Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock

Introduction: Rapid detection of, and optimized treatment for, severe sepsis and septic shock is crucial for successful outcome. Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in the plasma of patients with severe sepsis and septic shock in the ICU. Methods: A prospective study was conducted of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. A total of 179 patients was included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission. Results: HBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of >= 15 ng/mL and/or a HBP (ng/mL)/white blood cell count (10(9)/L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n = 151) and in the whole group (n = 179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days. Conclusions: Plasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with a non-septic illness in the ICU. HBP was associated with severity of disease and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis. Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections

Higher plasma drug levels in elderly people living with HIV treated with darunavir

Background The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged < 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and sideeffects in PLHIV aged < 65 years of age, with controls > 49 years of age. Methods Patients < 65 years of age and controls > 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. Results Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (<49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). Conclusions Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged < 65 years of age, compared to controls >49 years of age

Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox

Mpox represents a persistent health concern with varying disease severity. Reinfections with mpox virus (MPXV) are rare, possibly indicating effective memory responses to MPXV or related poxviruses, notably vaccinia virus (VACV) from smallpox vaccination. We assessed cross-reactive and virus-specific CD4+ and CD8+ T cells in healthy individuals and mpox convalescent donors. Cross-reactive T cells were most frequently observed in healthy donors over 45 years. Notably, long-lived memory CD8+ T cells targeting conserved VACV/MPXV epitopes were identified in older individuals more than four decades after VACV exposure and exhibited stem-like characteristics, defined by T cell factor-1 (TCF-1) expression. In mpox convalescent donors, MPXV-reactive CD4+ and CD8+ T cells were more prevalent compared to controls, demonstrating enhanced functionality and skewing towards effector phenotypes, which correlated with milder disease. Collectively, we report robust effector memory MPXV-specific T cell responses in mild mpox and long-lived TCF-1+ VACV/MPXV-specific CD8+ T cells decades after smallpox vaccination

Host cell adhesion of Plasmodium falciparum - infected erythrocytes

Excessive binding of Plasmodium falciparum-infected erythrocytes to the microvascular endothelium (cytoadherence) and to uninfected eryrthrocytes (rosetting) are regarded as key-events in the development of a severe malaria infection. P.falciparum rosetting was confirmed to be associated with the development of cerebral malaria in The Gambia. It was also found that there is a lack of anti-rosetting activity in sera from children with severe malaria disease, estahlishing the importance of rosetting as a marker for a parasite prone to cause complicated malaria The parasite makes use of serum proteins such as immunoglobulins and fibrinogen to acquire or improve its binding abilities to uninfected erythrocytes, but there seems to exist a variation inbetween strains. The binding of non-immune immunoglobulins and fibrinogen to the surface of the P. falciparum-infected erythrocytes causes the formation of a fibrillar structure which is connected to the ability to form rosettes. Further, polyclonal antibodies directed towards human immunoglobulins or fibrinogen could disrupt already formed rosettes. The endothelial receptor PECAM-I/CD31 was shown to be a cytoadhesion receptor for P. falciparum. PECAM-I/CD31 is involved in endothelial-endothelial binding as well as leukocyte-endothelial binding. The adhesion of P. falciparum is mediated by domains 1-2, close to the leukocyte binding site. P.falciparum clones that were by micro-manipulalion selecled for the rosette formation ability and then tested for adhesion to a series of known P. falciparum receptors were tound to be multi-adhesive, i.e. the PRBC recognise multiple host cell receptors. The trypsin sensitivity of the high molecular weight surface exposed, P. falciparum erythrocyte membrane protein I (PfEMPI) was similar to the trypsin sensitivity of most binding features studied (rosetting, blood group A adhesion, CD36-binding, auto-agglutination and immunoglobulin-binding) except binding to human umbilical vein endothelial cells that was abolished only at higher trypsin concentrations. Taken together, this suggests that PfEMPI is the main mediator of P. falciparum adhesion, yet other parasite polypepthles, such as the low molecular weight Rosettins, may play important roles. In this thesis several new adhesive phenotypes of P. falciparum have been identified that may play crucial roles in the process leading to severe, sometimes fatal, P. falciparum infection