Presepsin as a diagnostic and prognostic biomarker of severe bacterial infections and COVID-19.

We aimed to develop presepsin as a marker of diagnosis of severe infections of either bacterial and viral origin. The derivation cohort was recruited from 173 hospitalized patients with acute pancreatitis or post-operative fever or infection suspicion aggravated by at least one sign of the quick sequential organ failure assessment (qSOFA). The first validation cohort was recruited from 57 admissions at the emergency department with at least one qSOFA sign and the second validation cohort from 115 patients with COVID-19 pneumonia. Presepsin was measured in plasma by the PATHFAST assay. Concentrations more than 350 pg/ml had sensitivity 80.2% for sepsis diagnosis in the derivation cohort (adjusted odds ratio 4.47; p < 0.0001). In the derivation cohort, sensitivity for 28-day mortality prognosis was 91.5% (adjusted odds ratio 6.82; p: 0.001). Concentrations above 350 pg/ml had sensitivity 93.3% for the diagnosis of sepsis in the first validation cohort; this was 78.3% in the second validation cohort of COVID-19 aiming at the early diagnosis of acute respiratory distress syndrome necessitating mechanical ventilation. The respective sensitivity for 28-day mortality was 85.7% and 92.3%. Presepsin may be a universal biomarker for the diagnosis of severe infections of bacterial origin and prediction of unfavorable outcome.

Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial.

The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.

Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients.

INTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-α by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.

Polymicrobial bloodstream infections: Epidemiology and impact on mortality.

The aim of this study was to investigate the impact of polymicrobial bloodstream infections (pBSIs) on the outcome of sepsis in an area where antimicrobial resistance is of concern. This was a retrospective analysis of data collected prospectively from patients developing BSI outside of an intensive care unit (non-ICU patients) or after ICU admission. Demographics and clinical characteristics were compared for patients with pBSI versus monomicrobial BSI (mBSI) and following stratification by ICU or non-ICU and severity of sepsis status. Possible risk factors for adverse outcome were explored by multivariate analysis, and outcomes were measured by Cox regression analysis. Among 412 patients with BSI, 47 patients (11.4%) with pBSI were recorded; compared with patients with mBSI, they had significantly higher APACHE II scores and presented more frequently with severe sepsis/septic shock. The all-cause 28-day mortality was significantly higher for pBSI versus mBSI (38.3% vs. 24.7%; P=0.033), whereas appropriateness of treatment was comparable (78.7% vs. 86.6%). Primary bacteraemia by combinations of Enterococcus faecalis, Klebsiella pneumoniae and Acinetobacter baumannii was predominant among pBSIs; in mBSIs, urinary tract infections by Escherichia coli, K. pneumoniae or Pseudomonas aeruginosa predominated. Multivariate analysis demonstrated pBSI as a significant contributor to 28-day mortality (HR=1.86; P=0.039), along with presence of two or more co-morbidities (HR=2.35; P=0.004). In conclusion, pBSIs differed epidemiologically from mBSIs, with the emergence of enterococcal species, and portended an almost two-fold increased risk of 28-day mortality. Prospective studies are warranted to elucidate possibly modifiable factors.

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

INTRODUCTION: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed. METHODS: A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden. RESULTS: Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥ 17 and suPAR ≥ 12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥ 12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥ 17 and suPAR ≥ 12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort. CONCLUSIONS: A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

Early changes of procalcitonin may advise about prognosis and appropriateness of antimicrobial therapy in sepsis.

PURPOSE: The objective of this study is to define if early changes of procalcitonin (PCT) may inform about prognosis and appropriateness of administered therapy in sepsis. METHODS: A prospective multicenter observational study was conducted in 289 patients. Blood samples were drawn on day 1, that is, within less than 24 hours from advent of signs of sepsis, and on days 3, 7, and 10. Procalcitonin was estimated in serum by the ultrasensitive Kryptor assay (BRAHMS GmbH, Hennigsdorf, Germany). Patients were divided into the following 2 groups according to the type of change of PCT: group 1, where PCT on day 3 was decreased by more than 30% or was below 0.25 ng/mL, and group 2, where PCT on day 3 was either increased above 0.25 ng/mL or decreased less than 30%. RESULTS: Death occurred in 12.3% of patients of group 1 and in 29.9% of those of group 2 (P < .0001). Odds ratio for death of patients of group 1 was 0.328. Odds ratio for the administration of inappropriate antimicrobials of patients of group 2 was 2.519 (P = .003). CONCLUSIONS: Changes of serum PCT within the first 48 hours reflect the benefit or not of the administered antimicrobial therapy. Serial PCT measurements should be used in clinical practice to guide administration of appropriate antimicrobials.

Risk factors and outcomes associated with acquisition of colistin-resistant KPC-producing Klebsiella pneumoniae: a matched case-control study.

A matched 1:3 case-control study investigated factors predicting colistin-resistant versus colistin-susceptible KPC-producing Klebsiella pneumoniae acquisition and its impact on patient outcomes. Case patients were more often admitted from other institutions (P = 0.019) and had longer therapy with beta-lactam/beta-lactamase inhibitors (P = 0.002) and higher overall mortality (P = 0.05). All 52 study isolates were clonally related, suggesting horizontal dissemination. None of these parameters independently predicted colistin resistance, which probably occurred in a susceptible KPC-KP strain that was subsequently disseminated horizontally.