{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:12:00Z","timestamp":1791551520646,"version":"4.3.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Neonatal sepsis is a major cause of morbidity and mortality in both preterm and term infants. Early-onset neonatal sepsis (EONS) presents within the first 72 h of life. Diagnosis is difficult as signs and symptoms are non-specific, and inflammatory markers are widely used to confirm or rule out neonatal sepsis. Interleukin-6 (IL-6) is part of the fetal inflammatory response syndrome (FIRS) and therefore an interesting early marker for neonatal sepsis. The main objective for this review was to assess the diagnostic potential of IL-6, alone and in combination, for diagnosis of early neonatal sepsis (EONS) in term and preterm infants, in cord and peripheral blood, and in dependence of timing of sample collection. IL-6 diagnostic accuracy studies for diagnosing EONS published between 1990 and 2020 were retrieved using the PubMed database. We included 31 out of 204 articles evaluating the potential of IL-6 for the diagnosis of EONS in a study population of newborns with culture-proven and\/or clinically suspected sepsis. We excluded articles dealing with neonatal bacterial infections other than sepsis and biomarkers other than inflammatory markers, those written in languages other than English or German, studies that did not distinguish between EONS and late-onset sepsis, and animal and <jats:italic>in vitro<\/jats:italic> studies. Full-text articles were checked for other relevant studies according to the PRISMA criteria. We identified 31 studies on IL-6 diagnostic accuracy for EONS diagnosis between 1990 and 2020 including a total of 3,276 infants. Sensitivity and specificity were reported, and subgroup analysis was performed. A STARD checklist adapted for neonates with neonatal sepsis was used for quality assessment. The range of IL-6 sensitivity and specificity in neonatal samples was 42.1\u2013100% and 43\u2013100%; the median values were 83 and 83.3%, respectively. IL-6 accuracy was better in preterm infants than in mixed-study populations. Early sample collection at the time of sepsis suspicion had the highest sensitivity when compared to other time points. Cord blood IL-6 had higher diagnostic value compared to peripheral blood. The biomarker combination of IL-6 and CRP was found to be highly sensitive, but poorly specific. Limitations of this review include use of only one database and inclusion of a heterogeneous group of studies and a small number of studies looking at biomarker combinations; a strength of this review is its focus on early-onset sepsis, since type of sepsis was identified as a significant source of heterogeneity in IL-6 diagnostic accuracy studies. We concluded that IL-6 has a good performance as an early diagnostic marker of EONS within a study population of preterm infants, with best results for cord blood IL-6 using cutoff values above 30 pg\/ml.<\/jats:p>","DOI":"10.3389\/fped.2022.840778","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T22:53:52Z","timestamp":1648508032000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":59,"title":["Reliability of Interleukin-6 Alone and in Combination for Diagnosis of Early Onset Neonatal Sepsis: Systematic Review"],"prefix":"10.3389","volume":"10","author":[{"given":"Julia","family":"Eichberger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Resch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1111\/apa.12764","article-title":"Meta-analysis shows that infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications.","volume":"103","author":"Bakhuizen","year":"2014","journal-title":"Acta Paediatr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/s0022-3476(98)70448-2","article-title":"Interleukin-6 concentrations in neonates evaluated for sepsis.","volume":"132","author":"Doellner","year":"1998","journal-title":"J Pediatr."},{"key":"B3","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1097\/00006454-200003000-00013","article-title":"Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant.","volume":"19","author":"Kashlan","year":"2000","journal-title":"Pediatr Infect Dis J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1080\/14767058.2019.1606194","article-title":"Diagnostic accuracy of interleukin-6 for early-onset sepsis in preterm neonates.","volume":"34","author":"Ebenebe","year":"2021","journal-title":"J Matern Fetal Neonatal Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1007\/s10096-020-03981-x","article-title":"Identification of progranulin as a novel diagnostic biomarker for early-onset sepsis in neonates.","volume":"39","author":"Yang","year":"2020","journal-title":"Eur J Clin Microbiol Infect Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e69341","DOI":"10.1371\/journal.pone.0069341","article-title":"Umbilical cord blood IL-6 as predictor of early-onset neonatal sepsis in women with preterm prelabour rupture of membranes.","volume":"8","author":"Cobo","year":"2013","journal-title":"PLoS One."},{"key":"B7","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1097\/PCC.0b013e3181e2a53b","article-title":"A clinic-biological score for diagnosing early-onset neonatal infection in critically ill preterm infants.","volume":"12","author":"Labenne","year":"2011","journal-title":"Pediatr Crit Care Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1002\/(SICI)1520-6661(199709\/10)6:5<254::AID-MFM2>3.0.CO;2-F","article-title":"Value of umbilical artery and vein levels of interleukin-6 and soluble intracellular adhesion molecule-1 as predictors of neonatal hematologic indices and suspected early sepsis.","volume":"6","author":"Smulian","year":"1997","journal-title":"J Mater Fetal Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1080\/08035259950169314","article-title":"Evaluation of interleukin-6, tumour necrosis factor-alpha and interleukin-1beta for early diagnosis of neonatal sepsis.","volume":"88","author":"Silveira","year":"1999","journal-title":"Acta Paediatr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/s0022-3476(96)70123-3","article-title":"Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection.","volume":"129","author":"Messer","year":"1996","journal-title":"J Pediatr."},{"key":"B11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.earlhumdev.2016.12.002","article-title":"Biomarkers for the diagnosis of neonatal sepsis and necrotizing enterocolitis: clinical practice guidelines.","volume":"105","author":"Gilfillan","year":"2017","journal-title":"Early Hum Dev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/S0140-6736(98)08148-3","article-title":"Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation.","volume":"352","author":"K\u00fcster","year":"1998","journal-title":"Lancet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1203\/00006450-199201000-00003","article-title":"Defective production of interleukin-6 by monocytes: a possible mechanism underlying several host defense deficiencies of neonates.","volume":"31","author":"Schibler","year":"1992","journal-title":"Pediatr Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1080\/080352501317061602","article-title":"Cord blood levels of cytokines as predictors of early neonatal sepsis.","volume":"90","author":"Santana","year":"2001","journal-title":"Acta Paediatr."},{"key":"B15","doi-asserted-by":"crossref","first-page":"F229","DOI":"10.1136\/adc.2002.023838","article-title":"Diagnostic markers of infection in neonates.","volume":"89","author":"Ng","year":"2004","journal-title":"Arch Dis Child Fetal Neonatal Edn."},{"key":"B16","doi-asserted-by":"publisher","first-page":"F221","DOI":"10.1136\/fn.77.3.f221","article-title":"Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants.","volume":"77","author":"Ng","year":"1997","journal-title":"Arch Dis Child Fetal Neonatal Edn."},{"key":"B17","doi-asserted-by":"publisher","first-page":"432","DOI":"10.3109\/00365513.2014.900696","article-title":"Cord blood procalcitonin and Interleukin-6 are highly sensitive and specific in the prediction of early-onset sepsis in preterm infants.","volume":"74","author":"Steinberger","year":"2014","journal-title":"Scand J Clin Lab Invest."},{"key":"B18","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1093\/clinchem\/47.6.1016","article-title":"Serial measurements of C-reactive protein and interleukin-6 in the immediate postnatal period: reference intervals and analysis of maternal and perinatal confounders.","volume":"47","author":"Chiesa","year":"2001","journal-title":"Clin Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1097\/SHK.0000000000000753","article-title":"Multiplex cytokine profiling identifies interleukin-27 as a novel biomarker for neonatal early onset sepsis.","volume":"47","author":"He","year":"2017","journal-title":"Shock."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e203","DOI":"10.1111\/j.1651-2227.2011.02577.x","article-title":"Cord blood interleukin-6 as a predictor of early-onset neonatal sepsis.","volume":"101","author":"Cernada","year":"2012","journal-title":"Acta Paediatr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1097\/00006454-200009000-00014","article-title":"Cytokines as markers of bacterial sepsis in newborn infants: a review.","volume":"19","author":"Mehr","year":"2000","journal-title":"Pediatr Infect Dis J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cyto.2015.03.015","article-title":"Fetal and early neonatal interleukin-6 response.","volume":"76","author":"Chiesa","year":"2015","journal-title":"Cytokine."},{"key":"B23","first-page":"p. 45","author":"Newcombe","year":"2005","journal-title":"Proportions and Their Differences. Statistics With Confidence."},{"key":"B24","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.cca.2015.01.031","article-title":"Translational research and biomarkers in neonatal sepsis.","author":"Delanghe","year":"2015","journal-title":"Clin Chim Acta"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e13146","DOI":"10.1097\/MD.0000000000013146","article-title":"Interleukin-6 for early diagnosis of neonatal sepsis with premature rupture of the membranes: a meta-analysis.","volume":"97","author":"Qiu","year":"2018","journal-title":"Medicine."},{"key":"B26","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s12519-012-0347-3","article-title":"Umbilical blood biomarkers for predicting early-onset neonatal sepsis.","volume":"8","author":"Fan","year":"2012","journal-title":"World J Pediatr."},{"key":"B27","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1038\/jp.2013.186","article-title":"Inflammatory markers in cord blood or maternal serum for early detection of neonatal sepsis-a systemic review and meta-analysis.","volume":"34","author":"Su","year":"2014","journal-title":"J Perinatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"542.e1","DOI":"10.1016\/j.ajog.2013.08.030","article-title":"The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates.","volume":"209","author":"Hofer","year":"2013","journal-title":"Am J Obstet Gynecol."},{"key":"B29","first-page":"224","article-title":"Comparison of umbilical cord interleukin-6 in preterm infants with premature rupture of membranes and intact membranes.","volume":"29","author":"Gharehbaghi","year":"2008","journal-title":"Saudi Med J."},{"key":"B30","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/(SICI)1520-6661(199905\/06)8:3<88::AID-MFM4>3.0.CO;2-#","article-title":"Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying early neonatal sepsis.","volume":"8","author":"Smulian","year":"1999","journal-title":"J Mater Fetal Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"E26","DOI":"10.1097\/ANC.0000000000000631","article-title":"Serum biomarkers for the early detection of the early-onset neonatal sepsis: a single-center prospective study.","volume":"19","author":"Ahmed","year":"2019","journal-title":"Adv Neonatal Care."},{"key":"B32","first-page":"219","article-title":"Early and late markers for the detection of early-onset neonatal sepsis.","volume":"55","author":"Bender","year":"2008","journal-title":"Danish Med Bull."},{"key":"B33","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/00006454-199704000-00007","article-title":"Interleukin 6 in neonates with early and late onset infection.","volume":"16","author":"Panero","year":"1997","journal-title":"Pediatr Infect Dis J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1159\/000047130","article-title":"Cord blood levels of interleukin-6 and interleukin-8 for the immediate diagnosis of early-onset infection in premature infants.","volume":"80","author":"Krueger","year":"2001","journal-title":"Biol Neonate."},{"key":"B35","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1373\/49.1.60","article-title":"C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection.","volume":"49","author":"Chiesa","year":"2003","journal-title":"Clin Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"E61","DOI":"10.1542\/peds.108.4.e61","article-title":"Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis.","volume":"108","author":"Martin","year":"2001","journal-title":"Pediatrics."},{"key":"B37","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1159\/000244366","article-title":"Immunologic parameters in cord blood indicating early-onset sepsis.","volume":"70","author":"Lehrnbecher","year":"1996","journal-title":"Biol Neonate."},{"key":"B38","doi-asserted-by":"publisher","first-page":"388","DOI":"10.3855\/jidc.5950","article-title":"Evaluation of recent methods versus conventional methods for diagnosis of early-onset neonatal sepsis.","volume":"9","author":"Al-Zahrani","year":"2015","journal-title":"J Infect Dev Ctries."},{"key":"B39","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1128\/cdli.9.2.440-445.2002","article-title":"Elevated levels of lipopolysaccharide-binding protein and soluble CD14 in plasma in neonatal early-onset sepsis.","volume":"9","author":"Berner","year":"2002","journal-title":"Clin Diagn Lab Immunol."},{"key":"B40","first-page":"180","article-title":"Procalcitonin versus CRP as an early indicator of fetal infection in preterm premature rupture of membranes.","volume":"53","author":"Canpolat","year":"2011","journal-title":"Turk J Pediatr."},{"key":"B41","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1159\/000364871","article-title":"Serial ultrasonographic examination of the fetal thymus in the prediction of early neonatal sepsis in preterm premature rupture of membranes.","volume":"78","author":"Cetin","year":"2014","journal-title":"Gynecol Obstet Invest."},{"key":"B42","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1515\/jpm.2010.071","article-title":"Diagnostic value of interleukin-6 and C-reactive protein on early onset bacterial infection in preterm neonates with respiratory distress.","volume":"38","author":"Rego","year":"2010","journal-title":"J Perinat Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1111\/j.0001-6349.2005.00747.x","article-title":"Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome.","volume":"84","author":"Hatzidaki","year":"2005","journal-title":"Acta Obstet Gynecol Scand."},{"key":"B44","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1159\/000047118","article-title":"Inflammatory mediators in umbilical plasma from neonates who develop early-onset sepsis.","volume":"80","author":"D\u00f8llner","year":"2001","journal-title":"Biol Neonate."},{"key":"B45","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1111\/j.1651-2227.2003.tb00534.x","article-title":"Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate.","volume":"92","author":"Resch","year":"2003","journal-title":"Acta Paediatr."},{"key":"B46","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1203\/00006450-199810000-00002","article-title":"Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis.","volume":"44","author":"Berner","year":"1998","journal-title":"Pediatr Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1111\/iwj.13079","article-title":"A meta-analysis of interleukin-6 as a valid and accurate index in diagnosing early neonatal sepsis.","volume":"16","author":"Sun","year":"2019","journal-title":"Int Wound J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1097\/EDE.0b013e318207fc5c","article-title":"Adjusting for differential-verification bias in diagnostic-accuracy studies: a Bayesian approach.","volume":"22","author":"de Groot","year":"2011","journal-title":"Epidemiology."},{"key":"B49","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1503\/cmaj.050090","article-title":"Evidence of bias and variation in diagnostic accuracy studies.","volume":"174","author":"Rutjes","year":"2006","journal-title":"CMAJ."},{"key":"B50","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1007\/s00134-010-1819-3","article-title":"Diagnostic utility of elevated serum soluble triggering receptor expressed on myeloid cells (sTREM)-1 in infected neonates.","volume":"36","author":"Sarafidis","year":"2010","journal-title":"Intensive Care Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1159\/000081979","article-title":"Serum amyloid A protein is a useful inflammatory marker during late-onset sepsis in preterm infants.","volume":"87","author":"Arnon","year":"2005","journal-title":"Biol Neonate."},{"key":"B52","doi-asserted-by":"publisher","first-page":"101146","DOI":"10.1016\/j.siny.2020.101146","article-title":"The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications.","volume":"25","author":"Jung","year":"2020","journal-title":"Semin Fetal Neonatal Med."},{"key":"B53","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1542\/peds.91.3.617","article-title":"Score for neonatal acute physiology: a physiologic severity index for neonatal intensive care.","volume":"91","author":"Richardson","year":"1993","journal-title":"Pediatrics."},{"key":"B54","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1056\/NEJM197810262991705","article-title":"Problems of spectrum and bias in evaluating the efficacy of diagnostic tests.","volume":"299","author":"Ransohoff","year":"1978","journal-title":"N Engl J Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1017\/s1481803500009891","article-title":"Incorporation bias in studies of diagnostic tests: how to avoid being biased about bias.","volume":"10","author":"Worster","year":"2008","journal-title":"CJEM."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.840778\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T22:54:00Z","timestamp":1648508040000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.840778\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":55,"alternative-id":["10.3389\/fped.2022.840778"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.840778","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]},"article-number":"840778"}}