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 ... -  《-》

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 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 ... -  《-》

Validation of a Novel Assay to Distinguish Bacterial and Viral Infections.

Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and C-reactive protein [CRP]) was developed to assist in differentiation between bacterial and viral disease. We performed double-blind, multicenter assay evaluation using serum remnants collected at 5 pediatric emergency departments and 2 wards from children ≥3 months to ≤18 years without (n = 68) and with (n = 529) suspicion of acute infection. Infectious cohort inclusion criteria were fever ≥38°C and symptom duration ≤7 days. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results. Assay performers were blinded to the reference standard. Assay cutoffs were predefined. Of 529 potentially eligible patients with suspected acute infection, 100 did not fulfill infectious inclusion criteria and 68 had insufficient serum. The resulting cohort included 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The assay distinguished between bacterial and viral patients with 93.8% sensitivity (95% confidence interval: 87.8%-99.8%) and 89.8% specificity (85.6%-94.0%); 11.7% had an equivocal assay outcome. The assay outperformed CRP (cutoff 40 mg/L; sensitivity 88.2% [80.4%-96.1%], specificity 73.2% [67.6%-78.9%]) and procalcitonin testing (cutoff 0.5 ng/mL; sensitivity 63.1% [51.0%-75.1%], specificity 82.3% [77.1%-87.5%]). Double-blinded evaluation confirmed high assay performance in febrile children. Assay was significantly more accurate than CRP, procalcitonin, and routine laboratory parameters. Additional studies are warranted to support its potential to improve antimicrobial treatment decisions.

Srugo I ，Klein A ，Stein M ，Golan-Shany O ，Kerem N ，Chistyakov I ，Genizi J ，Glazer O ，Yaniv L ，German A ，Miron D ，Shachor-Meyouhas Y ，Bamberger E ，Oved K ，Gottlieb TM ，Navon R ，Paz M ，Etshtein L ，Boico O ，Kronenfeld G ，Eden E ，Cohen R ，Chappuy H ，Angoulvant F ，Lacroix L ，Gervaix A ... -  《-》

A novel host-protein assay outperforms routine parameters for distinguishing between bacterial and viral lower respiratory tract infections.

Bacterial and viral lower respiratory tract infections (LRTIs) are often clinically indistinguishable, leading to antibiotic overuse. We compared the diagnostic accuracy of a new assay that combines 3 host-biomarkers (TRAIL, IP-10, CRP) with parameters in routine use to distinguish bacterial from viral LRTIs. Study cohort included 184 potentially eligible pediatric and adult patients. Reference standard diagnosis was based on adjudication by an expert panel following comprehensive clinical and laboratory investigation (including respiratory PCRs). Experts were blinded to assay results and assay performers were blinded to reference standard outcomes. Evaluated cohort included 88 bacterial and 36 viral patients (23 did not fulfill inclusion criteria; 37 had indeterminate reference standard outcome). Assay distinguished bacterial from viral LRTI patients with sensitivity of 0.93±0.06 and specificity of 0.91±0.09, outperforming routine parameters, including WBC, CRP and chest x-ray signs. These findings support the assay's potential to help clinicians avoid missing bacterial LRTIs or overusing antibiotics.

Stein M ，Lipman-Arens S ，Oved K ，Cohen A ，Bamberger E ，Navon R ，Boico O ，Friedman T ，Etshtein L ，Paz M ，Gottlieb TM ，Kriger O ，Fonar Y ，Pri-Or E ，Yacobov R ，Dotan Y ，Hochberg A ，Grupper M ，Chistyakov I ，Potasman I ，Srugo I ，Eden E ，Klein A ... -  《-》