The pandemic 2019 novel coronavirus disease (COVID-19) shares certain clinical characteristics with other acute viral infections. We studied the whole-blood transcriptomic host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using RNAseq from 24 healthy controls and 62 prospectively enrolled patients with COVID-19. We then compared these data to non-COVID-19 viral infections, curated from 23 independent studies profiling 1,855 blood samples covering six viruses (influenza, respiratory syncytial virus (RSV), human rhinovirus (HRV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Ebola, dengue). We show gene expression changes in COVID-19 versus non-COVID-19 viral infections are highly correlated (r = 0.74, p < 0.001). However, we also found 416 genes specific to COVID-19. Inspection of top genes revealed dynamic immune evasion and counter host responses specific to COVID-19. Statistical deconvolution of cell proportions maps many cell type proportions concordantly shifting. Discordantly increased in COVID-19 were CD56bright natural killer cells and M2 macrophages. The concordant and discordant responses mapped out here provide a window to explore the pathophysiology of the host response to SARS-CoV-2.

Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods.

Hydrogen sulfide (H₂S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H₂S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H₂S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P. aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase (Cse) gene (Cse^-/-) and wild-type mice with a physiological expression (Cse^+/+). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse^+/+ donor; c) treatment with H₂S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H₂S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H₂S compared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H₂S higher and less than 5.3 μΜ (p = 7 x 10⁻⁶). In mice expression of Cse and application of STS afforded protection against infection with multidrug-resistant P. aeruginosa. Cyclophosphamide pretreatment eliminated the survival benefit of Cse^+/+ mice, whereas BMT increased the survival of Cse^-/- mice. Cse^-/- mice had increased pathogen loads compared to Cse^+/+ mice. Phagocytic activity of leukocytes from Cse^-/- mice was reduced but was restored after H₂S supplementation. An H₂S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H₂S is a potential independent parameter correlating with the outcome of P. aeruginosa. H₂S provides resistance to infection by MDR bacterial pathogens.

Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5–24.9 kg/m²; n = 67), overweight (BMI, 25.0–29.9 kg/m²; n = 56), and obesity (BMI ≥30 kg/m²; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight (P = 0.008) and overweight (P = 0.02), whereas adiponectin and resistin plasma concentrations were not different (P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients (P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731–0.914) than C-reactive protein (AUC 0.758; CI 0.658–0.857), PCT (AUC 0.593; CI 0.474–0.711) and White Blood Cell count (AUC 0.577; CI 0.46–0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases.