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COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces \"microthrombi strings\" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.

Background: Multiorgan dysfunction (MOD) is one of four consensus based criteria for the diagnosis of intrapartum asphyxia. The theoretical concept behind MOD is the diving reflex (conservation of blood flow to vital organs at the cost of non-vital organs). Objectives: To assess the patterns of involvement of each major organ/system and combinations of involvement in infants with post-asphyxial hypoxic-ischaemic encephalopathy (HIE), and to describe this in relation to long term outcome. Design: Retrospective cohort study. Setting: Regional tertiary neonatal intensive care unit at the Hospital for Sick Children, Toronto, Canada. Patients: Term neonates with post-intrapartal asphyxial HIE assessed for kidney, cardiovascular system, lung, and liver function. Outcome: Death and presence or absence of severe neurodevelopmental disability. Results: Out of 130 of 144 eligible infants with outcome data, 80 (62%) had severe adverse outcome and 50 (38%) had good outcome. All infants had evidence of MOD (at least one organ dysfunction in addition to HIE). Renal, cardiovascular, pulmonary, and hepatic dysfunction was present in 58–88% of infants with good outcome and 64–86% of infants with adverse outcome. Conclusions: MOD was present in all the infants with severe post-asphyxial HIE. However, there was no association between MOD and outcome in these infants. No relation between individual or combinations of organ involvements and long term outcomes was observed.

Background: Abnormalities in hematologic, biochemical, and immunologic biomarkers have been shown to be associated with severity and mortality in Coronavirus Disease 2019 (COVID-19). Therefore, early evaluation and monitoring of both liver and kidney functions, as well as hematologic parameters, are pivotal to forecast the progression of COVID-19. Objectives: In this study, we performed a systematic review and meta-analysis to investigate the association between several complications, including acute kidney injury (AKI), acute liver injury (ALI), and coagulopathy, with poor outcomes in COVID-19. Design: Systematic review and meta-analysis Setting: Observational studies reporting AKI, ALI, and coagulopathy along with the outcomes of clinically validated death, severe COVID-19, or intensive care unit (ICU) care were included in this study. The exclusion criteria were abstract-only publications, review articles, commentaries, letters, case reports, non-English language articles, and studies that did not report key exposures or outcomes of interest. Patients: Adult patients diagnosed with COVID-19. Measurements: Data extracted included author, year, study design, age, sex, cardiovascular diseases, hypertension, diabetes mellitus, respiratory comorbidities, chronic kidney disease, mortality, severe COVID-19, and need for ICU care. Methods: We performed a systematic literature search from PubMed, SCOPUS, EuropePMC, and the Cochrane Central Database. AKI and ALI follow the definition of the included studies. Coagulopathy refers to the coagulopathy or disseminated intravascular coagulation defined in the included studies. The outcome of interest was a composite of mortality, need for ICU care, and severe COVID-19. We used random-effects models regardless of heterogeneity to calculate risk ratios (RRs) for dichotomous variables. Heterogeneity was assessed using I2. Random effects meta-regression was conducted for comorbidities and the analysis was performed for one covariate at a time. Results: There were 3615 patients from 15 studies. The mean Newcastle-Ottawa scale of the included studies was 7.3 ± 1.2. The AKI was associated with an increased the composite outcome (RR: 10.55 [7.68, 14.50], P < .001; I2: 0%). Subgroup analysis showed that AKI was associated with increased mortality (RR: 13.38 [8.15, 21.95], P < .001; I2: 24%), severe COVID-19 (RR: 8.12 [4.43, 14.86], P < .001; I2: 0%), and the need for ICU care (RR: 5.90 [1.32, 26.35], P = .02; I2: 0%). The ALI was associated with increased mortality (RR: 4.02 [1.51, 10.68], P = .005; I2: 88%) in COVID-19. Mortality was higher in COVID-19 with coagulopathy (RR: 7.55 [3.24, 17.59], P < .001; I2: 69%). The AKI was associated with the composite outcome and was not influenced by age (P = .182), sex (P = .104), hypertension (P = .788), cardiovascular diseases (P = .068), diabetes (P = .097), respiratory comorbidity (P = .762), and chronic kidney disease (P = .77). Limitations: There are several limitations of this study. Many of these studies did not define the extent of AKI (grade), which may affect the outcome. Acute liver injury and coagulopathy were not defined in most of the studies. The definition of severe COVID-19 differed across studies. Several articles included in the study were published at preprint servers and are not yet peer-reviewed. Most of the studies were from China; thus, some patients might overlap across the reports. Most of the included studies were retrospective in design. Conclusions: This meta-analysis showed that the presence of AKI, ALI, and coagulopathy was associated with poor outcomes in patients with COVID-19.

In addition to protective “immune response”, sepsis is characterized by destructive “endothelial response” of the host, leading to endotheliopathy and its molecular dysfunction. Complement activation generates membrane attack complex (MAC). MAC causes channel formation to the cell membrane of pathogen, leading to death of microorganisms. In the host, MAC also may induce channel formation to innocent bystander endothelial cells (ECs) and ECs cannot be protected. This provokes endotheliopathy, which activates two independent molecular pathways: inflammatory and microthrombotic. Activated inflammatory pathway promotes the release of inflammatory cytokines and triggers inflammation. Activated microthrombotic pathway mediates platelet activation and exocytosis of unusually large von Willebrand factor multimers (ULVWF) from ECs and initiates microthrombogenesis. Excessively released ULVWF become anchored to ECs as long elongated strings and recruit activated platelets to assemble platelet-ULVWF complexes and form “microthrombi”. These microthrombi strings trigger disseminated intravascular microthrombosis (DIT), which is the underlying pathology of endotheliopathy-associated vascular microthrombotic disease (EA-VMTD). Sepsis-induced endotheliopathy promotes inflammation and DIT. Inflammation produces inflammatory response and DIT orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome (MODS). Systemic inflammatory response syndrome (SIRS) is a combined phenotype of inflammation and endotheliopathy-associated (EA)-VMTD. Successful therapeutic design for sepsis can be achieved by counteracting the pathologic microthrombogenesis.

Background Systemic inflammation in COVID-19 often leads to multiple organ failure, including acute kidney injury (AKI). Renal replacement therapy (RRT) in combination with sequential extracorporeal blood purification therapies (EBP) might support renal function, attenuate systemic inflammation, and prevent or mitigate multiple organ dysfunctions in COVID-19. Aim Describe overtime variations of clinical and biochemical features of critically ill patients with COVID-19 treated with EBP with a hemodiafilter characterized by enhanced cytokine adsorption properties. Methods An observational prospective study assessing the outcome of patients with COVID-19 admitted to the ICU (February to April 2020) treated with EBP according to local practice. Main endpoints included overtime variation of IL-6 and multiorgan function-scores, mortality, and occurrence of technical complications or adverse events. Results The study evaluated 37 patients. Median baseline IL-6 was 1230 pg/ml (IQR 895) and decreased overtime ( p  < 0.001 Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 24 h ( p  = 0.001). The reduction in serum IL-6 concentrations correlated with the improvement in organ function, as measured in the decrease of SOFA score (rho = 0.48, p  = 0.0003). Median baseline SOFA was 13 (IQR 6) and decreased significantly overtime ( p  < 0.001 at Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 48 h (median 8 IQR 5, p  = 0.001). Compared to the expected mortality rates, as calculated by APACHE IV, the mean observed rates were 8.3% lower after treatment. The best improvement in mortality rate was observed in patients receiving EBP early on during the ICU stay. Premature clotting (running < 24 h) occurred in patients (18.9% of total) which featured higher effluent dose (median 33.6 ml/kg/h, IQR 9) and higher filtration fraction (median 31%, IQR 7.4). No electrolyte disorders, catheter displacement, circuit disconnection, unexpected bleeding, air, or thromboembolisms due to venous cannulation of EBP were recorded during the treatment. In one case, infection of vascular access occurred during RRT, requiring replacement. Conclusions EBP with heparin-coated hemodiafilter featuring cytokine adsorption properties administered to patients with COVID-19 showed to be feasible and with no adverse events. During the treatment, patients experienced serum IL-6 level reduction, attenuation of systemic inflammation, multiorgan dysfunction improvement, and reduction in expected ICU mortality rate.

We sought to determine whether an early high-density lipoprotein cholesterol (HDL-C) measurement at emergency department (ED) admission is prognostic of multiorgan dysfunction syndrome (MODS) and death in a suspected sepsis cohort. Two hundred patients with clinically suspected sepsis were recruited at admission to our tertiary care hospital's ED. Lipids were measured at the time of first ED blood draw. Clinical data were collected via chart review. Primary outcomes of interest were development of MODS and 28-day mortality. Secondary outcomes included need for critical care, single-organ failures, days alive and free of vasopressor and ventilator support, and 90-day mortality. High-density lipoprotein cholesterol was greatly decreased in patients who developed MODS and/or died and remained stable over the first week of admission. Receiver operator characteristic analysis demonstrated that HDL-C had superior predictive ability compared with all routine clinical markers for both development of MODS and 28-day mortality, and identified an HDL-C cutoff of 25.1 mg/dL below which patients were at significantly greater risk for development of all adverse outcomes. Plasma HDL-C level was characterized by early decrease and high stability, and was the best prognostic marker for adverse outcomes in a suspected sepsis cohort.

IntroductionDue to its mood-stabilizing properties, clozapine is known for reducing symptom severity in manic episodes of treatment-resistant bipolar disorder as well as in treatment-resistant schizophrenia. However, its use may be hindered by potential adverse effects, including hematologic ones, such as non-dose-dependent eosinophilia. The mechanism of the underlying process probably involves a type-I hypersensitivity reaction, which can manifest as either transient asymptomatic eosinophilia or as eosinophilia with multiorgan dysfunction.ObjectivesWe present the case of a patient diagnosed with manic episode of schizoaffective disorder who developed eosinophilia, with severe systemic manifestations, in response to clozapine therapy. A review of literature will be conducted in order to provide further insight into the phenomenon.MethodsCase report and literature review.ResultsThe incidence of eosinophilia reported in literature ranges between 0.2% and 62%, with its appearance about three weeks after clozapine initiation. Although clozapine is an antipsychotic that normally requires frequent monitoring due to the potential side effect of agranulocytosis, we would like to place emphasis on the possible risk of eosinophilia, in connection with potential fatal complications. As described in this report, eosinophilia could long remain unrecognized due to subsequent multiorgan involvement, including lymphadenopathy, leukocytosis, lymphopenia, anemia, liver enzyme elevations, as well as pleural effusion, all of which were described in our patient.ConclusionsClozapine-associated eosinophilia may be used as an early marker of possible clozapine-induced systemic complications and it may warrant prompt discontinuation of the causing drug, as suggested by the literature.

Endotoxin septic shock is marked by severe organ failure and mortality rate that exceeds fifty percent, underscoring the critical need to tailor management strategies. Monitoring -endotoxin activity can guide the initiation and direction of adjunctive treatment for refractory septic shock through hemoadsorption. Thus, intervening based on the pathophysiological foundation may potentially improve outcomes. This represents a step towards precision medicine in the management of septic shock adjunctive therapies, addressing a knowledge gap in this pathology that remains insufficiently defined. Despite its potential, in the setting of refractory septic shock and multiorgan dysfunction with extreme endotoxin activity (EAA ≥ 0.9), the data about efficacy of endotoxin hemoadsorption is scarce.

Sepsis-induced acute kidney injury (AKI) carries high mortality, and treatment options beyond supportive care are limited. Mesenchymal stem cells (MSCs) offer therapeutic potential due to their paracrine properties but are limited by poor survival and engraftment post-transplantation. Preconditioning with melatonin (MEL) may enhance MSC efficacy. This study aimed to compare the renoprotective effects of MSCs alone versus melatonin-preconditioned MSCs (MSCs+MEL) in a rat model of septic AKI. Polymicrobial sepsis was induced in male Wistar rats via cecal ligation and puncture (CLP). Three hours post-CLP, animals received an intraperitoneal injection of either MSCs (1 × 10^6), MSCs+MEL, or vehicle. Renal function, oxidative/antioxidant markers, inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB), apoptosis, and histopathology were assessed. CLP-induced sepsis resulted in significant AKI, evidenced by elevated inflammatory and apoptotic markers, oxidative stress, and histopathological damage. Both treatment groups showed improved kidney function and histology compared to untreated septic controls. However, the MSCs+MEL combination was significantly more effective. It superiorly reduced the expression of IL-1β, IL-6, TNF-α, NF-κB, attenuated oxidative stress and apoptosis, enhanced antioxidant defenses, and resulted in more pronounced histological improvement, as confirmed by immunohistochemistry. Preconditioning with melatonin synergistically enhances the therapeutic efficacy of MSCs in septic AKI. The MSCs+MEL combination exerts superior renoprotection by more robustly mitigating inflammation, oxidative stress, and apoptosis while promoting tissue repair.

Disseminated strongyloidiasis carries high mortality in immunosuppressed populations. We report a case of refractory Strongyloides stercoralis-induced severe diarrhea and sepsis successfully treated with fecal microbiota transplantation (FMT). A 68-year-old male with nephrotic syndrome on long-term glucocorticoids developed hyperinfection syndrome manifesting as septic shock, multiorgan dysfunction, and intractable diarrhea (>30 episodes/day). Conventional therapies including antiparasitics (albendazole), antibiotics, and probiotics failed. FMT achieved rapid symptom resolution and microbiota restoration. This case highlights FMT's potential in modulating gut-parasite interactions and suggests its role as adjunctive therapy for parasitic hyperinfection syndromes.