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Background: In the treatment of oncological diseases in children, the search for opportunities for the earlier detection of complications to improve treatment results is very important. Metabolomic studies are actively conducted to stratify different groups of patients in order to identify the most promising markers. Methods: Three groups of patients participated in this study: healthy children as a control group (n = 18), children with various malignant oncological diseases (leukemia, lymphoma, nephroblastoma, ependymoma, etc.) as patients (n = 40) without complications, and patients (n = 31) with complications (inflammatory and infectious). The mitochondrial metabolites (succinic and fumaric acids); biomarkers related to inflammation such as C-reactive protein (CRP), procalcitonin (PCT), and presepsin (PSP); and sepsis-associated aromatic metabolites, such as phenyllactic (PhLA), hydroxyphenyllactic (p-HPhLA), and hydroxyphenylacetic acids (p-HPhAA), were identified. Results: It was found that children with malignant oncological diseases had profound metabolic dysfunction compared to healthy children, regardless of the presence of systemic inflammatory response syndrome (SIRS) or sepsis. The prognostic ability of procalcitonin and presepsin for detecting sepsis was high: AUROC = 0.875, cut-off value (Youden index) = 0.913 ng/mL, and AUROC = 0.774, with cut-off value (Youden index) of 526 pg/mL, respectively. Conclusions: A significant increase in aromatic microbial metabolites and biomarkers in non-survivor patients that is registered already in the first days of the development of complications indicates the appropriateness of assessing metabolic dysfunction for its timely targeted correction.

Infectious diseases are associated with low iron levels and the induction of hepcidin, the primary protein regulating cellular iron export. Bone morphogenetic protein 6 (BMP6), a key regulator of hepcidin expression, has not yet been analyzed in the plasma of patients with systemic inflammatory response syndrome (SIRS) or sepsis. An analysis of 38 SIRS, 39 sepsis, and 78 septic shock patients revealed similar levels of BMP6 in sepsis and septic shock, which were lower compared to patients with SIRS and healthy controls. Plasma BMP6 levels did not correlate with procalcitonin and C-reactive protein levels in patients with SIRS or sepsis/septic shock. Neither bacterial nor SARS-CoV-2 infections affected plasma BMP6 levels. There was no difference in BMP6 levels between ventilated and non-ventilated patients, or between patients with and without dialysis. Vasopressor therapy did not alter BMP6 levels. Survivors had plasma BMP6 levels similar to non-survivors. Due to the high variability of plasma BMP6 levels, these analyses have limited clinical relevance. Iron, ferritin, and transferrin levels were known in at least 50% of patients but did not correlate with plasma BMP6 levels. In conclusion, this study showed normal BMP6 plasma levels in SIRS, which are reduced in patients with sepsis and septic shock. This suggests that the commonly observed increase in hepcidin levels and the decline in iron levels in SIRS, sepsis, and septic shock are not due to higher BMP6.

Histopathologic examination of intestinal biopsies from dogs with acute hemorrhagic diarrhea syndrome (AHDS) reveals necrotizing enteritis and epithelial integrity loss. Serum iohexol measurement has been utilized to assess intestinal permeability. Our hypothesis is that dogs with AHDS have increased intestinal permeability, which is associated with the severity of clinical signs. In this prospective case–control study, 53 client-owned dogs (28 AHDS, 25 healthy controls) were evaluated. Clinical severity was assessed using the AHDS index and systemic inflammatory response syndrome (SIRS) criteria. Simultaneously, dogs received oral iohexol, and serum iohexol concentrations (SICs) were measured two hours later. Results indicated significantly higher (p = 0.002) SIC in AHDS dogs (median: 51 µg/mL; min–max: 9–246) than in healthy controls (30 µg/mL; 11–57). There was a significant positive correlation between AHDS index and SIC (rS = 0.4; p = 0.03) and a significant negative between SIC and serum albumin concentrations (Pearson r = −0.55; p = 0.01). Dogs with severe AHDS (mean 106 µg/mL; range: 17–246) demonstrated significantly higher (p = 0.002) SIC than those with mild to moderate disease (29 µg/mL; 9–54). These findings underscore the association between intestinal permeability and clinical severity in dogs with AHDS assessed by iohexol.

Insulin-like growth factor-binding protein (IGFBP)-2 regulates the bioactivity of the anabolic hormone’s insulin-like growth factors, which are decreased in sepsis and contribute to the catabolic status of severely ill patients. The circulating levels of IGFBP-2 in critical illness have been rarely studied; therefore, we evaluated IGFBP-2 plasma levels in patients with systemic inflammatory response syndrome (SIRS) or sepsis as well as healthy controls. Our analysis of 157 SIRS/sepsis patients revealed higher plasma IGFBP-2 levels compared to 22 healthy controls. Plasma IGFBP-2 levels correlated positively with procalcitonin but not with C-reactive protein, interleukin-6, or the leukocyte count. Septic shock patients exhibited higher IGFBP-2 levels than those with SIRS. Bacterial or SARS-CoV-2 infection did not influence plasma IGFBP-2 levels. There was no difference in the IGFBP-2 levels between ventilated and non-ventilated SIRS/sepsis patients, and vasopressor therapy did not alter these levels. Dialysis patients had elevated plasma IGFBP-2 levels. Survivors had lower plasma IGFBP-2 levels than non-survivors. In conclusion, our study indicates that plasma IGFBP-2 levels are associated with disease severity, renal failure, and mortality in SIRS/sepsis patients.

Several studies conducted on humans demonstrate the increase in cardiac troponins and the onset of arrhythmias in the course of systemic inflammatory response syndrome (SIRS). The aim of the current study was to assess the blood concentration of cardiac troponin I (cTnI) and electrocardiographic findings in SIRS-affected cats. Seventeen shorthair cats hospitalized with SIRS were enrolled (Group 1). SIRS diagnosis was performed based on the detection of at least two of the four criteria such as abnormal body temperature, abnormal heart rate (i.e., tachycardia or bradycardia), abnormal respiratory rate (i.e., tachypnea or bradypnea), and alterations of white blood cell number (i.e., leukocytes or band neutrophils). Ten cats screened for elective surgery such as neutering or dental procedures were evaluated as a control population (Group 2). They were considered healthy based on history, physical examination, hematological and biochemical profile, urinalysis, coprological exam, thyroxine assay, blood pressure measurement, and echocardiography. A physical examination, complete blood cell count, biochemistry test (including an electrolyte panel), electrocardiographic examination, and cTnI assay were carried out in each cat enrolled. Traumatic events, gastrointestinal, neoplastic, respiratory, and neurological disorders were identified as causes of SIRS in Group 1. In Group 1, a significantly higher concentration of cTnI than that in Group 2 was recorded (p = 0.004). In 37.5% of cats with SIRS, ventricular premature complexes occurring in couplets with multiform configuration were detected. Similarly, to humans, data herein reported would indicate possible cardiac damage present in cats with SIRS diagnosis.

Background/Objective: SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study, we present the results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS and to determine if any patient subgroups appeared to present a diagnostic challenge for the test. Methods: (1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. (2) Principal component analysis and k-means clustering analysis to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables. Results: No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response. Conclusions: We conclude that for this patient cohort, SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis.

Background : In the treatment of oncological diseases in children, the search for opportunities for the earlier detection of complications to improve treatment results is very important. Metabolomic studies are actively conducted to stratify different groups of patients in order to identify the most promising markers. Methods : Three groups of patients participated in this study: healthy children as a control group (n = 18), children with various malignant oncological diseases (leukemia, lymphoma, nephroblastoma, ependymoma, etc.) as patients (n = 40) without complications, and patients (n = 31) with complications (inflammatory and infectious). The mitochondrial metabolites (succinic and fumaric acids); biomarkers related to inflammation such as C-reactive protein (CRP), procalcitonin (PCT), and presepsin (PSP); and sepsis-associated aromatic metabolites, such as phenyllactic (PhLA), hydroxyphenyllactic ( p -HPhLA), and hydroxyphenylacetic acids ( p -HPhAA), were identified. Results : It was found that children with malignant oncological diseases had profound metabolic dysfunction compared to healthy children, regardless of the presence of systemic inflammatory response syndrome (SIRS) or sepsis. The prognostic ability of procalcitonin and presepsin for detecting sepsis was high: AUROC = 0.875, cut-off value (Youden index) = 0.913 ng/mL, and AUROC = 0.774, with cut-off value (Youden index) of 526 pg/mL, respectively. Conclusions : A significant increase in aromatic microbial metabolites and biomarkers in non-survivor patients that is registered already in the first days of the development of complications indicates the appropriateness of assessing metabolic dysfunction for its timely targeted correction.

The objective of this retrospective study was to evaluate the clinical significance of fecal quantitative real-time polymerase chain reaction (qPCR) Salmonella results when taking the cycle threshold values (Ct) into account. The study included 120 Salmonella qPCR-positive fecal samples obtained from 88 hospitalized horses over a 2-year period. The mean Ct of the qPCR test was evaluated in regard to (1) clinical outcome and (2) systemic inflammatory response syndrome (SIRS) status (no SIRS, moderate SIRS, or severe SIRS) of the sampled horses. An ROC analysis was performed to establish the optimal cut-off Ct values associated with severe SIRS. The mean ± SD Ct value was significantly lower in samples (1) from horses with a fatal issue (27.87 ± 5.15 cycles) than in surviving horses (31.75 ± 3.60 cycles), and (2) from horses with severe SIRS (27.87 ± 2.78 cycles) than from horses with no (32.51 ± 3.59 cycles) or moderate (31.54 ± 3.02 cycles) SIRS. In the ROC analysis, the optimal cut-off value of Ct associated with a severe SIRS was 30.40 cycles, with an AUC value of 0.84 [95% confidence interval 0.76–0.91] and an OR of 0.64 [0.51–0.79]. Results suggest that including the Ct value in the interpretation of fecal qPCR results could improve the diagnostic value of this test for clinical salmonellosis in horses.

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as in a mouse model of UTI. Samples of blood and urine were collected from adult patients with UTIs and obstructive uropathy (n = 36) during the first 3 days at the hospital and during a follow-up. Bacterial burden and urinary ecDNA were evaluated in a mouse UTI model (n = 26) at baseline; 24, 48, and 72 h after UTI induction; and 7 days after UTI induction. The plasma ecDNA did not change during urosepsis, but the plasma DNase activity increased significantly at the follow-up. The urinary ecDNA decreased significantly during hospitalization and remained low until the follow-up (90% lower vs. admission). No change was seen in the urinary DNase activity. C-reactive protein (CRP) and procalcitonin are positively correlated with plasma and urinary ecDNA. A UTI caused sepsis in 23% of mice. The urinary ecDNA decreased by three-fold and remained low until day 7 post-infection. Urinary bacterial burden is correlated with urinary ecDNA. Urinary ecDNA is a potential non-invasive marker for monitoring the effects of treatment during urosepsis and is related to UTI progression in the experimental animal model.

Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) has shown constant incidence throughout time, despite advances in endoscopic technology, devices, or personal skills of the operating endoscopists, with prevention and prediction of severity in PEP being constant concerns. Several prospective studies have investigated the role of systemic inflammatory response syndrome (SIRS) criteria or the quick Sequential Organ Failure Assessment (qSOFA) score in the PEP severity assessment. However, there are no clearly defined tools for the prediction of PEP severity. Methods: A total of 403 patients were prospectively monitored 60 days after ERCP for the detection of PEP development. Consequently, we evaluated the lengths of stay, incidence of organic dysfunction, and mortality rates of these patients. The predictive power of the univariate model was evaluated by using the receiver operating characteristic curve and analyzing the area under the curve (AUC). Results: Incidence of PEP was similar to that reported in the majority of trials. The 60-day survival rate of PEP patients reached 82.8%. A qSOFA score ≥ 1 is a very good predictor for organ dysfunction (AUC 0.993, p < 0.0001). SIRS can also be considered a significant predictor for organic dysfunctions in PEP patients (AUC 0.926, p < 0.0001). However, only qSOFA was found to significantly predict mortality in PEP patients (AUC 0.885, p = 0.003), with SIRS criteria showing a much lower predictive power. Neither SIRS nor qSOFA showed any predictive value for the length of stay of PEP patients. Conclusion: Our study offers novel information about severity prediction in PEP patients. Both SIRS criteria and qSOFA showed good predictive value for organic dysfunction, mortality, and hospitalization.

The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of the MMP profile in cardiac surgery. All studies meeting the inclusion criteria (i.e., those reporting detailed data about MMP release during and after CPB) were selected after screening the literature published between July 1975 and August 2022. Fifteen trials that enrolled a total of 431 participants were included. MMP levels were found to be significantly correlated with CPB in all included studies. The gelatinases MMP-2 and MMP-9 were highly released in cardiac surgery with CPB. MMP-9 levels were found to be increased after CPB start and during the duration of CPB. Particularly, it is overexpressed both in the myocardial tissue and circulating in the bloodstream. Also, MMP-2 levels increased after CPB both in plasma and in myocardial tissue. MMP-7, MMP-8, and MMP-13 levels increased after CPB start and remained elevated up to 6 h later. Increased levels of MMPs were associated with adverse post-operative outcomes. Conversely, TIMP-1 decreased with CPB. Mechanical and pharmacological strategies were applied in two studies to analyze their effect on the inflammatory response to cardiac surgery and CPB and on postoperative outcomes. New targeted MMP inhibitor therapies could protect against systemic inflammatory response syndrome after CPB and should be the subject of future large prospective multicenter randomized clinical trials.

Infectious diseases are associated with low iron levels and the induction of hepcidin, the primary protein regulating cellular iron export. Bone morphogenetic protein 6 (BMP6), a key regulator of hepcidin expression, has not yet been analyzed in the plasma of patients with systemic inflammatory response syndrome (SIRS) or sepsis. An analysis of 38 SIRS, 39 sepsis, and 78 septic shock patients revealed similar levels of BMP6 in sepsis and septic shock, which were lower compared to patients with SIRS and healthy controls. Plasma BMP6 levels did not correlate with procalcitonin and C-reactive protein levels in patients with SIRS or sepsis/septic shock. Neither bacterial nor SARS-CoV-2 infections affected plasma BMP6 levels. There was no difference in BMP6 levels between ventilated and non-ventilated patients, or between patients with and without dialysis. Vasopressor therapy did not alter BMP6 levels. Survivors had plasma BMP6 levels similar to non-survivors. Due to the high variability of plasma BMP6 levels, these analyses have limited clinical relevance. Iron, ferritin, and transferrin levels were known in at least 50% of patients but did not correlate with plasma BMP6 levels. In conclusion, this study showed normal BMP6 plasma levels in SIRS, which are reduced in patients with sepsis and septic shock. This suggests that the commonly observed increase in hepcidin levels and the decline in iron levels in SIRS, sepsis, and septic shock are not due to higher BMP6.

Systemic inflammatory response syndrome (SIRS) is a very common finding in critically ill patients. To accurately identify patients with SIRS and those who need intensive care, several markers have been evaluated, including cortisol, WBC or lactate. It is widely known that a stress leukogram includes eosinopenia as one of its main markers (neutrophilia, eosinopenia, lymphopenia and mild monocytes). It is known that cortisol concentration in plasma is the main stress biomarker and is strongly correlated with the severity of disease in horses. However, it is not possible to measure this parameter routinely in clinical conditions. Hence, in this study it was hypothesized that the eosinophil count could be a reliable parameter to identify critically ill horses. Horses included in this study were divided into three groups: Group A (sick horses received at the Emergency Unit which did not fulfil the criteria for SIRS), Group B (horses that meet two or more criteria for inclusion in the definition of SIRS) and a control group of healthy horses. In this study, horses with SIRS showed lower eosinophil counts than healthy horses. Moreover, non-surviving horses exhibited lower eosinophil counts than survivors. Eosinopenia could be used to identify horses with SIRS and can be useful as a prognostic marker.

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04–2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01–1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06–4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58–26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype.

(1) Background: Systemic inflammatory response syndrome (SIRS) can occur due to a large number of traumatic or non-traumatic diseases. Hyperbaric oxygen therapy (HBOT) may be used as a main or adjuvant treatment for inflammation, leading to the main aim of this study, which was to verify the applicability of HBOT as a safe and tolerable tool in SIRS-positive dogs. (2) Methods: This prospective cohort study included 49 dogs who showed two or more parameters of SIRS, divided into the Traumatic Study Group (n = 32) and the Non-Traumatic Study Group (n = 17). All dogs were submitted to HBOT for 60–90 min sessions, with 2.4–2.8 ATA. (3) Results: This study revealed that 73.5% (36/49) of dogs showed improvement, and the minimum number of HBOT sessions was two, with a mean of 12.73. The number of days between diagnosis and the beginning of HBOT showed statistical significance (p = 0.031) relative to the clinical outcome. No dogs showed any major side effects. (4) Conclusions: We concluded that HBOT may be safe and tolerable for SIRS-positive dogs, and that it should be applied as early as possible.

The Surviving Sepsis Campaign recently recommended that qSOFA not be used as a single parameter for identification of sepsis. Thus, we evaluated the efficacy of SIRS and qSOFA scores in identifying intrauterine infection. This case–control study evaluates SIRS and qSOFA criteria fulfillment in preterm premature rupture of membranes (n = 453)—at high infection risk—versus elective cesarean—at low infection risk (n = 2004); secondary outcomes included intrauterine infection and positive culture rates. At admission, 14.8% of the study group and 4.6% of control met SIRS criteria (p = 0.001), as did 12.5% and 5.5% on post-operation day (POD) 1 (p = 0.001), with no significant differences on POD 0 or 2. Medical records did not suffice for qSOFA calculation. In the study group, more cultures (29.8% versus 1.9%—cervix; 27.4% versus 1.1%—placenta; 7.5% versus 1.7%—blood; p = 0.001—all differences) and positive cultures (5.5% versus 3.0%—urine—p = 0.008; 4.2% versus 0.2%—cervix—p = 0.001; 7.3% versus 0.0%—placenta—p = 0.001; 0.9% versus 0.1%—blood—p = 0.008) were obtained. Overall, 10.6% of the study group and 0.4% of control met the intrauterine infection criteria (p = 0.001). Though a significant difference was noted in SIRS criteria fulfillment in the study group versus control, there was considerable between-group overlap, questioning the utility of SIRS in intrauterine infection diagnosis. Furthermore, the qSOFA scores could not be assessed.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Insulin-like growth factor-binding protein (IGFBP)-2 regulates the bioactivity of the anabolic hormone's insulin-like growth factors, which are decreased in sepsis and contribute to the catabolic status of severely ill patients. The circulating levels of IGFBP-2 in critical illness have been rarely studied; therefore, we evaluated IGFBP-2 plasma levels in patients with systemic inflammatory response syndrome (SIRS) or sepsis as well as healthy controls. Our analysis of 157 SIRS/sepsis patients revealed higher plasma IGFBP-2 levels compared to 22 healthy controls. Plasma IGFBP-2 levels correlated positively with procalcitonin but not with C-reactive protein, interleukin-6, or the leukocyte count. Septic shock patients exhibited higher IGFBP-2 levels than those with SIRS. Bacterial or SARS-CoV-2 infection did not influence plasma IGFBP-2 levels. There was no difference in the IGFBP-2 levels between ventilated and non-ventilated SIRS/sepsis patients, and vasopressor therapy did not alter these levels. Dialysis patients had elevated plasma IGFBP-2 levels. Survivors had lower plasma IGFBP-2 levels than non-survivors. In conclusion, our study indicates that plasma IGFBP-2 levels are associated with disease severity, renal failure, and mortality in SIRS/sepsis patients.

(1) Alkaline phosphatase (AP) is consumed during cardiopulmonary bypass (CPB). A high AP depletion leads to an impaired outcome after cardiac surgery. However, data is scarce on the postoperative course of AP under venoarterial ECMO (VA-ECMO) support. (2) A total of 239 patients with VA-ECMO support between 2000 and 2019 at the Department of Cardiac Surgery (Vienna General Hospital, Austria) were included in this retrospective analysis. Blood samples were collected at several timepoints (baseline, postoperative day (POD) 1–7, POD 14 and 30). Patients were categorized according to the relative AP drop (p = 0.000). A greater AP drop was associated with a significantly higher need for renal replacement therapy (40.9% vs. 61.9%; p = 0.002) and an impaired 1-year survival (51.4% vs. 66.0%; p = 0.031). (4) CPB exceeds the negative impact of VA-ECMO; still, ECMO seems to delay alkaline phosphatase recovery. A greater initial AP drop bears the risk of higher morbidity and mortality.

Systemic inflammatory response syndrome (SIRS) and sepsis are two conditions which are difficult to differentiate clinically and which are strongly impacted for prompt intervention. This study identified potential lipid signatures that are able to differentiate SIRS from sepsis and to predict prognosis. Forty-two patients, including 21 patients with sepsis and 21 patients with SIRS, were involved in the study. Liquid chromatography coupled to mass spectrometry and multivariate statistical methods were used to determine lipids present in patient plasma. The obtained lipid signatures revealed 355 features for the negative ion mode and 297 for the positive ion mode, which were relevant for differential diagnosis of sepsis and SIRS. These lipids were also tested as prognosis predictors. Lastly, L-octanoylcarnitine was found to be the most promising lipid signature for both the diagnosis and prognosis of critically ill patients, with accuracies of 75% for both purposes. In short, we presented the determination of lipid signatures as a potential tool for differential diagnosis of sepsis and SIRS and prognosis of these patients.

The objective of this retrospective study was to evaluate the clinical significance of fecal quantitative real-time polymerase chain reaction (qPCR) Salmonella results when taking the cycle threshold values (Ct) into account. The study included 120 Salmonella qPCR-positive fecal samples obtained from 88 hospitalized horses over a 2-year period. The mean Ct of the qPCR test was evaluated in regard to (1) clinical outcome and (2) systemic inflammatory response syndrome (SIRS) status (no SIRS, moderate SIRS, or severe SIRS) of the sampled horses. An ROC analysis was performed to establish the optimal cut-off Ct values associated with severe SIRS. The mean ± SD Ct value was significantly lower in samples (1) from horses with a fatal issue (27.87 ± 5.15 cycles) than in surviving horses (31.75 ± 3.60 cycles), and (2) from horses with severe SIRS (27.87 ± 2.78 cycles) than from horses with no (32.51 ± 3.59 cycles) or moderate (31.54 ± 3.02 cycles) SIRS. In the ROC analysis, the optimal cut-off value of Ct associated with a severe SIRS was 30.40 cycles, with an AUC value of 0.84 [95% confidence interval 0.76-0.91] and an OR of 0.64 [0.51-0.79]. Results suggest that including the Ct value in the interpretation of fecal qPCR results could improve the diagnostic value of this test for clinical salmonellosis in horses.

In 2005, an international pediatric sepsis consensus conference defined systemic inflammatory response syndrome (SIRS) for children

An understanding of common human diversity in innate immune pathways should be beneficial in understanding autoimmune diseases, susceptibility to infection, and choices of anti-inflammatory treatment. Such understanding could also result in definition of currently unknown components of human inflammation pathways. A cellular genome-wide association studies (GWAS) platform, termed Hi-HOST (High-throughput human in vitro susceptibility testing), was developed to assay in vitro cellular phenotypes of infection in genotyped lymphoblastoid cells from genetically diverse human populations. Hi-HOST allows for measurement of multiple host and pathogen parameters of infection/inflammation including: bacterial invasion and intracellular replication, host cell death, and cytokine production. Hi-HOST has been used to successfully define a significant portion of the heritable human diversity in inflammatory cell death in response to Salmonella typhimurium. It also led to the discovery of genetic variants important to protection against systemic inflammatory response syndrome (SIRS) and protection against death and bacteremia in individuals with SIRS. Our laboratory is currently using this platform to define human diversity in autophagy and the NLPR3 inflammasome pathways, and to define new components that can impact the expression of phenotypes related to these pathways.

The use of minimized extracorporeal circulation (MiECC) during cardiac surgery is associated with a reduced inflammatory reaction compared to conventional cardiopulmonary bypass (cCPB). Since it is unknown if MiECC also reduces the amount of free-circulating mitochondrial DNA (mtDNA), this study aims to compare MiECC-induced mtDNA release to that of cCPB as well as to identify potential relations between the plasma levels of mtDNA and an adverse outcome. Overall, 45 patients undergoing cardiac surgery with either cCPB or MiECC were included in the study. MtDNA encoding for NADH dehydrogenase 1 was quantified with quantitative polymerase chain reaction. The plasma amount of mtDNA was significantly lower in patients undergoing cardiac surgery with MiECC compared to cCPB (MiECC: 161.8 (65.5−501.9); cCPB 190.8 (82−705.7); p < 0.001). Plasma levels of mtDNA showed comparable kinetics independently of the study group and peaked during CPB (MiECC preoperative: 68.2 (26.5−104.9); MiECC 60 min after start of CPB: 536.5 (215.7−919.6); cCPB preoperative: 152.5 (80.9−207.6); cCPB 60 min after start of CPB: 1818.0 (844.2−3932.2); all p < 0.001). Patients offering an mtDNA blood concentration of >650 copies/µL after the commencement of CPB had a 5-fold higher risk for postoperative atrial fibrillation independently of the type of cardiopulmonary bypass. An amount of mtDNA being higher than 650 copies/µL showed moderate predictive power (AUROC 0.71 (0.53−071)) for the identification of postoperative atrial fibrillation. In conclusion, plasma levels of mtDNA were lower in patients undergoing cardiac surgery with MiECC compared to cCPB. The amount of mtDNA at the beginning of the CPB was associated with postoperative atrial fibrillation independent of the type of cardiopulmonary bypass.

The Surviving Sepsis Campaign recently recommended that qSOFA not be used as a single parameter for identification of sepsis. Thus, we evaluated the efficacy of SIRS and qSOFA scores in identifying intrauterine infection. This case-control study evaluates SIRS and qSOFA criteria fulfillment in preterm premature rupture of membranes ( n = 453)-at high infection risk-versus elective cesarean-at low infection risk ( n = 2004); secondary outcomes included intrauterine infection and positive culture rates. At admission, 14.8% of the study group and 4.6% of control met SIRS criteria ( p = 0.001), as did 12.5% and 5.5% on post-operation day (POD) 1 ( p = 0.001), with no significant differences on POD 0 or 2. Medical records did not suffice for qSOFA calculation. In the study group, more cultures (29.8% versus 1.9%-cervix; 27.4% versus 1.1%-placenta; 7.5% versus 1.7%-blood; p = 0.001-all differences) and positive cultures (5.5% versus 3.0%-urine- p = 0.008; 4.2% versus 0.2%-cervix- p = 0.001; 7.3% versus 0.0%-placenta- p = 0.001; 0.9% versus 0.1%-blood- p = 0.008) were obtained. Overall, 10.6% of the study group and 0.4% of control met the intrauterine infection criteria ( p = 0.001). Though a significant difference was noted in SIRS criteria fulfillment in the study group versus control, there was considerable between-group overlap, questioning the utility of SIRS in intrauterine infection diagnosis. Furthermore, the qSOFA scores could not be assessed.

Immunoglobulin IgM is important for controlling viral and bacterial infections, and low immunoglobulin levels have been found in sepsis. There is a clear need to stratify sepsis patients according to the presence of an invading organism, compared to no organism identified, and SIRS patients, where organ dysfunction is a result of a non-infective process. The aim of this pilot study in a small cohort of patients with sepsis was to evaluate the association between IgM plasma levels and survival in 47 patients with sepsis and 11 patients diagnosed with organ failure without the identification of a pathogen (SIRS). Patients were admitted to the intensive care unit (ICU) at The Royal Glamorgan Hospital, Llantrisant, UK between 2010 and 2014. We found that low IgM levels were associated with sepsis, but not SIRS. IgM levels did not differ significantly for culture-positive (CP) compared with culture-negative (CN, no organism found) sepsis samples. Kaplan-Meier analysis was used to compare survival curves according to IgM levels, with no significant difference. We observed significantly higher survival in the CP samples when comparing with CN. Cut-off value for IgM (266 μg/mL) for diagnosis of sepsis patients was determined using receiver operator characteristic (ROC) curves with 70% sensitivity, 69% specificity and 92% negative predictive values (NPV), respectively. The corresponding area under the curve (AUC) for the discrimination of sepsis patients was AUC = 0.73, and in a subgroup analysis of CP was AUC = 0.77 and for CN was AUC = 0.79. We confirm IgM as a good diagnostic marker of sepsis. These findings indicate a difference in the pathology between culture-positive versus negative sepsis, SIRS and survival. This indicates that IgM is likely relevant to pathology, because of its role in the early immune response against pathogens, the potentially protective role of natural IgM antibodies, and supports its application in immunoglobulin therapy.

Deciding whether to delay non-lifesaving orthopaedic trauma surgery to prevent multiple organ failure (MOF) or sepsis is frequently disputed and largely based on expert opinion. We hypothesise that neutrophils and monocytes differentially express activation markers prior to patients developing these complications. Peripheral blood from 20 healthy controls and 162 patients requiring major orthopaedic intervention was collected perioperatively. Neutrophil and monocyte L-selectin, CD64, CD11, CD18, and CXCR1 expression were measured using flow cytometry. The predictive ability for MOF and sepsis was assessed using the Receiver Operating Characteristic (ROC) comparing to C-reactive protein (CRP). Neutrophil and monocyte L-selectin were significantly higher in patients who developed sepsis. Neutrophil L-selectin (AUC 0.692 [95%CI 0.574-0.810]) and monocyte L-selectin (AUC 0.761 [95%CI 0.632-0.891]) were significant predictors of sepsis and were not significantly different to CRP (AUC 0.772 [95%CI 0.650-0.853]). Monocyte L-selectin was predictive of MOF preoperatively and postoperatively (preop AUC 0.790 [95%CI 0.622-0.958]). CD64 and CRP were predictive of MOF at one-day postop (AUC 0.808 [95%CI 0.643-0.974] and AUC 0.809 [95%CI 0.662-0.956], respectively). In the perioperative period, elevated neutrophil and monocyte L-selectin are predictors of postoperative sepsis. Larger validation studies should focus on these biomarkers for deciding the timing of long bone/pelvic fracture fixation.

Introduction: Big data-based artificial intelligence (AI) has become increasingly important in medicine and may be helpful in the future to predict diseases and outcomes. For severely injured patients, a new analytics tool has recently been developed (WATSON Trauma Pathway Explorer) to assess individual risk profiles early after trauma. We performed a validation of this tool and a comparison with the Trauma and Injury Severity Score (TRISS), an established trauma survival estimation score. Methods: Prospective data collection, level I trauma centre, 1 January 2018-31 December 2019., Inclusion Criteria: Primary admission for trauma, injury severity score (ISS) ≥ 16, age ≥ 16., Parameters: Age, ISS, temperature, presence of head injury by the Glasgow Coma Scale (GCS)., Outcomes: SIRS and sepsis within 21 days and early death within 72 h after hospitalisation., Statistics: Area under the receiver operating characteristic (ROC) curve for predictive quality, calibration plots for graphical goodness of fit, Brier score for overall performance of WATSON and TRISS. Results: Between 2018 and 2019, 107 patients were included (33 female, 74 male; mean age 48.3 ± 19.7; mean temperature 35.9 ± 1.3; median ISS 30, IQR 23-36). The area under the curve (AUC) is 0.77 (95% CI 0.68-0.85) for SIRS and 0.71 (95% CI 0.58-0.83) for sepsis. WATSON and TRISS showed similar AUCs to predict early death (AUC 0.90, 95% CI 0.79-0.99 vs. AUC 0.88, 95% CI 0.77-0.97; p = 0.75). The goodness of fit of WATSON ( X 2 = 8.19, Hosmer-Lemeshow p = 0.42) was superior to that of TRISS ( X 2 The validation supports previous reports in terms of feasibility of the WATSON Trauma Pathway Explorer and emphasises its relevance to predict SIRS, sepsis, and early death when compared with the TRISS method.p < 0.05), as was the overall performance based on Brier score (0.06 vs. 0.11 points). Discussion: The validation supports previous reports in terms of feasibility of the WATSON Trauma Pathway Explorer and emphasises its relevance to predict SIRS, sepsis, and early death when compared with the TRISS method.

Myristic acid is identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Its significant decrease has been observed in patients with septic shock not responding to treatment. Another study has reported a close correlation of myristic acid levels with the outcome of severe trauma patients. Myristic acid concentrations were investigated in a cohort of septic patients and patients with Systemic Inflammatory Response Syndrome (SIRS) in 5 consecutive days following diagnosis and compared to healthy controls. The study population groups-Sepsis 34, SIRS 31, and Healthy Control 120 patients were included. Serum samples were analyzed using gas chromatography and mass spectrometry. The myristic acid levels in the Sepsis Group and SIRS Group were found to be significantly higher when compared to healthy controls. The serum concentration of myristic acid in septic patients with bacteraemia was higher than in septic patients without bacteraemia. Most patients with sepsis and SIRS had the highest levels of myristic acid within 24 h after an established diagnosis. Myristic acid should be considered as a new candidate marker of severe inflammation and sepsis. A simplified analysis and sufficient body of validated data are necessary steps towards the introduction of this metabolite into routine clinical practice.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening condition clinically presenting as SIRS (Systemic Inflammatory Response Syndrome). However, there is no comprehensive data concerning diagnostic algorithms, prevalence, outcome and biomarker performance in SIRS patients. We conducted a prospective observational cohort study on 451 consecutive patients fulfilling ≥2 SIRS criteria. The Hscore and the HLH-2004 criteria were used to determine the presence of sHLH, and the correlation of the screening-biomarkers ferritin, sCD25, and sCD163 with both scores was assessed. Out of 451 standard-care SIRS patients, five patients had high Hscores (≥169), suggesting incipient or HLH-like disease, and these patients were in urgent need for intensified therapy. However, none of these patients fulfilled five HLH-2004 criteria required for formal diagnosis. From the studied biomarkers, ferritin correlated strongest to both the HLH-2004 criteria and the Hscore (rs = 0.72, 0.41, respectively), and was the best predictor of 30-day survival (HR:1.012 per 100 μg/L, 95% CI: 1.004-1.021), when adjusted for patient's age, sex, bacteremia and malignant underlying-disease. Also, the HLH-2004 (HR per point increase: 1.435, 95% CI: 1.1012-2.086) and the Hscore (HR per point increase:1.011, 95% CI: 1.002-1.020) were independent predictors of 30-day-survival. The Hscore detected patients in hyperinflammatory states requiring urgent therapy escalation. Degrees of hyperinflammation, as assessed by ferritin and both HLH scores, are associated with worse outcomes., Competing Interests: All authors declare that they have no conflict of interest.

The prognostic value of quick Sepsis-related Organ Failure Assessment (qSOFA) score in geriatric patients is uncertain. We aimed to compare qSOFA vs. Systemic Inflammatory Response Syndrome (SIRS) criteria for mortality prediction in older multimorbid subjects, admitted for suspected sepsis in a geriatric ward. We prospectively enrolled 272 patients (aged 83.7 ± 7.4). At admission, qSOFA and SIRS scores were calculated. Mortality was assessed during hospital stay and three months after discharge. The predictive capacity of qSOFA and SIRS was assessed by calculating the Area Under the Receiver Operating Characteristic Curve (AUROC), through pairwise AUROC comparison, and multivariable logistic regression analysis. Both qSOFA and SIRS exhibited a poor prognostic performance (AUROCs 0.676, 95% CI 0.609⁻0.738, and 0.626, 95% CI 0.558⁻0.691 for in-hospital mortality; 0.684, 95% CI 0.614⁻0.748, and 0.596, 95% CI 0.558⁻0.691 for pooled three-month mortality, respectively). The predictive capacity of qSOFA showed no difference to that of SIRS for in-hospital mortality (difference between AUROCs 0.05, 95% CI -0.05 to 0.14, p = 0.31), but was superior for pooled three-month mortality (difference between AUROCs 0.09, 95% CI 0.01⁻0.17, p = 0.029). Multivariable logistic regression analysis, accounting for possible confounders, including frailty, showed that both scores were not associated with in-hospital mortality, although qSOFA, unlike SIRS, was associated with pooled three-month mortality. In conclusion, neither qSOFA nor SIRS at admission were strong predictors of mortality in a geriatric acute-care setting. Traditional geriatric measures of frailty may be more useful for predicting adverse outcomes in this setting.

Objective: The use of serum ammonia as a novel marker for sepsis compared to lactic acid levels in intensive care unit (ICU) patients., Design and Interventions: Single arm, prospective clinical trial to collect arterial blood samples from patients with sepsis. Serial ammonia and lactic acid levels were sent every six hours for a total of three days., Measurements and Results: Compare mean levels of ammonia and lactic acid in terms of diagnosing sepsis and patient outcome, including length of stay and mortality. A total of 30 patients were enrolled in the pilot study. On admission, mean ammonia level was 35.7 μmol/L and lactic acid was 3.06 mmole/L. Ammonia levels checked at the end of day 2 (ammonia 2-4) and the beginning of day 3 (ammonia 3-1) were higher in patients who had a microbial culture-proven sepsis ( p -values 0.029 and 0.002, respectively) compared to those without culture-positive sepsis. Ammonia levels did predict a longer hospital stay; ammonia level of more than 40 μmol/L had a mean hospital stay of 17.6 days vs. patients with normal levels who had a mean hospital stay of 9.62 days ( p -value 0.0082)., Conclusion: Elevated ammonia level can be a novel biomarker for sepsis, comparable to conventional markers. Ammonia levels have a prognostic utility as elevated levels were associated with longer hospital stay.

In 2005, an international pediatric sepsis consensus conference defined systemic inflammatory response syndrome (SIRS) for children <18 years of age, but excluded premature infants. In 2012, Hofer et al. investigated the predictive power of SIRS for term neonates. In this paper, we examined the accuracy of SIRS in predicting sepsis in neonates, irrespective of their gestational age (i.e., pre-term, term, and post-term). We also created two prediction models, named Model A and Model B, using binary logistic regression. Both models performed better than SIRS. We also developed an android application so that physicians can easily use Model A and Model B in real-world scenarios. The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) in cases of SIRS were 16.15%, 95.53%, 3.61, and 0.88, respectively, whereas they were 29.17%, 97.82%, 13.36, and 0.72, respectively, in the case of Model A, and 31.25%, 97.30%, 11.56, and 0.71, respectively, in the case of Model B. All models were significant with p < 0.001., Competing Interests: The authors declare no conflict of interest.

An understanding of common human diversity in innate immune pathways should be beneficial in understanding autoimmune diseases, susceptibility to infection, and choices of anti-inflammatory treatment. Such understanding could also result in definition of currently unknown components of human inflammation pathways. A cellular genome-wide association studies (GWAS) platform, termed Hi-HOST (High-throughput human in vitro susceptibility testing), was developed to assay in vitro cellular phenotypes of infection in genotyped lymphoblastoid cells from genetically diverse human populations. Hi-HOST allows for measurement of multiple host and pathogen parameters of infection/inflammation including: bacterial invasion and intracellular replication, host cell death, and cytokine production. Hi-HOST has been used to successfully define a significant portion of the heritable human diversity in inflammatory cell death in response to Salmonella typhimurium. It also led to the discovery of genetic variants important to protection against systemic inflammatory response syndrome (SIRS) and protection against death and bacteremia in individuals with SIRS. Our laboratory is currently using this platform to define human diversity in autophagy and the NLPR3 inflammasome pathways, and to define new components that can impact the expression of phenotypes related to these pathways.