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.

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. 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. 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. 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.

Papan C ，Argentiero A ，Porwoll M ，Hakim U ，Farinelli E ，Testa I ，Pasticci MB ，Mezzetti D ，Perruccio K ，Etshtein L ，Mastboim N ，Moscoviz E ，Ber TI ，Cohen A ，Simon E ，Boico O ，Shani L ，Gottlieb TM ，Navon R ，Barash E ，Oved K ，Eden E ，Simon A ，Liese JG ，Knuf M ，Stein M ，Yacobov R ，Bamberger E ，Schneider S ，Esposito S ，Tenenbaum T ... -  《-》

A host-protein signature is superior to other biomarkers for differentiating between bacterial and viral disease in patients with respiratory infection and fever without source: a prospective observational study.

Ashkenazi-Hoffnung L ，Oved K ，Navon R ，Friedman T ，Boico O ，Paz M ，Kronenfeld G ，Etshtein L ，Cohen A ，Gottlieb TM ，Eden E ，Chistyakov I ，Srugo I ，Klein A ，Ashkenazi S ，Scheuerman O ... -  《-》

A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study.

A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86·7% (95% CI 75·8-93·1), a specificity of 91·1% (87·9-93·6), a positive predictive value of 60·5% (49·9-70·1), and a negative predictive value of 97·8% (95·6-98·9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87·8% (74·5-94·7), specificity 93·0% (89·6-95·3), positive predictive value 62·1% (49·2-73·4), and negative predictive value 98·3% (96·1-99·3). This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. MeMed Diagnostics.

van Houten CB ，de Groot JAH ，Klein A ，Srugo I ，Chistyakov I ，de Waal W ，Meijssen CB ，Avis W ，Wolfs TFW ，Shachor-Meyouhas Y ，Stein M ，Sanders EAM ，Bont LJ ... -  《-》

Identifying patients with bacterial infections using a combination of C-reactive protein, procalcitonin, TRAIL, and IP-10 in the emergency department: a prospective observational cohort study.

The aim was to effectively reduce the unnecessary use of broad spectrum antibiotics in the emergency department (ED), patients with bacterial infections need to be identified accurately. We investigated the diagnostic value of a combination of biomarkers for bacterial infections, C-reactive protein (CRP), and procalcitonin (PCT), together with biomarkers for viral infections, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and interferon-gamma-induced protein-10 (IP-10), in identifying suspected and confirmed bacterial infections in a general ED population with fever. This is a sub-study in the HiTEMP cohort. Patients with fever were included during ED triage, and blood samples were obtained. Using both diagnostics and expert panel analysis, all patients were classified as having either suspected or confirmed bacterial infections, or non-bacterial disease. Using multivariable logistic regression analysis, three biomarker models were analysed: model 1, CRP, TRAIL, IP-10; model 2, PCT, TRAIL, IP-10; and model 3, CRP, PCT, TRAIL, IP-10. A total of 315 patients were included, of whom 228 patients had a suspected or confirmed bacterial infection. The areas under the curve for the combined models were the following: model 1, 0.730 (95% CI 0.665-0.795); model 2, 0.748 (95% CI 0.685-0.811); and model 3, 0.767(95% CI 0.704-0.829). These findings show that a combination of CRP, PCT, TRAIL and IP-10 can identify bacterial infections with higher accuracy than single biomarkers and combinations of a single bacterial biomarkers combined with TRAIL and IP-10.

van der Does Y ，Rood PPM ，Ramakers C ，Schuit SCE ，Patka P ，van Gorp ECM ，Limper M ... -  《-》

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

Papan C ，Argentiero A ，Adams O ，Porwoll M ，Hakim U ，Farinelli E ，Testa I ，Pasticci MB ，Mezzetti D ，Perruccio K ，Simon A ，Liese JG ，Knuf M ，Stein M ，Yacobov R ，Bamberger E ，Schneider S ，Esposito S ，Tenenbaum T ... -  《-》