Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source.

BACKGROUND: Improved tools are required to detect bacterial infection in children with fever without source (FWS), especially when younger than 3 years old. The aim of the present study was to investigate the diagnostic accuracy of a host signature combining for the first time two viral-induced biomarkers, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon γ-induced protein-10 (IP-10), with a bacterial-induced one, C-reactive protein (CRP), to reliably predict bacterial infection in children with fever without source (FWS) and to compare its performance to routine individual biomarkers (CRP, procalcitonin (PCT), white blood cell and absolute neutrophil counts, TRAIL, and IP-10) and to the Labscore. METHODS: This was a prospective diagnostic accuracy study conducted in a single tertiary center in children aged less than 3 years old presenting with FWS. Reference standard etiology (bacterial or viral) was assigned by a panel of three independent experts. Diagnostic accuracy (AUC, sensitivity, specificity) of host individual biomarkers and combinatorial scores was evaluated in comparison to reference standard outcomes (expert panel adjudication and microbiological diagnosis). RESULTS: 241 patients were included. 68 of them (28%) were diagnosed with a bacterial infection and 5 (2%) with invasive bacterial infection (IBI). Labscore, ImmunoXpert, and CRP attained the highest AUC values for the detection of bacterial infection, respectively 0.854 (0.804-0.905), 0.827 (0.764-0.890), and 0.807 (0.744-0.869). Labscore and ImmunoXpert outperformed the other single biomarkers with higher sensitivity and/or specificity and showed comparable performance to one another although slightly reduced sensitivity in children < 90 days of age. CONCLUSION: Labscore and ImmunoXpert demonstrate high diagnostic accuracy for safely discriminating bacterial infection in children with FWS aged under and over 90 days, supporting their adoption in the assessment of febrile patients.

Host test based on tumor necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein-10 and C-reactive protein for differentiating bacterial and viral respiratory tract infections in adults: diagnostic accuracy study.

OBJECTIVES: To assess the performance of a test (called BV), integrating the blood levels of three immune proteins into a score, to differentiate bacterial from viral infection among adults with suspected lower respiratory tract infection (LRTI). METHODS: Prospective diagnostic accuracy study, enrolling febrile adults >18 years with LRTI signs or symptoms for less than 7 days presenting to several hospitals' emergency departments in Israel. The main exclusion criterion was immunodeficiency. Reference standard diagnosis (bacterial/viral/indeterminate) was based on three experts independently reviewing comprehensive patient data including follow-up data. BV generated three results: viral infection or other nonbacterial condition (0 ≤ score < 35), equivocal (35 ≤ score ≤ 65) and bacterial infection including co-infection (65 < score ≤ 100). BV performance was assessed against the reference standard with indeterminate reference standard and equivocal BV cases removed. RESULTS: Of 490 enrolled patients, 415 met eligibility criteria (median age 56 years, interquartile range 35). The reference standard classified 104 patients as bacterial, 210 as viral and 101 as indeterminate. BV was equivocal in 9.6% (30/314). Excluding indeterminate reference standard diagnoses and equivocal BV results, BV's sensitivity for bacterial infection was 98.1% (101/103; 95% confidence interval 95.4-100), specificity 88.4% (160/181; 83.7-93.1) and negative predictive value 98.8% (160/162; 97.1-100). DISCUSSION: BV exhibited high diagnostic performance for febrile adults with suspected LRTI among patients with reference standard diagnoses of bacterial or viral LRTI.

A host signature based on TRAIL, IP-10, and CRP for reducing antibiotic overuse in children by differentiating bacterial from viral infections: a prospective, multicentre cohort study.

OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.

Differential Serum and Urine CRP, IP-10, and TRAIL Levels in Pediatric Urinary Tract Infection.

Background: It is estimated that clinical evaluation and urinalysis are unable to diagnose >10% of urinary tract infections (UTI) in young children. TNF-related apoptosis induced ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP) exhibit differential expression in the blood in response to bacterial vs. viral infection. We assessed if the urinary and serum levels of these host biomarkers discriminate UTI, nephronia, and response to antibiotic treatment. Methods: Hospitalized febrile children aged <18 years with suspected UTI based on abnormal urinalysis were recruited prospectively between 2016 and 2018; also, non-febrile controls were recruited. Following urine culture results and hospitalization course, participants were divided into three groups based on AAP criteria and expert adjudication: UTI, viral infection, and indeterminate. Results: Seventy-three children were enrolled, 61 with suspected UTI and 12 non-febrile controls. Of the 61 with suspected UTI, 40 were adjudicated as UTI, 10 viral infection, and 11 as indeterminate. Urinary CRP and IP-10 levels were significantly higher in the UTI group (p ≤ 0.05). Urinary CRP differentiated UTI from non-bacterial etiology in children under and over 3 months of age, with AUCs 0.98 (95% CI: 0.93-1.00) and 0.82 (0.68-0.95), respectively. Similarly, urinary IP-10 discriminated with AUCs of 0.80 (0.59-1.00) and 0.90 (0.80-1.00), respectively. Serum CRP and IP-10 levels were significantly higher in UTI cases with nephronia (p ≤ 0.03). UTI-induced changes in the levels of urinary and serum biomarkers resolved during recovery. Conclusions: CRP, IP-10, and TRAIL represent biomarkers with potential to aid the clinician in diagnosis and management of UTI.

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019.

OBJECTIVES: To determine whether placental cell therapy PLacental eXpanded (PLX)-PAD (Pluristem Therapeutics, Haifa, Israel) may be beneficial to treating critically ill patients suffering from acute respiratory distress syndrome due to coronavirus disease 2019. DESIGN: Retrospective case report of critically ill coronavirus disease 2019 patients treated with PLacental eXpanded (PLX)-PAD from March 26, 2020, to April 4, 2020, with follow-up through May 2, 2020. SETTING: Four hospitals in Israel (Rambam Health Care Campus, Bnai Zion Medical Center, and Samson Assuta Ashdod University Hospital), and Holy Name Medical Center in New Jersey. PATIENTS: Eight critically ill patients on invasive mechanical ventilation, suffering from acute respiratory distress syndrome due to coronavirus disease 2019. INTERVENTIONS: Intramuscular injection of PLacental eXpanded (PLX)-PAD (300 × 106 cells) given as one to two treatments. MEASUREMENTS AND MAIN RESULTS: Mortality, time to discharge, and changes in blood and respiratory variables were monitored during hospitalization to day 17 posttreatment. Of the eight patients treated (median age 55 yr, seven males and one female), five were discharged, two remained hospitalized, and one died. By day 3 postinjection, mean C-reactive protein fell 45% (240.3-131.3 mg/L; p = 0.0019) and fell to 77% by day 5 (56.0 mg/L; p < 0.0001). Pao2/Fio2 improved in 5:8 patients after 24-hour posttreatment, with similar effects 48-hour posttreatment. A decrease in positive end-expiratory pressure and increase in pH were statistically significant between days 0 and 14 (p = 0.0032 and p = 0.00072, respectively). A decrease in hemoglobin was statistically significant for days 0-5 and 0-14 (p = 0.015 and p = 0.0028, respectively), whereas for creatinine, it was statistically significant between days 0 and 14 (p = 0.032). CONCLUSIONS: Improvement in several variables such as C-reactive protein, positive end-expiratory pressure, and Pao2/Fio2 was observed following PLacental eXpanded (PLX)-PAD treatment, suggesting possible therapeutic effect. However, interpretation of the data is limited due to the small sample size, use of concomitant investigational therapies, and the uncontrolled study design. The efficacy of PLacental eXpanded (PLX)-PAD in coronavirus disease 2019 should be further evaluated in a controlled clinical trial.

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases.

OBJECTIVE: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. STUDY DESIGN AND SETTING: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. RESULTS: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. CONCLUSION: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility.

A simple method for proximal anastomoses marking during CABG for future coronary angiography.

Evaluation of aortic proximal anastomoses in patients who have undergone coronary artery bypass surgery poses a special challenge to the interventional cardiologist during follow-up angiography procedures. We present a simple, safe, and fast technique for proximal anastomoses marking using hemostatic clips. Successful visualization of the graft marker was achieved using medium-sized hemoclips during fluoroscopy. The use of hemoclips for this procedure proved to be straightforward and required no additional surgical training.

Infective endocarditis caused by Finegoldia magna following aortic dissection repair: a case report and data evaluation.

BACKGROUND: Finegoldia magna (F. magna) is a rare pathogen causing infective endocarditis (IE). Only 7 cases are documented in the literature. CASE REPORT: We report a case of infective endocarditis in a 45-year-old male due to F. magna 2 months after a Bentall procedure. He presented with fever, dyspnea, and chest pain. Aerobic and anaerobic blood samples were drawn before empirical antibiotic treatment was initiated. A transesophageal echocardiogram (TEE) demonstrated several findings involving the prosthetic valve, including a vegetation. The patient underwent a second aortic repair procedure. Tissue cultures obtained from 2 sources in the infected area during the operation were positive for F. magna. The antibiotic regimen was changed in accordance with susceptibility testing to piperacillin/tazobactam. Two weeks after the operation, the patient was released with a recommendation for antibiotic treatment for 8 weeks. CONCLUSIONS: We report this case because F. magna in a rare pathogen causing endocarditis. This was a case of prosthetic valve F. magna IE in which the definitive diagnosis was based on tissue cultures following sterile blood cultures. Data evaluation of all F. magna IE reported cases illustrated that tissue cultures were the predominant microbiologic diagnostic tool used.

Novel emboli protection system during cardiac surgery: a multi-center, randomized, clinical trial.

BACKGROUND: Stroke is a major cause of morbidity and mortality during open-heart surgery. Up to 60% of intraoperative cerebral events are emboli induced. This randomized, controlled, multicenter trial is the first human study evaluating the safety and efficacy of a novel aortic cannula producing simultaneous forward flow and backward suction for extracting solid and gaseous emboli from the ascending aorta and aortic arch upon their intraoperative release. METHODS: Sixty-six patients (25 females; 68±10 years) undergoing elective aortic valve replacement surgery, with or without coronary artery bypass graft surgery, were randomized to the use of the CardioGard (CardioGard Medical, Or-Yehuda, Israel) Emboli Protection cannula ("treatment") or a standard ("control") aortic cannula. The primary endpoint was the volume of new brain lesions measured by diffusion-weighted magnetic resonance imaging (DW-MRI), performed preoperatively and postoperatively. Device safety was investigated by comparisons of complications rate, namely neurologic events, stroke, renal insufficiency and death. RESULTS: Of 66 patients (34 in the treatment group), 51 completed the presurgery and postsurgery MRI (27 in the treatment group). The volume of new brain lesion for the treatment group was (mean±standard error of the mean) 44.00±64.00 versus 126.56±28.74 mm3 in the control group (p=0.004). Of the treatment group, 41% demonstrated new postoperative lesions versus 66% in the control group (p=0.03). The complication rate was comparable in both groups. CONCLUSIONS: The CardioGard cannula is safe and efficient in use during open-heart surgery. Efficacy was demonstrated by the removal of a substantial amount of emboli, a significant reduction in the volume of new brain lesions, and the percentage of patients experiencing new brain lesions.

Novel emboli protection cannula during cardiac surgery: first animal study.

BACKGROUND: Stroke after open heart surgery is a major cause of morbidity and mortality. Up to 60% of intraoperative cerebral events are caused by emboli generated by manipulations of the aorta during surgery. This is the first animal study evaluating the safety and efficacy of a novel aortic cannula designed to extract solid and gaseous emboli during cardiac surgery. METHODS: Seven domestic pigs were connected to cardiopulmonary bypass using a CardioGard 24F aortic cannula. Three pigs that were cannulated with a standard aortic cannula were defined as controls. Several main flow and suction regimens were carried out. Osseous particles of different sizes were injected into the proximal aorta to simulate emboli. RESULTS: The CardioGard cannula demonstrated an overall emboli retrieval rate of 77%. A rate of 88.45% was demonstrated during the low-flow regimen used clinically during aortic manipulation. Gaseous and solid emboli were eliminated by suction, as demonstrated by epi-carotid ultrasound. No significant changes were observed in hemodynamic and laboratory parameters. CONCLUSIONS: The CardioGard cannula is as simple to use as a regular commercially available aortic cannula, having a similar safety profile and proven efficacy in capturing intraoperative emboli.

A novel emboli protection cannula during cardiac surgery: in vitro results.

OBJECTIVE: Intraoperative cerebral events are mainly caused by emboli generated by operative manipulation of the aorta. This study aimed to delineate the distribution profiles of emboli with 2 widely used cannulae and a third novel research cannula that simultaneously produces forward flow and backward suction to extract emboli from the distal aorta during cardiac surgery. METHODS: The current in vitro study used a silicone model of the aortic arch and branches. The main outcome measure was the distribution profile of embolic particles of different sizes to the aortic branches; 2 commercial cannulae and a third novel cannula with and without suction were used. The research cannula was examined at different suction levels and the amount of particles retrieved was measured. RESULTS: For the research curved-tip cannula, most of the small emboli were released into the brachiocephalic trunk in the model (P < .05). For the straight-tip cannula, most of the small emboli were released into the descending aorta (P < .05). Regarding the commercial curved-tipped cannula, most of the small emboli were released into the brachiocephalic trunk (47.14% ± 4.78%; P < .05) and the medium and large emboli were predominantly released into the descending aorta. Using suction, the research cannula retrieved most of the emboli released into the aorta for all particle sizes (50%-83%; P < .05). CONCLUSIONS: A straight-tip cannula may be safer in terms of cerebral embolic consequences during cardiac surgery. Furthermore, the use of the research aortic cannula may be beneficial in the cardiac surgery setting by reducing the postoperative risk for stroke.

Malnutrition in cardiac surgery: food for thought.

BACKGROUND: Undernourished patients treated in general surgery departments suffer from prolonged and complicated hospitalizations, and higher mortality rates compared with well nourished patients. Pivotal information regarding patients' nutritional status and its effect on clinical outcome is lacking for cardiac surgery patients. We investigated the prevalence of malnutrition risk and its association with 30-day hospital mortality and postoperative complications. METHODS AND RESULTS: Four hundred and three patients who underwent cardiac surgery during 2008 and were screened with the Malnutrition Universal Screening Tool (MUST) on admission were enrolled. Univariate and multivariate logistic regression analyses compared the association of high and low risk for malnutrition with length of hospitalization (LOS), in-hospital and 30-day mortality, and postoperative complications. Almost 20% of the patients were found to be at high risk for malnutrition. Univariate analyses revealed higher in-hospital mortality rates (p = 0.03) and greater incidence of LOS and antibiotic treatment longer than 21 days (p = 0.002 and p = 0.04, respectively), vasopressor treatment longer than 11 days (p = 0.02), and positive blood cultures (p = 0.02) in patients belonging to the high-risk MUST group. Incorporation of the MUST in a multivariate model with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) significantly improved postoperative complications prediction, as well as in-hospital and 30-day mortality, compared with the EuroSCORE alone. CONCLUSIONS: Malnutrition is prevalent in patients undergoing cardiac surgery, associated with higher postoperative mortality and morbidity. Preoperative MUST screening has emerged as highly relevant for enabling early diagnosis of patients at malnutrition risk, predicting postoperative mortality and morbidity, thus promoting well timed treatment. Prospective studies are needed to explore whether intervention can decrease malnutrition risk.

Investigation of risks for cerebral embolism associated with the hemodynamics of cardiopulmonary bypass cannula: a numerical model.

Cerebral emboli originating in the ascending aorta are a major cause of noncardiac complications following cardiac surgery. The hemodynamics of the aortic cannula has been proven to play a significant role in emboli generation and distribution. The aim of the current study was to perform a thorough numerical investigation in order to examine the effect of the design and orientation of the cannula used during cardiopulmonary bypass on the risk to develop cerebral embolism. Hemodynamic analyses compared numerical models of 27 cases consisting of six different cannula orientations, four aortic anatomies, and three cannula designs. The cannula designs included a straight-tip (ST) cannula, a moderately curved tip cannula (TIP1 ), and a sharp-angle curved cannula (TIP2 ). Outcome measures included hemodynamic parameters such as emanating jet velocity, jet velocity drop, maximal shear stress, aortic wall reaction, emboli pathlines and distribution between upper and lower vessels, and stagnation regions. Based on these parameters, the risks for hemolysis, atheroembolism, and cerebral embolism were evaluated and compared. On one hand, the jet emerging from the ST cannula generated large wall-shear stress at the aortic wall; this may have triggered the erosion and distribution of embolic atheromatous debris from the aortic arch. On the other hand, it diverted more emboli from the clamp region to the descending aorta and thus reduced the risk for cerebral embolism. The TIP1 cannula demonstrated less shear stress on the aortic wall and diverted more emboli from the clamp region toward the upper vessels. The TIP2 cannula exhibited a stronger emanating jet, higher shear stress inside the cannula, and highly disturbed flow, which was more stagnant near the clamp region. Current findings support the significant impact of the cannula design and orientation on emboli generation and distribution. Specifically, the straight tip cannula demonstrated a reduced risk of cerebral embolism, which may be pivotal in the clinical setting.

Numerical investigation of a novel aortic cannula aimed at reducing cerebral embolism during cardiovascular bypass surgery.

The generation of emboli during cardiopulmonary bypass (CPB) is profoundly affected by the hemodynamic properties of the aortic cannula used in the current study. The aim of the current work was to numerically investigate the hemodynamic efficiency and feasibility of a novel, backward suction cannula (BSC), designed to drastically reduce the potential risk for cerebral emboli (CEP). In line with the standard cannulae, the BSC provides oxygenated blood from the CPB machine through its primary lumen. However, the unique feature of the BSC lies in its secondary lumen, which is used to suck blood and embolic matter back from the surgical field to the CPB machine for filtration. Analysis included a numerical investigation of the hemodynamic characteristics of 44 different models, encompassing various anatomic orientations, cannula types, cannula orientations and flow conditions. Hemodynamic efficacy and CEP were assessed via trajectories of particle released from the surgical region, while the cannula feasibility was evaluated through potential for atheroembolism (AP) and index for hemolysis (IH). Differences between the investigated cannulae in terms of these measures were tested using analyses of variance tests (ANOVAs). Results indicate that the BSC exhibited a significant improvement of the cannula performance in terms of CEP with no significant change in the risk for other hemodynamic complications, such as hemolysis or atheroembolism (AP and IH). These findings suggest the advantageous use of the BSC in the clinical setting for its potential to diminish the risk for cerebral emboli, which presents the most pertinent cause of noncardiac complications following open heart surgery.