving the management and prognosis of sepsis patients.

In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with \'immunoparalysis\', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets\' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.

Hyperinflammation occurs in sepsis, especially in the early phase, and it could have both positive and negative effects on sepsis. Previously, we showed that a new concept of NF-κB inhibitor, exosome-based super-repressor IκBα (Exo-srIκB) delivery, has a beneficial effect on sepsis. Here, we further investigate the therapeutic effects of Exo-srIκB at different severities and phases of sepsis using an animal polymicrobial intra-abdominal infection model. We used a rat model of fecal slurry polymicrobial sepsis. First, we determined the survival effects of Exo-srIκB on sepsis according to the severity. We used two different severities of the animal sepsis model. The severe model had a mortality rate of over 50%. The mild/moderate model had a less than 30% mortality rate. Second, we administered the Exo-srIκB at various time points (1 h, 6 h, and 24 h after fecal slurry administration) to determine the therapeutic effect of Exo-srIκB at different phases of sepsis. Lastly, we determined the effects of the Exo-srIκB on cytokine production, arterial blood gas, electrolyte, and lactate. The survival gain was statistically significant in the severe sepsis model when Exo-srIκB was administered 6 h after sepsis. Interleukin 6 and interleukin-10 were significantly decreased in the kidney when administered with Exo-srIκB. The laboratory data showed that lactate, glucose, and potassium levels were significantly lowered in the NF-κB inhibitor group. In conclusion, Exo-srIκB exhibited a beneficial therapeutic effect when administered 6 h post fecal slurry administration in a severe sepsis model.

I propose that a deficiency of essential fatty acids (EFAs) and an alteration in their (EFAs) metabolism could be a major factor in the pathogenesis of sepsis and sepsis-related mortality. The failure of corticosteroids, anti-TNF-α, and anti-interleukin-6 monoclonal antibodies can be attributed to this altered EFA metabolism in sepsis. Vitamin C; folic acid; and vitamin B1, B6, and B12 serve as co-factors necessary for the activity of desaturase enzymes that are the rate-limiting steps in the metabolism of EFAs. The altered metabolism of EFAs results in an imbalance in the production and activities of pro- and anti-inflammatory eicosanoids and cytokines resulting in both hyperimmune and hypoimmune responses seen in sepsis. This implies that restoring the metabolism of EFAs to normal may form a newer therapeutic approach both in the prevention and management of sepsis and other critical illnesses.

Hemophagocytic lymphohistiocytosis (HLH) associated with dengue infection presents a unique challenge in clinical practice due to its rarity, rapid progression, and overlapping clinical features. This comprehensive review navigates the complexity of HLH-dengue syndrome by examining its pathophysiology, clinical manifestations, diagnostic criteria, and therapeutic strategies. HLH, characterized by uncontrolled immune activation and cytokine dysregulation, can occur as a secondary complication of dengue infection, leading to severe multiorgan dysfunction and high mortality if not promptly recognized and treated. The review underscores the significance of early diagnosis through vigilant clinical monitoring and appropriate diagnostic tests, such as bone marrow examinations and genetic studies. Collaboration between infectious disease specialists, hematologists, and critical care teams is essential for optimal management. Despite advancements in understanding HLH-dengue syndrome, further research is needed to elucidate its underlying mechanisms and explore novel treatment approaches. This review provides insights into the clinical implications of HLH-dengue syndrome and emphasizes the importance of a multidisciplinary approach to improve patient outcomes in this challenging clinical scenario.

In our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as diabetes mellitus, hypertension, and coronary heart disease of the patients were determined as the variables to be matched. We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR 4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR 5.1) were lower in the Anakinra group than SoC. No patient experienced cerebrovascular accident and/or clinically evident deep venous thrombosis both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and acute coronary syndrome (ACS) were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as ACS. In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with severe and critical COVID-19.