Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes.

BACKGROUND: Circulating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. OBJECTIVES: We aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. METHODS: Histone-fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). RESULTS: Fibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 µg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate-severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. CONCLUSION: Fibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis.

C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP-VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro-generated and naturally occurring CRP-VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcγ and scavenger receptors are involved and a competitive mechanism for clearance of CRP-VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP-VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis.

Evidence of Significant Ceftriaxone and Quinolone Resistance in Cirrhotics with Spontaneous Bacterial Peritonitis.

OBJECTIVES: There are few studies addressing the impact of cephalosporin and quinolone resistance on hospital length of stay and mortality in spontaneous bacterial peritonitis (SBP). We aim to describe the shifting epidemiology of SBP at our institution and its impact on clinical outcomes. METHODS: We performed a single-center retrospective cohort study of all cases of SBP from 2005 to 2015 at a transplant center. Cases were identified using hospital billing data. Patient data were confirmed using the electronic medical record. Univariate and multivariate logistic regression and Cox proportional hazards models were used to identify factors that were associated with prolonged hospital length of stay and reduced survival. Culture-positive cases (N = 56) were compared to culture-negative cases (N = 104). Subpopulation analysis of the culture-positive cases compared ceftriaxone-resistant (N = 25) to ceftriaxone-susceptible (N = 31) cases. RESULTS: We identified 160 cases of SBP (56 culture positive and 104 culture negative; 21 nosocomial, 79 hospital associated, and 60 community acquired). Forty-five percent (N = 25 total, 13 hospital associated and 6 nosocomial) of bacterial isolates were resistant to ceftriaxone, with 37.5% (N = 21) being gram positive, including 8 methicillin-resistant staphylococcus and 6 vancomycin-resistant enterococcus. Multivariate analysis identified hospital-associated SBP, age, alcoholic cirrhosis, and MELD-Na score as variables associated with worse survival (P < 0.05), with a trend toward worse survival in culture-positive cases (P = 0.123). Only MELD-Na was associated with prolonged length of stay. CONCLUSIONS: The burden of resistant pathogens causing SBP is significant, notably in hospital-associated SBP. Culture-positive SBP may represent a higher risk group compared to culture-negative SBP.

Pseudoceramide for childhood eczema: does it work?

OBJECTIVES: Atopic eczema is a chronic relapsing skin disease associated with atopy, and characterised by reduced skin hydration, impaired skin integrity (transepidermal water loss), and poor quality of life. Proper emollient usage is an important facet of its management. This study aimed to establish an approach to evaluate the efficacy of using an emollient over a 4-week period. DESIGN: Prospective observational study. SETTING: A paediatric dermatology out-patient clinic of a university teaching hospital in Hong Kong. PATIENTS: Consecutive new patients aged 5 to 18 years with atopic eczema diagnosed according to Hanifin and Rajka's criteria were recruited from March to August 2009. They or their parents were instructed to liberally apply the test emollient to the flexures and areas affected with eczema, twice daily. Outcome assessments were repeated 2 and 4 weeks later. MAIN OUTCOME MEASURES: Skin hydration and transepidermal water loss in the right forearm (2 cm below antecubital flexure), and disease severity (SCORing Atopic Dermatitis index) and Children's Dermatology Life Quality Index. At the end of the study period, a global assessment of treatment was recorded. RESULTS: Thirty-three patients with atopic eczema were recruited and treated with applications of a pseudoceramide-containing cream (Curel, Kao, Japan). The mean age of the patients (16 males and 17 females) was 12 (standard deviation, 4) years. Four weeks following the use of the cream, skin hydration improved significantly and fewer patients were using topical corticosteroids. In these patients, there was no deterioration in transepidermal water loss, eczema severity, or quality of life. CONCLUSION: The pseudoceramide cream improved skin hydration but not severity or quality of life over a 4-week usage.