TABLE 3.

Characteristics of IL-6 accuracy studies for diagnosing EONS using biomarker combinations.

Author, Year, Country, (Reference)	EONS definition	Recruitment	Reference standard in infected neonates	Reference standard in control neonates	Sample studied, time of sample collection	Test	Biomarker combination	Criterion for positive test	Cutoffs: IL-6 (pg/mL), CRP (mg/L), PCT (ng/mL), TNF-α (pg/mL)	Sensitivity (95% CI), %	Specificity (95% CI), %	AUC	PPV, %	NPV, %
Ebenebe et al., Germany, (4)	≤72 h	1,202 preterm infants with a birth weight < 2,000 g: 67 infected, 115 uninfected	(1) Positive blood culture or (2) CRP ≥ 5 mg/l and ≥ 3 clinical signs	Gestational age and birth-weight matched neonates that did not fulfill criteria of EONS	IL-6: neonatal blood, 0 h (PNA) and maternal blood (CRP), <24 h (before delivery)	IL-6: electrochem iluminescence assay, CRP: particle enhanced immune-nephelometry	IL-6 + CRP	and	IL-6: 40, CRP: 10	49.0	82.4	NA	14.1	96.5
							IL-6 + CRP	Either/or		90.2	43.1	NA	8.6	98.7
					Neonatal blood, 0 h (PNA)	IL-6: electroch emiluminescence assay, CRP: particle enhanced immune-nephelometry	IL-6 + CRP	and	IL-6: 40, CRP: 10	23.4	100	NA	100.0	96.8
							IL-6 + CRP	either/or		75	71.7		13.6	98
Steinberger et al., Austria, (17)	NS	218 NICU preterm infants with risk factors for EONS: 30 infected, 188 uninfected	(1) Positive blood culture or (2) ≥3 categories of clinical signs or (3) ≥1 categories of clinical signs, and ≥2 laboratory abnormalities (CRP, WBC, I:T ratio)	NA	Cord blood	IL-6: ELISA, PCT: LUMItest procalcitonin kit	IL-6 + PCT	and	IL-6: 10, PCT: 0.5	58.8	99.0	0.850 (0.731–0.968)	NA	NA
							IL-6 + PCT	Either/or	IL-6: 15.85, PCT: 0.235 (ROC, Youden)	91.7 (71.2–99.0)	77.1 (67.4–85.0)	0.915 (0.822–1.000)	42.1 (26.3–59.2)	98.7 (92.8–99.8)
Rego et al., Brazil, (42)	NS	144 NICU preterm infants (130 VLBW) presenting RDS during the first 24 h of life: 44 infected, 100 infected	In addition to RDS, (1) ≥ 2 categories of clinical signs, or clinical chorioamnionitis, and positive blood or CSF culture or (2) ≥2 categories of clinical sepsis, or clinical chorioamnionitis, and a hematologic sepsis score >3 or 3) radiographic evidence of pneumonia and a hematologic sepsis score >3	No clinical signs and a hematologic sepsis score <3	Peripheral blood	Chemilum inescence immunoassay system	IL-6 + CRP	and/or	IL-6: 36, CRP: 60 (ROC, maximum sensitivity and specificity >50%)	93 (80–98)	37 (27–48)	NA	41 (31–51)	92 (78–98)
Bender et al., Denmark, (32)	EONS (=72 h)	123 NICU preterm and term infants with at least 1 clinical sign suggesting EONS: 29 infected, 94 uninfected	(1) Positive blood culture or (2) clinical signs and CRP > 5 mg/dl	(1) Clinical signs and CRP ≤ 5 mg/dL and antibiotic therapy for 3 days or (2) clinical signs, but no antibiotic therapy	Blood, 0 h (after suspicion of sepsis)	IL-6: flow cytometry (LUMINEX), PCT: immunol uminometric assay (LUMItest R PCT; BRAHMS Diagnostica, Berlin, Germany)	IL-6 + PCT	Either/or	IL-6: 250, PCT: 25 (specificity of the single marker ∼95%)	71	88	NA	65	91
							IL-6 + PCT	either/or	IL-6: 12, PCT: 5.75 (sensitivity and specificity of the single marker almost identical)	93	46	NA	35	95
Silveira and Procianoy, Brazil, (9)	EONS (≤5 days)	117 NICU preterm and term infants with suspected sepsis: 66 infected, 51 uninfected	(1) Positive blood and/or CSF culture and ≥3 categories of clinical sepsis or (2) negative cultures and ≥3 categories of clinical sepsis	PROM, but no complete criteria for clinical sepsis, no antibiotic treatment up to discharge from hospital, no hospital readmission (<1 month)	Peripheral blood, 0 h (after suspicion of sepsis), 82.9% at ≤24 h PNA	Quantitative sandwich enzyme immunoassay technique (Quantikine)	IL-6 + TNF-α	and/or	IL-6: 32, TNF-α: 12 (ROC, NS)	98.5	NA	NA	60.7	90
Doellner et al., Norway, (2)	NS	113 NICU preterm and term infants: 24 infected, 89 uninfected	(1) Positive blood/CSF culture and clinical signs for sepsis/meningitis or (2) negative blood culture, ≥3 categories of clinical signs and abnormal laboratory results (CRP, I:T ratio) or (3) negative blood culture, respiratory symptoms, X-ray consistent with pneumonia and abnormal laboratory results	Initially suspected of having an infection (not confirmed)	Peripheral blood, on admission to the NICU or on the next day, >92% <4 days (PNA)	IL-6–dependent mouse hybridoma cell line B13.29 (clone B9), as described by Ng [(15) cite]	IL-6 + CRP	and/or	IL-6: 50 pg/ml, CRP: 10 mg/L (NA)	96	74	NA	49	99

NA, not available; NS, not specified; UV, umbilical vein; UA, umbilical artery; PNA, postnatal age; NICU, neonatal intensive care unit; CSF, cerebrospinal fluid; CRP, C-reactive protein; WBC, white blood count; PC, platelet count; ABC, absolute band count; EONS, early-onset neonatal sepsis; AUC, area under the curve; PPV, positive predictive value; NPV, negative predictive value; GA, gestational age.