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Background: Risk stratification of emergency department patients with suspected acute infections and/or suspected sepsis remains challenging. We prospectively validated a 29-messenger RNA host response classifier for predicting severity in these patients. Methods: We enrolled adults presenting with suspected acute infections and at least one vital sign abnormality to six emergency departments in Greece. Twenty-nine target host RNAs were quantified on NanoString nCounter and analyzed with the Inflammatix Severity 2 (IMX-SEV-2) classifier to determine risk scores as low, moderate, and high severity. Performance of IMX-SEV-2 for prediction of 28-day mortality was compared with that of lactate, procalcitonin, and quick sequential organ failure assessment (qSOFA). Results: A total of 397 individuals were enrolled; 38 individuals (9.6%) died within 28 days. Inflammatix Severity 2 classifier predicted 28-day mortality with an area under the receiver operator characteristics curve of 0.82 (95% confidence interval [CI], 0.74-0.90) compared with lactate, 0.66 (95% CI, 0.54-0.77); procalcitonin, 0.67 (95% CI, 0.57-0.78); and qSOFA, 0.81 (95% CI, 0.72-0.89). Combining qSOFA with IMX-SEV-2 improved prognostic accuracy from 0.81 to 0.89 (95% CI, 0.82-0.96). The high-severity (rule-in) interpretation band of IMX-SEV-2 demonstrated 96.9% specificity for predicting 28-day mortality, whereas the low-severity (rule-out) band had a sensitivity of 78.9%. Similarly, IMX-SEV-2 alone accurately predicted the need for day-7 intensive care unit care and further boosted overall accuracy when combined with qSOFA. Conclusions: Inflammatix Severity 2 classifier predicted 28-day mortality and 7-day intensive care unit care with high accuracy and boosted the accuracy of clinical scores when used in combination.

The validation of new biomarkers for the diagnosis and risk stratification of patients with sepsis at an early point is essential for successful treatment. Recent publications prompted us to investigate of heparin binding protein (HBP) for the emergency department (ED) admissions.In this multicenter, cross-sectional study, HBP and procalcitonin (PCT) were measured within the first hour upon admission to the ED in plasma samples of 371 patients with signs of infection. Patients were classified into non-sepsis and sepsis by the Sepsis-3 definitions and were followed up for outcome.HBP was significantly higher in patients with sepsis and was positively correlated to PCT and C-reactive protein, absolute neutrophil and monocyte counts, creatinine, bilirubin and lactate. Sensitivity, specificity, positive predictive value, and negative predictive value of HBP more than 19.8 ng/mL for the diagnosis of sepsis was 66.3%, 44.9%, 49.3%, and 62.2%, respectively; and for prediction of early death was 100%, 41.0%, 4.5%, and 100%, respectively. Single HBP and PCT could not predict 28-day mortality; this was performed with sensitivity, specificity, positive predictive value, and negative predictive value 44.8%, 81.8%, 17.3%, and 94.6% when used in combination.Admission HBP can be used as a tool for the early diagnosis of sepsis and for the risk of early death in the ED.

Study designWhether or not to administer antibiotics is a common and challenging clinical decision in patients with suspected infections presenting to the emergency department (ED). We prospectively validate InSep, a 29-mRNA blood-based host response test for the prediction of bacterial and viral infections.MethodsThe PROMPT trial is a prospective, non-interventional, multi-center randomized, controlled clinical trial that enrolled 397 adult patients presenting to the ED with signs of acute infection and at least one vital sign change. The infection status was adjudicated using chart review (including a syndromic molecular respiratory panel, procalcitonin and C-reactive protein) by three infectious disease physicians blinded to InSep results. InSep (version BVN-2) was performed using PAXgene Blood RNA processed and quantified on NanoString nCounter SPRINT. InSep results (likelihood of bacterial and viral infection) were compared to the adjudicated infection status.ResultsSubject mean age was 64 years, comorbidities were significant for diabetes (17.1%), chronic obstructive pulmonary disease (13.6%), and severe neurological disease (6.8%); 16.9% of subjects were immunocompromised. Infections were adjudicated as bacterial (14.1%), viral (11.3%) and noninfected (0.25%): 74.1% of subjects were adjudicated as indeterminate. InSep distinguished bacterial vs. viral/noninfected patients and viral vs. bacterial/noninfected patients using consensus adjudication with AUROCs of 0.94 (95% CI 0.90-0.99) and 0.90 (95% CI 0.83-0.96), respectively. AUROCs for bacterial vs. viral/noninfected patients were 0.88 (95%CI 0.79-0.96) for PCT, 0.80 (95% CI 0.72-89) for CRP and 0.78 (95% CI 0.69-0.87) for white blood cell counts (of note, the latter biomarkers were provided as part of clinical adjudication). To enable clinical actionability, InSep incorporates score cutoffs to allocate patients into interpretation bands. The Very Likely (rule in) InSep bacterial band showed a specificity of 98% compared to 94% for the corresponding PCT band (>0.5 ug/L); the Very Unlikely (rule-out) band showed a sensitivity of 95% for InSep compared to 86% for PCT. For the detection of viral infections, InSep demonstrated a specificity of 93% for the Very Likely band (rule in) and a sensitivity of 96% for the Very Unlikely band (rule out).ConclusionInSep demonstrated high accuracy for predicting the presence of both bacterial and viral infections in ED patients with suspected acute infections or suspected sepsis. When translated into a rapid, point-of-care test, InSep will provide ED physicians with actionable results supporting early informed treatment decisions to improve patient outcomes while upholding antimicrobial stewardship.Take-home messageInSep host response test is a point-of-care test providing with accuracy the likelihood for bacterial or viral infection for patients admitted at the emergencies InSep provided information on the likelihood of bacterial co-infection among patients with COVID-19.

Sepsis-3 definitions generated controversies regarding their general applicability. The Sepsis-3 Task Force outlined the need for validation with emphasis on the quick Sequential Organ Failure Assessment (qSOFA) score. This was done in a prospective cohort from a different healthcare setting.Patients with infections and at least two signs of systemic inflammatory response syndrome (SIRS) were analysed. Sepsis was defined as total SOFA ≥2 outside the intensive care unit (ICU) or as an increase of ICU admission SOFA ≥2. The primary endpoints were the sensitivity of qSOFA outside the ICU and sepsis definition both outside and within the ICU to predict mortality.In all, 3346 infections outside the ICU and 1058 infections in the ICU were analysed. Outside the ICU, respective mortality with ≥2 SIRS and qSOFA ≥2 was 25.3% and 41.2% (p0.0001); the sensitivities of qSOFA and of sepsis definition to predict death were 60.8% and 87.2%, respectively. This was 95.9% for sepsis definition in the ICU. The sensitivity of qSOFA and of ≥3 SIRS criteria for organ dysfunction outside the ICU was 48.7% and 72.5%, respectively (p0.0001). Misclassification outside the ICU with the 1991 and Sepsis-3 definitions into stages of lower severity was 21.4% and 3.7%, respectively (p0.0001) and 14.9% and 3.7%, respectively, in the ICU (p0.0001). Adding arterial pH ≤7.30 to qSOFA increased sensitivity for prediction of death to 67.5% (p 0.004).Our analysis positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity. However, qSOFA score had inadequate sensitivity for early risk assessment.

Contains fulltext : 172802.pdf (Publisher’s version ) (Closed access) Based on the concept of the individualized nature of sepsis, we investigated the significance of the -251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8.

This study explores the role of procalcitonin (PCT) in predicting the outcome of sepsis. In a prospective multicentre observational investigation, blood was sampled within 24 h of onset of sepsis in 1156 hospitalised patients; 234 were in the intensive care unit (ICU) at the point of presentation of sepsis while 922 were not. PCT was estimated in serum by the ultrasensitive Kryptor assay in a double-blinded fashion. Among patients outside the ICU, mortality was 8% in those with PCT ≤0.12 ng/mL but 19.9% in those with PCT0.12 ng/mL [P0.0001, odds ratio (OR) for death: 2.606; 95% confidence interval (CI): 1.553-4.371]. Among patients whose sepsis presented in ICU, mortality was 25.6% in those with PCT ≤0.85 ng/mL but 45.3% in those with PCT0.85 ng/mL (P=0.002; OR for death: 2.404; 95% CI: 1.385-4.171). It is concluded that PCT cut-off concentrations can contribute to predicting the outcome of sepsis and might be of particular value in identifying patients who would benefit from ICU admission.

An 80-year-old woman on maintenance hemodialysis therapy developed severe hypercalcemia under vitamin D treatment for secondary hyperparathyroidism. To avoid the toxic calcemic effects, cinacalcet was introduced and the dose of vitamin D was substantially decreased. Cinacalcet targets the calcium-sensing receptor and decreases parathyroid hormone levels without increasing calcium and phosphorus levels. Three days after starting cinacalcet therapy, the patient developed palpable purpura on both upper and lower extremities that resolved after discontinuation of cinacalcet and administration of steroids. Skin biopsy of the initial eruption showed leukocytoclastic vasculitis. According to the Naranjo adverse drug reaction probability scale, leukocytoclastic vasculitis probably was caused by cinacalcet introduction. Drug-induced vasculitis is a poorly defined disorder, and, in most cases, no pathogenetic mechanism can be described. An idiosyncratic reaction to the agent often is proposed. Cinacalcet should be considered a causative agent of cutaneous leukocytoclastic vasculitis, and although this is the result of only a clinical observation, further attention is required in the future because cinacalcet recently has been introduced in the treatment of secondary hyperparathyroidism in patients on long-term hemodialysis therapy.

Single nucleotide polymorphisms (SNPs) of interleukin (IL)-6 are associated with the development of chronic renal disease (CRD). Their impact for sepsis in the field of CRD was investigated. One control cohort of 115 patients with CRD without infection and another case cohort of 198 patients with CRD and sepsis were enrolled. Genotyping at the −174 (rs1800795) and −572 positions of IL-6 (rs1800796) was done by restriction fragment length polymorphism. Circulating IL-6 was measured by an enzyme immunoassay. The GG genotype of rs1800796 was more frequent among cases (78.3 %) than controls (62.6 %). No difference in the genotype frequencies of rs1800795 between cases and controls were found. Odds ratio for sepsis was 2.07 (95%CI 1.24–3.44, p = 0.005) with the GG genotype of rs1800796, which was confirmed by logistic regression analysis taking into consideration the presence of chronic comorbidities. All-cause mortality until day 28 was similar between patients with the GG genotype and the GC/CC genotypes of rs1800796, but death caused from cardiovascular events not-related with infection was more frequent with the GG genotype (14.6 % vs 2.4 %, p = 0.031). Circulating IL-6 was greater among patients of the GC/CC genotypes of rs1800796 and multiple organ dysfunction (p = 0.013). The GG genotype of rs1800796 predisposes to sepsis in CRD and to 28-day mortality by sepsis-unrelated cardiovascular phenomena.

Background/Aims: To define whether bacterial translocation occurs over the course of acute edematous pancreatitis and to correlate its presence to the advent of an infection since data in humans are lacking. Methods: Thirty-three patients hospitalized over the period January 2000–January 2001 were subjected to venipuncture at regular time intervals for the collection of blood samples for blood culture and for determination of endotoxins and of C-reactive protein. Endotoxins were measured by the Limulus assay and C-reactive protein by nephelometry. Results: A wide range of concentrations of endotoxins was observed over the first 3 days of the disease. Mean (±SE) of endotoxins was 4.01 ± 1.36 and 2.42 ± 0.95 EU/ml 3 and 6 h, respectively, after admission of afebrile patients. Respective values 3 and 6 h after admission of febrile patients were 3.03 ± 1.14 and 5.84 ± 2.28 EU/ml (normal Conclusions: A significant level of endotoxemia is observed over the course of acute edematous pancreatitis, which might be correlated to the advent of the systemic inflammatory response.

Although much information is available for the function of circulating monocytes when signs of sepsis are apparent, little is known for natural killer (NK) cells. NK cells were isolated from 10 healthy controls and from 103 patients with sepsis within the first 24 h from diagnosis. NK cells were stimulated with lipopolysaccharide for cytokine production. Release of tumor necrosis factor-alpha and of interleukin (IL)-6 was below the limit of detection. Release of IL-23 and of interferon-gamma (IFNγ) was significantly greater among patients than among healthy volunteers. Release of IFNγ was pronounced in septic shock. Patients were divided into two subgroups based on the ratio of IFNγ to IL-23 released by the NK cells after stimulation: those with ratio ≤5 and 28-day survival 13.5%, and those with ratio >5 and 28-day survival 29.4% (p: 0.048). It is concluded that early after clinical development of sepsis, NK cells remain active for the production of IFNγ. Their activity is associated with the final outcome.

Based on former studies in experimental animals on the effect of octreotide on serum and ascitic levels of tumor necrosis factor-alpha and interleukin-6 in the field of necrotizing pancreatitis, the present study was designed to investigate the effect of octreotide on serum interleukin-6 of patients with acute edematous pancreatitis.A total of 36 patients with acute edematous pancreatitis and initiation of symptoms 12 hours before their admission were enrolled in the study; 20 were treated with octreotide 200 microg tid and 16 with octreotide 500 microg tid for five days. Blood was sampled at regular time intervals. Interleukin-6 was determined by an enzyme-immunoassay and C-reactive protein by nephelometry.Mean concentrations of interleukin-6 of patients treated with octreotide 200 microg tid were 59.52 pg/mL before and 94.08, 46.25, 49.94, 58.16 and 26.08 pg/mL at 3, 6, 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 57.19, 53.07, 57.83, 36.06, 54.29 and 65.49 pg/mL. Mean C-reactive protein of patients treated with octreotide 200 microg tid were 67.37 mg/L before and 48.51, 106.08 and 95.58 mg/L at 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 65.51, 60.56, 90.68 and 64.22 mg/L.A transient, but not statistically significant, decrease of serum interleukin-6 levels was documented after administration of octreotide in the field of acute edematous pancreatitis. That decrease was earlier after the application of the 500 microg tid dose than the 200 microg tid dose. Studies with a greater number of patients are mandatory to fully clarify the effect of octreotide, if any, on acute pancreatitis.

To define whether bacterial translocation occurs over the course of acute edematous pancreatitis and to correlate its presence to the advent of an infection since data in humans are lacking.Thirty-three patients hospitalized over the period January 2000-January 2001 were subjected to venipuncture at regular time intervals for the collection of blood samples for blood culture and for determination of endotoxins and of C-reactive protein. Endotoxins were measured by the Limulus assay and C-reactive protein by nephelometry.A wide range of concentrations of endotoxins was observed over the first 3 days of the disease. Mean (+/-SE) of endotoxins was 4.01 +/- 1.36 and 2.42 +/- 0.95 EU/ml 3 and 6 h, respectively, after admission of afebrile patients. Respective values 3 and 6 h after admission of febrile patients were 3.03 +/- 1.14 and 5.84 +/- 2.28 EU/ml (normal0.1 EU/ml); these values gradually decreased after the second day. No correlation was found between endotoxins and C-reactive protein. Endotoxins were increased as a result of the occurrence of an infection on the third day.A significant level of endotoxemia is observed over the course of acute edematous pancreatitis, which might be correlated to the advent of the systemic inflammatory response.