Role of biomarkers in pediatric sepsis: What evidence says?

Table 1 Overview of biomarkers in pediatric sepsis

Biomarker	Type	Reference range	Advantages	Limitations	Ref.
C-reactive protein	Acute phase protein	< 10 mg/L	Cost-effective, high availability, helpful for fungal infection detection, unaffected by immune suppression effects	Low accuracy, variable sensitivity and specificity for detecting bacterial infection	Lim et al[9]
Procalcitonin	Peptide hormone	0.5-2.0 ng/mL	High specificity and sensitivity, more specifically, for bacterial infection, moderate prognostic value	Costly, variable threshold values for various infections, altered serum levels in cases of renal dysfunction, variable sensitivity, and specificity	Lim et al[9]
Ferritin	Acute phase protein	20-200 ng/mL	Potential use for real-time treatment adjustments	Low specificity and sensitivity, elevated in various inflammatory and liver conditions, not specific to sepsis	Lim et al[9], Tonial et al[10]
IL-6	Cytokine	< 7 pg/mL	Promising use in pediatric patients with cancer and febrile neutropenia, key proinflammatory cytokine in the immune response	Few studies in the pediatric population. Low availability, high cost, low specificity, and sensitivity	Z Oikonomakou et al[7], Esposito et al[11]
IL-8	Cytokine	≤ 220 pg/mL	Exhibits prognostic value for pediatric sepsis	Complex interpretation, variability among patients, moderate sensitivity, and specificity	Z Oikonomakou et al[7], Esposito et al[11]
IL-10	Cytokine	< 5 pg/mL	Demonstrates good sensitivity and specificity	limited by variability in expression	Z Oikonomakou et al[7], Esposito et al[11]
Lactate	Metabolic marker	0.5-2.2 mmol/L	Elevated levels suggest impaired oxygen delivery and utilization	Low accuracy for sepsis detection, levels can be elevated in conditions other than sepsis, such as trauma or liver dysfunction	Tonial et al[10], Esposito et al[11]
Leukocytes	Hematological parameter	5000-15000 cells/μL	Inexpensive and quick to obtain	Changes in white blood cell count can occur due to various non-infectious conditions	Z Oikonomakou et al[7]
TNF-related apoptosis-inducing ligand	Apoptosis regulator	40-60 pg/mL	Play a role in prognostication	Limited pediatric-specific data, variability and standardization issues	Z Oikonomakou et al[7], Tonial et al[10]
TNF-α	Cytokine	< 8 pg/mL	Helpful in the early detection of sepsis	Lack of specificity, variable sensitivity	Z Oikonomakou et al[7], Tonial et al[10]

IL: Interleukin; TNF: Tumor necrosis factor.

Table 2 Study details depicting various biomarkers for pediatric sepsis

Country	Sample size	Age group	Biomarker	Main results			Cut-off value	Remarks	Ref.
				AUC value	Sensitivity (%)	Specificity (%)
India	124 patients	From 1 month to 15 years	PCT (day 0)	0.604	81.8	80.8	> 3.0 ng/mL	This study highlights PCT as a more reliable predictor than CRP for pediatric sepsis, especially in determining disease severity and guiding clinical management	Tyagi et al[12], 2024
			PCT (day 3)	0.993	86.2	89.8
			CRP (day 0)	0.848	63.6	61.0	10 mg/dL
			CRP (day 3)	0.85	84.7	62.8
Canada	20 sepsis patients	Median age 13 years	IL-6, IL-8, IL-10	1.00	-	-	95%CI: 1.00-1.00	P < 0.001	Leonard et al[5], 2024
			CRP	0.804	49.2	89.5	≥ 2.0 mg/dL	-
			PCT	0.746	54.1	87.5	≥ 0.3 ng/mL
Latvia	165 patients	From 1 month to 18 years	CRP	CRP of 0.799, PCT and IL-6 < CRP	83.0	65.0	69.9 mg/mL	The combination of CRP and sFAS enhanced sepsis prediction sensitivity over CRP alone, while the multi-biomarker panel of CRP, PCT, IL-6, sFAS, and sVCAM-1 achieved the highest AUC among all tested models	Rautiainen et al[13], 2022
			PCT		87.0	57.0	0.43 ng/mL
			G-CSF		28.0	83.0	61.58 pg/mL
			Eotaxin		51.0	69.0	61.77 pg/mL
			IL-10		51.0	68.0	23.03 pg/mL
			IL-8		45.0	77.0	21.90 pg/mL
			IL-6		86.0	46.0	18.30 pg/mL
			sVCAM-1		83.0	33.0	868 pg/mL
			sFAS		79.0	44.0	2538.29 pg/mL
United States	194 patients	From 1 month to 18 years	IL-8	0.68	72%	74%	43.5-209.5 pg/mL (survivors), 101-436 pg/mL (non-survivors)	Strongest significance of P < 0.001	Zinter et al[14], 2017
Multicenter, 8 European countries	38,480 children (17082 with WBC values)	0-18 years	WBC, ANC, CRP	0.71, 0.84, 0.71	56%, 32%, 87%, 55%, 55%	74%, 91%, 59%, 91%, 75%	WBC > 15000, WBC > 20000, CRP > 20, CRP > 80, ANC > 10	WBC is significantly associated with SBI; however, WBC does not have a diagnostic benefit than CRP in identifying children with SBI	Kemps et al[15], 2025
Brazil	350 patients	From 6 months to 18 years	CRP	0.648	-	-	> 6.5 mg/mL	In pediatric sepsis patients over six months old, ferritin, lactate, and CRP individually demonstrated strong prognostic value for mortality, and when combined, they predicted fatal outcomes in 75% of cases, whereas total leukocyte count lacked prognostic utility	Tonial et al[16], 2020
			Ferritin	0.785			> 135 ng/mL
			Lactate	0.762			> 1.7 mmol/L
			Leukocytes	0.508			-

ANC: Absolute neutrophil count; AUC: Area under the curve; CRP: C-reactive protein; IL: Interleukin; PCT: Procalcitonin; SBI: Serious bacterial infections; sFAS: Soluble FAS; sVCAM-1: Soluble vascular cell adhesion molecule-1; WBC: White blood cell.

Table 3 Overview of systematic review and meta-analysis in pediatric sepsis

Number	Ref.	Biomarkers studies	Number of studies (patients)	Study population	Main results	Conclusion	Limitations
1	Norman-Bruce et al[29], 2024	PCT and CRP	14 studies (n = 7755)	Children aged ≤ 90 days, with fever or history of fever within the preceding 48 hours	For detection of IBI, pAUC was higher for PCT than CRP (0.72 vs 0.28; P = 0.016), but PCT and CRP had similar pAUC values (0.55 vs 0.54; P = 0·92) for detection of SBI	PCT (cutoff of 0·5 ng/mL) had better diagnostic accuracy for IBI than CRP (cutoff of 20 mg/L), and it was similar for SBI	High heterogeneity for SBI studies, lack of a universal SBI definition, and potential bias
2	Qi et al[30], 2024	PCT	5 studies (n = 148)	Children with osteomyelitis	Pooled sensitivity and specificity of PCT were 0.58 (95%CI: 0.49-0.68) and 0.92 (0.90-0.93), respectively	PCT had the greatest AUC at 0.80 for the diagnosis of osteomyelitis in children	Small sample size, variable nature of included studies
3	Kim et al[31], 2021	PCT	18 studies (n = 1462)	Children with bacterial meningitis	pSn, pSp, and DOR of PCT for detecting bacterial meningitis were 087, 0.85, and 35.85, respectively. AUC was 0.921	Blood PCT has high diagnostic accuracy in detecting bacterial meningitis in children	Variable methodologies and small sample sizes
4	Boon et al[32], 2021	20 urine biomarkers and 4 blood biomarkers (CRP, PCT, WBC, absolute neutrophil count)	54 studies (n = 117531. UTI, 628-pyelonephritis, and 6320- bacteraemia)	Children with UTI presenting to ambulatory care	CRP and PCT had low accuracy for cystitis (AUC of 0.75 and 0.71). CRP < 20 mg/L might be useful for ruling out UTI, and PCT ≥ 2 ng/mL for ruling in pyelonephritis	CRP and PCT have low accuracy for cystitis, but can be used for pyelonephritis	Heterogeneous patient selection criteria
5	Shaikh et al[33], 2020	PCT, CRP, and ESR	25 studies (PCT, n = 1000; CRP, n = 189; ESR, n = 1910)	Children aged 0-18 years with culture-confirmed UTI	For cut-off values of 0.5 ng/mL for PCT, 20 mg/L for CRP, and 30 mm/hour for ESR, pSn were 081, 0.93, and 0.83, and pSp were 076, 0.37, and 0.57, respectively	All three tests were sensitive but not very specific for ruling in pyelonephritis	High heterogeneity, limited number of studies per test
6	Tsou et al[34], 2020	PCT	25 studies (n = 2864)	Children with bacterial pneumonia	For a cut-off of 0.5 ng/mL and 2 ng/mL, PCT had a pSn of 0.68 and 0.59, pSp of 0.60 and 0.71, and AUC of 0.68 and 0.71. Elevated PCT did not suggest bacterial pneumonia (odds ratio: 1.36, P = 0.18).	Moderate diagnostic accuracy (AUC = 0.74); best cut-off around 0.5-2 ng/mL	Variability in cutoffs and definitions. Variable timings of PCT measurement
7	Cui et al[35], 2019	PCT	7 studies (504 confirmed AA and 368 controls)	Children with AA and complicated appendicitis	pSn and pSp of PCT for the diagnosis of AA were 062 and 0.86. DOR was 21.4, and AUC was 0.955. PCT was more accurate in diagnosing complicated appendicitis (pSn of 0.89, pSp of 0.90, DOR of 76.73)	PCT was more accurate for complicated appendicitis (pSn of 0.89, pSp of 0.90) than for AA	Small number of studies; moderate heterogeneity; potential publication bias
8	Yoon et al[36], 2019	Presepsin, CRP, PCT	4 studies (n = 308)	Children aged from 1 month to 18 years with sepsis	pSn and AUC of presepsin (0.94 and 0.925) were higher than that of CRP (0.51 and 0.715) and PCT (0.76 and 0.820), whereas pSp of presepsin (0.71) was lower than that of CRP (0.81) and PCT (0.76).	Presepsin has higher sensitivity and diagnostic accuracy, but lower specificity, in detecting sepsis in children	Small sample size, differences in the reference standards
9	Arif and Phillips[28], 2019	30 different biomarkers. The most common were PCT, CRP, IL-6, and IL-8	41 studies (n = 4842)	Febrile neutropenia in children with cancer	The pSn and pSp for different biomarkers to detect any adverse outcome: CRP pSn of 40%, pSp of 65%; PCT pSn of 60%, pSp of 75%; IL-6 pSn of 65%, pSp of 70%; and IL-8 pSn of 70%, pSp of 60%	PCT > 0.5 ng/mL best predicted bacteraemia and severe sepsis: Sensitivity of 0.67, and specificity of 0.73	Inconsistencies in methodology and reporting of outcomes
10	Trippella et al[37], 2017	PCT	12 studies (n = 7260)	Children with fever without an apparent source	For IBI, sensitivity was 0.82 and 0.61, and specificity was 0.86 and 0.94 at PCT levels of 0.5 ng/mL and 2 ng/mL, respectively. For SBI, PCT had lower sensitivity (0.55 and 0.30) and specificity (0.85 and 0.95)	High diagnostic accuracy for IBI (AUC > 0.9) but poor for SBI, especially at higher PCT cutoffs	Inconsistent definitions, variable cut-offs, and heterogeneity in study populations

AA: Acute appendicitis; AUC: Area under the curve; CRP: C-reactive protein; DOR: Diagnostic odds ratio; ESR: Erythrocyte sedimentation rate; IBI: Invasive bacterial infections; IL: Interleukin; pAUC: Partial area under the curve; PCT: Procalcitonin; pSn: Pooled sensitivity; pSp: Pooled specificity; SBI: Serious bacterial infections; WBC: White blood cell; UTI: Urinary tract infections.