TABLE 2.
Characteristics of IL-6 accuracy studies for diagnosing EONS in a mixed population of preterm and term infants.
| Author, year, country, (reference) | EONS definition | Recruitment | Reference standard in infected neonates | Reference standard in control neonates | Sample studied, time of sample collection | Test | IL-6 cutoff (pg/mL) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | AUC (95% CI) | PPV, % | NPV, % |
| Yang et al., China, (5) | ≤72 h | 152 preterm (>34 weeks) and term infants at risk for EONS: 76 infected, 76 uninfected | (1) Positive blood or CSF culture or (2) ≥3 categories of clinical signs | Negative blood culture and <3 categories of clinical signs | Venous blood, ≤72 h (PNA) | MILLIPLEX Map Human Th17 Magnetic Bead Panel and Sepsis Panel (Millipore) | 153 | 42.1 | 93.4 | 0.704 (0.622–0.786) | 84.6 | 61.4 |
| Ahmed et al., Egypt, (31) | ≤72 h | 60 NICU preterm and term infants: 30 high suspicion of EONS, 30 matched controls | Clinical findings supporting the suspicion of neonatal sepsis | Age- and weight-matched neonates without the criteria of sepsis suspicion | Venous blood, ≤72 h (PNA) | ELISA | 24 (ROC, Youden) | 94.4 | 52.4 | 0.751 (0.623–0.854) | 45.9 | 95.7 |
| He et al., China, (19) | ≤72 h | 151 preterm (>34 weeks) and term infants with suspected EONS: 68 infected, 83 uninfected | (1) Positive blood or CSF culture and any abnormal finding or (2) negative culture results but ≥3 abnormal findings | Negative culture results and <3 abnormal findings | Venous blood, ≤72 h (PNA) | MILLIPLEX Map Human Th17 Magnetic Bead Panel and Sepsis Panel (Millipore) | 75.43 | 64.71 | 69.88 | 0.706 (0.626–0.777) | 63.77 | 70.74 |
| Al-Zahrani et al., Saudi Arabia, (38) | <1 week | 100 NICU preterm and term infants with suspected sepsis: 71 infected, 29 uninfected | (1) Positive blood culture and/or positive PCR results for bacterial 16S rDNA or (2) negative blood culture and PCR, but clinical signs of sepsis and positive sepsis screen. | Neonates suspected of having sepsis with negative blood culture, PCR and sepsis screen | Blood sample, ≤24 h (after NICU admission), <1 week (PNA) | ELISA | 60 | 63.6 | 69 | NA | 75.6 | 55.5 |
| Cernada et al., Spain, (20) | ≤72 h | 128 preterm and term infants with prenatal risk factors for EONS (77% asymptomatic at birth): 10 infected, 118 uninfected | (1) Positive blood culture and clinical sings or (2) ≥3 categories of clinical signs | NA | Cord blood, 0 h (PNA) | Chemiluminescence enzyme immunoassay in solid phase | 255.87 (ROC, NS) | 90 | 87.4 | 0.88 (0.7–1.06) (sic) | 37.5 | 99 |
| Bender et al., Denmark, (32) | ≤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 | Peripheral blood, 0 h (after suspicion of sepsis) | Flow cytometry (LUMINEX) | 250 (ROC, specificity ∼95%) | 59 (41–75) | 94 (87–97) | 0.77 | 76 | 88 |
| 12 (ROC, sensitivity ∼ specificity) | 71 | 71 | 0.77 | 43 | 89 | |||||||
| Resch et al., Austria, (45) | NS | 68 NICU preterm and term infants with suspected sepsis: 41 infected, 27 uninfected | (1) Positive blood culture or (2) ≥3 categories of clinical signs, positive sepsis screen and/or risk factors, and antibiotic therapy ≥7 days | Negative blood culture, negative sepsis screen, and antibiotic therapy ≤3 days | Venous or arterial blood, ≤12 h (PNA) | ELISA | ≥10 (ROC, NS) | 71 (56–82) | 67 (48–81) | NA | 76 | 60 |
| ≥60 (ROC, Youden) | 54 (39–68) | 100 (88–100) | NA | 100 | 59 | |||||||
| ≥150 (ROC, NS) | 46 (32–61) | 100 (88–100) | NA | 100 | 55 | |||||||
| Chiesa et al., Italy, (35) | ≤48 h | 134 NICU preterm and term infants: 19 infected, 115 uninfected | (1) Positive blood culture and clinical signs or (2) ≥3 clinical signs prompting ≥5 days of antibiotic therapy, and historical and clinical risk factors for EONS | Symptomatic infants who had negative body fluid cultures, and were apparently well within 24–48 h and received antibiotic treatment ≤3 days | Cord blood, 0 h (PNA) | ELISA | 200 (ROC, Youden) | 74 (51–88) | 89 (82–93) | NA | NA | NA |
| Peripheral blood, 24 h (PNA) | 30 (ROC, Youden) | 63 (41–81) | 71 (62–78) | NA | NA | NA | ||||||
| Peripheral blood, 48 h (PNA) | 20 (ROC, Youden) | 53 (32–73) | 70 (63–79) | NA | NA | NA | ||||||
| Martin et al., Sweden, (36) | ≤48 h | 32 NICU preterm and term infants with suspected sepsis: 20 infected, 12 uninfected | (1) Positive blood or CSF culture or (2) abnormal CRP, WBC and ≥1 category of clinical signs (i.e., oliguria, metabolic acidosis, or hypoxemia) | Clinical conditions apparently non-infectious | Peripheral blood, at admission, ≤48 h (PNA) | Chemiluminescence immunoassay | 160 (ROC, Youden) | 100 | 70 | NA | 67 | 100 |
| Krueger et al., Germany, (34) | ≤48 h | 136 preterm and term infants: 68 infected, 68 uninfected | (1) Clinical signs and positive blood culture or (2) clinical signs and abnormal laboratory results (CRP, I:T ratio), biological fluids positive for bacteria, or signs of inflammation in placenta | Non-infectious clinical conditions | Cord blood, 0 h (PNA) | Fully automated chemiluminescence immunoassay | 80 (ROC, ULC) | 87 | 90 | NA | NA | NA |
| Santana et al., Spain, (14) | NS | 31 preterm and term infants: 10 infected, 11 uninfected, 10 healthy controls | ≥2 categories of clinical signs, ≥1 abnormal laboratory findings, and positive blood culture | (1) Clinical conditions apparently non-infectious or (2) GA-matched neonates with normal postnatal course through the first month of life | Cord blood, 0 h (PNA) | Chemiluminescence enzymoimmunoassay in the solid phase | 100.8 (ROC, NS) | 50 | 87 | ∼0.5 | 31 | 66 |
| Silveira and Procianoy, Brazil, (9) | ≤5 days | 117NICU 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) | 32 (ROC, NS) | 90 | 43 | NA | 67.4 | 78.6 |
| Berner et al., Germany, (46) | ≤4 days | 136 preterm and term infants, cord blood samples available in 93 infants: 16 infected, 43 uninfected, 35 healthy controls | (1) Positive blood culture or (2) ≥3 categories of clinical signs or laboratory markers | (1) Clinical suspicion but neither positive culture, nor ≥3 categories of clinical signs or | Cord blood, 0 h (PNA) | Double-sandwich enzyme immunoassay (Quantikine) | 100 (NA) | 87 | 93 | NA | 76 | 97 |
| Døllner 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, at NICU admission 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] | 20 (NA) | 78 | 71 | NA | 40 | 93 |
| 50 (NA) | 61 | 76 | NA | 38 | 89 | |||||||
| Panero et al., Italy, (33) | ≤48 h | 60 NICU preterm and term infants: 13 infected, 47 uninfected | Positive blood culture and clinical signs of sepsis | Infants with various types of distress and non-specific abnormal clinical signs who were well within 48–72 h | Venous blood, ≤ 24 h (PNA) | Solid-phase sandwich enzyme-amplified sensitivity immunoassay (Medgenix) | 70 (ROC, NS) | 69 | 36 | NA | 23 | 81 |
| Venous blood, ≤24 h (PNA) | 200 (ROC, NS) | 38 | 70 | NA | 26 | 80 | ||||||
| Venous blood, 24–48 h (PNA) | 50 (ROC, NS) | 92 | 96 | NA | 86 | 98 | ||||||
| Smulian et al., United States, (8) | ≤72 h | 23 preterm and term infants with suspected EONS: 8 infected, 15 uninfected | (1) Positive blood or CSF culture or (2) clinical signs and ≥laboratory abnormalities (WBC, I:T ratio, PC, ABC, or abnormal spinal tap) | NA | Cord blood (UA), 0 h (PNA) | ELISA (Quantikine) | 7 (NA) | 88.5 | 66.6 | NA | 58.8 | 91 |
| Cord blood (UV), 0 h (PNA) | ELISA (Quantikine) | 7 (NA) | 88.5 | 93.3 | NA | 88.5 | 93.3 | |||||
| Lehrnbecher et al., Germany, (37) | ≤48 h | 46 NICU preterm and term infants: 13 infected, 33 uninfected | (1) Positive blood culture and ≥3 categories of clinical signs or (2) negative blood culture, ≥3 categories of clinical signs and ≥2 abnormal laboratory results in the first 48 h of life | NA | Cord blood, 0 h (PNA) | Enzyme immunoassay (Dianova-Immunotech) | 150 (ROC, NS) | 69 | 91 | NA | NA | NA |
| Messer et al., France, (10) | NS | 288 NICU/obstetric unit preterm and term infants: 71 infected (36 infected or probably infected, 35 possibly infected, 217 uninfected | (1) Positive blood and/or CSF culture, clinical signs, and abnormal laboratory results (CRP, WBC) or (2) Negative culture results but ≥3 categories of clinical signs and abnormal laboratory results or (3) negative culture results, <3 categories of clinical signs, abnormal laboratory results that could have another reason, neither exclusion nor confirmation of sepsis possible | Neither clinical nor biological signs of infection | Cord or peripheral blood, NA | ELISA (Hoffmann-La Roche) | 100 (ROC, ULC) | 83.3 | 90.3 | NA | NA | NA |
| Of the 288 infants, 220 were inborn: 39 infected (18 infected or probably infected, 21 possibly infected), 181 uninfected | Cord or peripheral blood, ≤1 h (PNA) | 100 | 92.3 | NA | 58.8 | 97 | ||||||
| Of the 288 infants, 254 were sampled within the first 12 h of life: NA | Cord or peripheral blood, ≤12 h (PNA) | 100 | 89 | NA | NA | NA |
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.