Circulating circular RNAs act as potential novel biomarkers for sepsis secondary to pneumonia: a prospective cohort study

doi:10.5847/wjem.j.1920-8642.2025.033

Abstract

Abstract:

BACKGROUND: Circulating biomarkers for sepsis are lacking, and research on circular RNAs (circRNAs) as potential biomarkers of pneumonia-induced sepsis is limited. This study aims to investigate the diagnostic and prognostic potential of circRNAs in patients with pneumonia-induced sepsis.
METHODS: This prospective cohort study included 40 healthy individuals, 60 patients with pneumonia, and 80 patients with pneumonia-induced sepsis. CircRNAs identified through RNA-sequencing were validated using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman correlation analysis was used to evaluate the associations between circRNAs, inflammatory markers, Sequential Organ Failure Assessment (SOFA) scores, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Receiver operating characteristic (ROC) curves analysis were used to assess the diagnostic performance of circRNAs, while ROC curves and Kaplan-Meier survival analysis were used to evaluate their prognostic value of 28-day mortality.
RESULTS: qRT-PCR confirmed the significant upregulation of Circ-CTD-2281E23.2 and downregulation of Circ-0075723 and Circ-0008679 in sepsis patients. Spearman correlation analysis showed that Circ-CTD-2281E23.2 was positively correlated with inflammatory markers and severity scores, whereas Circ-0075723 and Circ-0008679 were negatively correlated with these parameters. The area under the curve (AUC) values for Circ-CTD-2281E23.2, Circ-0075723, and Circ-0008679 in diagnosing pneumonia-induced sepsis were 0.728, 0.706, and 0.793, respectively. The combination of these circRNAs (AUC=0.846) and the combination with other clinical indicators (AUC=0.990) demostrated enhanced AUC values. The AUC values for Circ-CTD-2281E23.2 and Circ-0075723 in predicting 28-day mortality were 0.664 and 0.765, respectively.
CONCLUSION: This study suggest the additional diagnostic and prognostic value of circRNAs in pneumonia-induced sepsis. Circ-CTD-2281E23.2, Circ-0075723, and Circ-0008679 exhibit diagnostic potential, with Circ-CTD-2281E23.2 and Circ-0075723 showing positive prognostic value for 28-day mortality in sepsis patients.

Key words: Circular RNAs, Biomarker, Pneumonia-induced sepsis, Diagnosis, Prognosis

Chunxue Wang, Dianyin Yang, Yuxin Zhu, Qian Yang, Tong Liu, Xiandong Liu, Dongyang Zhao, Xiaowei Bao, Tiancao Dong, Li Shao, Lunxian Tang. Circulating circular RNAs act as potential novel biomarkers for sepsis secondary to pneumonia: a prospective cohort study[J]. World Journal of Emergency Medicine, 2025, 16(2): 144-152.

Figures/Tables 7

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Characteristics	Patients with pneumonia-induced sepsis (n=80)	Patients with pneumonia (n=60)	Healthy control (n=40)
General characteristics Age, years, mean±SD Male, n (%) Blood laboratory examination WBC, 10⁹/L, mean±SD Neutrophil cell count, 10⁹/L, median (IQR) Neutrophil percentage, %, mean±SD Lymphocyte cell count, 10⁹/L, median (IQR) Lymphocyte percentage, %, median (IQR) PLT, 10⁹/L, mean±SD CRP, mg/L, median (IQR) SAA, mg/L, median (IQR) IL-6, pg/mL, median (IQR) PCT, ng/mL, median (IQR) Comorbidities, n (%) Hypertension Diabetes Chronic renal insufficiency	72.11±12.13 37 (46.25) 16.10±2.99# 9.23 (6.11, 13.18) # 83.23 ± 6.22# 1.05 (0.311, 2.22) # 6.22 (3.21, 18.72) # 166.35 ± 91.44# 89.01 (44.08, 179.23) # 131.00 (50.60, 273.23) # 69.07 (21.21, 184.23) # 7.78 (1.12, 20.11) # 36 (45) # 28 (35) # 23 (28.75) *#	70.11±9.13 25 (41.67) 10.39±2.07* 6.90 (5.88, 11.01) * 77.11±7.23* 1.44 (0.91, 3.92) * 12.60 (8.32, 20.32) * 202.55±111.32 22.18 (15.88, 64.72) * 27.11 (18.22, 84.23) * 30.12 (12.03, 88.98) * 0.61 (0.06, 1.65) * 11 (18.33) 12 (20) 7 (11.67)	69.09±10.32 21 (52.5) 6.85±1.01 4.01 (3.11, 5.23) 62.21±8.88 2.13 (1.98, 3.01) 30.33 (25.41, 40.35) 201.43±111.32 1.13 (0.34, 2.88) 4.50 (2.22, 6.74) 8.22 (6.55, 10.18) 0.03 (0.01, 0.07) 6 (15) 9 (22.5) 5 (12.5)
Coronary heart disease Clinical scores, mean±SD SOFA score APACHE II score Prognosis, n (%) Survival Dead	24 (30) *# 6.28±2.13 17.21±8.89 53 (66.25) 27 (33.75)	9 (16) - - 60 (100) 0 (0)	5 (12.5) - - 40 (100) 0 (0)

Variables	Circ-CTD-2281E23.2		Circ-0075723		Circ-0008679
Variables	r	P-value	r	P-value	r	P-value
WBC	0.59	<0.001	-0.29	0.010	-0.31	0.010
CRP	0.38	0.010	-0.52	<0.001	-0.51	<0.001
SAA IL-6 PCT	0.45 0.69 0.62	<0.001 <0.001 <0.001	-0.31 -0.57 -0.68	0.003 0.010 0.004	-0.42 -0.71 -0.61	0.002 <0.001 <0.001
SOFA score	0.48	<0.001	-0.64	<0.001	-0.55	<0.001
APACHEII score	0.27	0.020	-0.24	0.002	-0.51	0.020

Variables	AUC	Sensitivity	Specificity	Cutoff
WBC	0.923	97.5%	76.0%	11.44×10⁹/L
CRP	0.936	97.5%	75.0%	22.15 mg/L
PCT	0.959	92.5%	93.0%	1.805 ng/mL
SAA	0.942	96.4%	80.0%	32.85 mg/L
IL-6	0.917	96.3%	76.0%	25.93 pg/mL
SOFA score	0.963	100%	83.0%	2.5
APACHEII score	0.951	100%	86.0%	10
Circ-CTD-2281E23.2	0.728	77.5%	62.0%	1.06
Circ-0075723	0.706	87.5%	53.0%	0.4
Circ-0008679	0.793	82.5%	70.0%	0.47
CircRNAs combination	0.846	86.3%	74.0%	-
All combination	0.990	96.0%	95.0%	-

Characteristics	Survivor (n=53)	Non-survivor (n=27)	P-value
General characteristics Age, years, mean±SD Male, n (%) Blood laboratory examination, mean±SD WBC, 10⁹/L CRP, mg/L SAA, mg/L IL-6, pg/mLD PCT, ng/mL LAC, mmol/L	66.38±10.76 20 (37.74) 15.12±1.60 57.13±27.17 69.84±27.20 57.76±24.24 5.58±3.40 3.61±1.68	75.34±12.16 11 (40.74) 18.31±3.17 117.30±39.66 146.90±47.67 114.01±30.81 13.70±11.38 5.20±2.16	0.02 0.79 0.03 <0.001 <0.001 <0.001 <0.001 <0.001
Comorbidities, n (%) Hypertension Diabetes Chronic renal insufficiency Coronary heart disease Clinical scores, mean±SD SOFA score APACHEII score Outcomes Length of ICU stay, days, mean±SD Relative expression of Circ-RNAs, mean±SD Circ-CTD-2281E23.2 Circ-0075723 Circ-0008679	20 (37.74) 16 (30.19) 13 (24.53) 13 (24.53) 5.54±1.92 13.81±1.98 17.70±6.51 1.59±0.86 0.25±0.21 0.23±0.19	16 (59.26) 12 (44.44) 10 (37.04) 11 (40.74) 9.83±1.64 19.92±4.94 10.11±4.64 2.43±1.48 0.10±0.09 0.17±0.15	0.07 0.21 0.24 0.14 <0.001 <0.001 <0.001 <0.001 <0.001 0.14

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