Proteomic biomarkers for early diagnosis and prognosis in pediatric sepsis

Table 1 Results of database search

Key terms for search	Results from PubMed	Results from Scopus	Results from Web of Science
Pediatric sepsis	25796	13583	13458
Proteomics in sepsis	996	826	522
Sepsis biomarkers	14390	11214	6977
Haptoglobin	11690	18786	10114
Interleukin-27	2219	2179	2452

Table 2 Comparative characteristics of the four included studies

Ref.	Wong et al[20]	Luo et al[21]	Pilar-Orive et al[22]	Shubin et al[23]
Setting/design	17-center PICU; prospective observational diagnostic biomarker study	Single-center; nested case-control; pneumonia-derived sepsis	Single-center; analytical observational case-control study	Single-center PICU/cardiac intensive care unit; prospective observational, proteomics
Number (analyzed) and age	231 (vs 61 control group); noted multicenter; ≤ 10 years	90 discovery samples pooled (20 controls); enzyme-linked immunosorbent assays validation (n = 35). Age strata: Infants (7-12 months), toddlers (13-36 months)	40 septic children (vs 24 healthy donors); 1 month to 16 years	35 sepsis (vs 28 control); 1 sepsis outlier removed 34 sepsis analyzed, 1-8 years
Specimen and timing	Serum; within first 24 hours	Plasma; processed ≤ 24 hours; -80 °C storage; top-12 depletion	Serum; single draw (study baseline)	Serum; day-1 post-presentation/CPB (per cohort definitions)
Comparators	Systemic inflammatory response syndrome (culture-neg) vs sepsis/septic shock (culture-pos)	Within-age outcome groups (improved vs no-improve vs non-survivors)	Healthy donors	Post-CPB infection-negative systemic inflammation (non-infectious systemic inflammation)
Sepsis marker	Interleukin-27	Haptoglobin, thrombospondin 1, SAA1/2	Soluble CD25, SAA1, leucine-rich alpha-2-glycoprotein 1	Signal transducer and activator of transcription 3
Response time	Rises within 4-6 hours	Rises within 2-4 hours	Rises within 4-6 hours	Rises within 2-4 hours
Clinical significance	Early diagnosis of sepsis; monitoring post-surgery recovery	Early diagnosis of sepsis; optimizing antibiotic treatment	Diagnosis of specific pathogens; prognosis of sepsis severity	Early diagnosis of sepsis; prognosis for severe sepsis
Strengths	High specificity for bacterial infection; rapid response	Good specificity for bacterial infections; rapid biomarker rise	Targeted multi-marker approach; provides pathogen-specific diagnostic cues	High specificity for sepsis; useful for early prognosis
Limitations	Low sensitivity in localized infections (false negatives)	False positives in non-bacterial inflammation; expensive test	Limited generalizability; potential for false positives in specific cases	Expensive; limited accessibility

CPB: Cardiopulmonary bypass; PICU: Pediatric intensive care unit; SAA: Serum amyloid A.

Table 3 Biomarkers characteristics

Biomarker/panel	Clinical context	Platform (discovery validation)	Threshold (per study)	AUC (95%CI)	Sens	Spec	Notes
Interleukin-27	Sepsis vs systemic inflammatory response syndrome (diagnostic)	Transcriptomics-driven discovery to serum immunoassay	≥ 5.0 ng/mL	0.811 (0.755-0.868)	0.61	0.92	“Rule-in” behavior; outperformed PCT; classification and regression tree with PCT improved prediction
HP (infants)	Prognosis (poor outcome)	TMT-LC-MS/MS to ELISA	Study-defined	0.875 (0.700-1.000)	0.83	1.00	Opposite directionality in toddlers; age-adapted use essential
THBS1 (infants)	Prognosis (poor outcome)	TMT-LC-MS/MS to ELISA	218.38 ng/mL	0.877 (0.701-1.000)	1.00	0.60	Infant-specific signal; not significant in toddlers
HP + THBS1 (infants, combined)	Prognosis (poor outcome)	TMT-LC-MS/MS to ELISA	Panel score	0.958 (0.868-1.000)	0.917	1.00	Best infant prognostic combo
Serum amyloid A 1	Sepsis vs healthy (diagnostic)	Label-free LC-MS to ELISA	35891 ng/mL (Youden)	0.978 (0.946-1.000)	0.889	1.00	Early rising acute-phase protein; split patients/controls cleanly
Soluble CD25	Sepsis vs healthy (diagnostic)	Label-free LC-MS to ELISA	3209 pg/mL (Youden)	0.970 (0.920-1.000)	0.946	1.00	Performed better than PCT in intensive care unit admission cohorts (cited by authors)
Leucine-rich alpha-2-glycoprotein 1	Sepsis vs healthy (diagnostic)	Label-free LC-MS to ELISA	56951.5 ng/mL (Youden)	0.933 (0.86-1.00)	0.867	0.89	Acute-phase-responsive glycoprotein; strong single-marker ROC
Slow off-rate modified aptamer (capture reagent) signature (multi-protein)	Sepsis vs post- cardiopulmonary bypass infection-negative systemic inflammation (diagnostic differentiation)	SOMAscan (aptamer-based high-plex proteomic platform) 1305-plex; linear models for microarray data + Benjamini-Hochberg false-discovery-rate correction, Boruta; weighted gene co-expression network analysis	-	-	-	-	111 differentially ex-pressed (proteins/genes) proteins (8.6% of panel); sepsis-correlated modules identified; no single-analyte ROC reported

AUC: Area under the receiver operating characteristic curve; CI: Confidence interval; ELISA: Enzyme-linked immunosorbent assays; HP: Haptoglobin; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; PCT: Procalcitonin; THBS1: Thrombospondin 1; TMT: Tandem mass tags; ROC: Receiver operating characteristic.