Isaac Srugo1,2, Adi Klein3, Michal Stein4, Orit Golan-Shany2, Nogah Kerem5,2, Irina Chistyakov5,2, Jacob Genizi2, Oded Glazer2, Liat Yaniv2, Alina German2, Dan Miron6, Yael Shachor-Meyouhas7, Ellen Bamberger5,2,8, Kfir Oved8, Tanya M Gottlieb8, Roy Navon8, Meital Paz8, Liat Etshtein8, Olga Boico8, Gali Kronenfeld8, Eran Eden8, Robert Cohen9, Helène Chappuy10, François Angoulvant11, Laurence Lacroix12, Alain Gervaix12. 1. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; isaac.srugo@b-zion.org.il. 2. Department of Pediatrics, Bnai-Zion Medical Center, Haifa, Israel. 3. Department of Pediatrics and. 4. Infectious Disease Unit, Hillel Yaffe Medical Center, Hadera, Israel. 5. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 6. Pediatric Disease Service, Emek Medical Center, Afula, Israel. 7. Pediatric Infectious Disease Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel. 8. MeMed, Tirat Carmel, Israel. 9. Clinical Research Center, Centre Intercommunal de Creteil, Creteil, France. 10. Pediatric Emergency Department, Assistance Publique des Hôpitaux de Paris, Armand Trousseau Hospital, Pierre et Marie Curie University, Paris, France. 11. Pediatric Emergency Department, Assistance Publique des Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris Descartes University, Paris, France; and. 12. Pediatric Emergency Division, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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%]). CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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%]). CONCLUSIONS: 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.
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