Acute vascular endothelial dysfunction is a central event in the pathogenesis of sepsis, increasing vascular permeability, promoting activation of the coagulation cascade, tissue edema and compromising perfusion of vital organs. Aging and chronic diseases (hypertension, dyslipidaemia, diabetes mellitus, chronic kidney disease, cardiovascular disease, cerebrovascular disease, chronic pulmonary disease, liver disease, or cancer) are recognized risk factors for sepsis. In this article we review the features of endothelial dysfunction shared by sepsis, aging and the chronic conditions preceding this disease. Clinical studies and review articles on endothelial dysfunction in sepsis, aging and chronic diseases available in PubMed were considered. The main features of endothelial dysfunction shared by sepsis, aging and chronic diseases were: (1) increased oxidative stress and systemic inflammation, (2) glycocalyx degradation and shedding, (3) disassembly of intercellular junctions, endothelial cell death, blood-tissue barrier disruption, (4) enhanced leukocyte adhesion and extravasation, (5) induction of a pro-coagulant and anti-fibrinolytic state. In addition, chronic diseases impair the mechanisms of endothelial reparation. In conclusion, sepsis, aging and chronic diseases induce similar features of endothelial dysfunction. The potential contribution of pre-existent endothelial dysfunction to sepsis pathogenesis deserves to be further investigated.

Background: Intensive care unit-acquired pneumonia (ICU-AP) is a severe complication in patients admitted to the ICU. Lymphocytopenia is a marker of poor prognosis in patients with community-acquired pneumonia, but its impact on ICU-AP prognosis is unknown. We aimed to evaluate whether lymphocytopenia is an independent risk factor for mortality in non-immunocompromised patients with ICU-AP. Methods: Prospective observational cohort study of patients from six ICUs of an 800-bed tertiary teaching hospital (2005 to 2016). Results: Of the 473 patients included, 277 (59%) had ventilator-associated pneumonia (VAP). Receiver operating characteristic (ROC) analysis of the lymphocyte counts at diagnosis showed that 595 cells/mm³ was the best cut-off for discriminating two groups of patients at risk: lymphocytopenic group (lymphocyte count <595 cells/mm³, 141 patients (30%)) and non-lymphocytopenic group (lymphocyte count ≥595 cells/mm³, 332 patients (70%)). Patients with lymphocytopenia presented more comorbidities and a higher sequential organ failure assessment (SOFA) score at the moment of pneumonia diagnosis. Also, 28-day mortality and 90-day mortality were higher in patients with lymphocytopenia (28-day: 38 (27%) versus 59 (18%), 90-day: 74 (53%) versus 111 (34%)). In the multivariable model, <595 cells/mm³ resulted to be an independent predictor for 90-day mortality (Hazard Ratio 1.41; 95% Confidence Interval 1.02 to 1.94). Conclusion: Lymphocytopenia is an independent predictor of 90-day mortality in non-immunocompromised patients with ICU-AP.

Intravenous immunoglobulins (IVIGs) have not yet demonstrated robust evidence in the benefit for treatment of sepsis. In spite of multiple clinical trials performed with IVIG in sepsis, it remains an experimental therapy for this severe condition. Nonetheless, these trials do not address a number of potential confounding factors, concerning both the patient and the IVIG preparations, which could greatly affect the final result. To name a few, endogenous levels of immunoglobulin isotypes and subclasses are not assessed prior to treatment. The presence/absence of patient antibodies against the microorganism(s) causing sepsis is not evaluated. The accuracy of antibiotic prescription is not included as an adjusting variable. The degree of patient immunosuppression (previous or induced by sepsis) is not documented. In turn, the concentration and antimicrobial specificities of the antibodies contained in the batches of IVIG are not assessed. Neither the pharmacokinetics of IVIG nor its potential immunomodulatory effects are evaluated. In addition, the concept of ‘window of opportunity’ for IVIG administration following diagnosis of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition.