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Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases.

Background Recent single-center reports have suggested that community-acquired bacteremic co-infection in the context of Coronavirus disease 2019 (COVID-19) may be an important driver of mortality; however, these reports have not been validated with a multicenter, demographically diverse, cohort study with data spanning the pandemic. Methods In this multicenter, retrospective cohort study, inpatient encounters were assessed for COVID-19 with community-acquired bacteremic co-infection using 48-h post-admission blood cultures and grouped by: (1) confirmed co-infection [recovery of bacterial pathogen], (2) suspected co-infection [negative culture with ≥ 2 antimicrobials administered], and (3) no evidence of co-infection [no culture]. The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation. COVID-19 bacterial co-infection risk factors and impact on primary outcomes were determined using multivariate logistic regressions and expressed as adjusted odds ratios with 95% confidence intervals (Cohort, OR 95% CI, Wald test p value). Results The studied cohorts included 13,781 COVID-19 inpatient encounters from 2020 to 2022 in the University of Alabama at Birmingham (UAB, n = 4075) and Ochsner Louisiana State University Health—Shreveport (OLHS, n = 9706) cohorts with confirmed (2.5%), suspected (46%), or no community-acquired bacterial co-infection (51.5%) and a comparison cohort consisting of 99,170 inpatient encounters from 2010 to 2019 (UAB pre-COVID-19 pandemic cohort). Significantly increased likelihood of COVID-19 bacterial co-infection was observed in patients with elevated ≥ 15 neutrophil-to-lymphocyte ratio (UAB: 1.95 [1.21–3.07]; OLHS: 3.65 [2.66–5.05], p < 0.001 for both) within 48-h of hospital admission. Bacterial co-infection was found to confer the greatest increased risk for in-hospital mortality (UAB: 3.07 [2.42–5.46]; OLHS: 4.05 [2.29–6.97], p < 0.001 for both), ICU admission (UAB: 4.47 [2.87–7.09], OLHS: 2.65 [2.00–3.48], p < 0.001 for both), and mechanical ventilation (UAB: 3.84 [2.21–6.12]; OLHS: 2.75 [1.87–3.92], p < 0.001 for both) across both cohorts, as compared to other risk factors for severe disease. Observed mortality in COVID-19 bacterial co-infection (24%) dramatically exceeds the mortality rate associated with community-acquired bacteremia in pre-COVID-19 pandemic inpatients (5.9%) and was consistent across alpha, delta, and omicron SARS-CoV-2 variants. Conclusions Elevated neutrophil-to-lymphocyte ratio is a prognostic indicator of COVID-19 bacterial co-infection within 48-h of admission. Community-acquired bacterial co-infection, as defined by blood culture-positive results, confers greater increased risk of in-hospital mortality, ICU admission, and mechanical ventilation than previously described risk factors (advanced age, select comorbidities, male sex) for COVID-19 mortality, and is independent of SARS-CoV-2 variant.

Sepsis in children is typically presumed to be bacterial in origin until proven otherwise, but frequently bacterial cultures ultimately return negative. Although viruses may be important causative agents of culture-negative sepsis worldwide, the incidence, disease burden and mortality of viral-induced sepsis is poorly elucidated. Consideration of viral sepsis is critical as its recognition carries implications on appropriate use of antibacterial agents, infection control measures, and, in some cases, specific, time-sensitive antiviral therapies. This review outlines our current understanding of viral sepsis in children and addresses its epidemiology and pathophysiology, including pathogen-host interaction during active infection. Clinical manifestation, diagnostic testing, and management options unique to viral infections will be outlined.

Objectives: Compare the impact of initial extubation to positive airway pressure versus high-flow nasal cannula on postoperative outcomes in neonates and infants after congenital heart surgery. Design: Retrospective cohort study with propensity-matched analysis. Setting: Cardiac ICU within a tertiary care children’s hospital. Patients: Patients less than 6 months old initially extubated to either high-flow nasal cannula or positive airway pressure after cardiac surgery with cardiopulmonary bypass were included (July 2012 to December 2015). Interventions: None. Measurements and Main Results: Of 258 encounters, propensity matching identified 49 pairings of patients extubated to high-flow nasal cannula versus positive airway pressure. Extubation failure was 12% for all screened encounters. After matching, there was no difference in extubation failure rate between groups (positive airway pressure 16% vs high-flow nasal cannula 10%; p = 0.549). However, compared with high-flow nasal cannula, patients initially extubated to positive airway pressure experienced greater resource utilization: longer time to low-flow nasal cannula (83 vs 28 hr; p = 0.006); longer time to room air (159 vs 110 hr; p = 0.013); and longer postsurgical hospital length of stay (22 vs 14 d; p = 0.015). Conclusions: In this pediatric cohort, primary extubation to positive airway pressure was not superior to high-flow nasal cannula with respect to prevention of extubation failure after congenital heart surgery. Compared with high-flow nasal cannula, use of positive airway pressure was associated with increased hospital resource utilization. Prospective initiatives aimed at establishing best clinical practice for postoperative noninvasive respiratory support are needed.