This study aimed to investigate the associations of serum cold-inducible RNA-binding protein (CIRP) and C-X-C motif chemokine ligand 5 (CXCL5) with prognosis in children with Mycoplasma pneumoniae pneumonia (MPP) and their relationship with neutrophil extracellular traps (NETs). A total of 485 children with MPP admitted between January 2022 and March 2025 were enrolled. Patients were categorized into good-prognosis (n = 379) and poor-prognosis (n = 106) groups based on therapeutic efficacy at 1 week after treatment completion. Serum levels of CIRP, CXCL5, and NET markers (myeloperoxidase-DNA complex [MPO-DNA] and citrullinated histone H3 [CitH3]) were measured. Multivariable logistic regression was used to analyze factors influencing prognosis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate predictive value. Spearman correlation analysis was used to examine the correlations of CIRP and CXCL5 with NET markers. Compared with the good-prognosis group, the poor-prognosis group exhibited longer fever duration, higher neutrophil percentage, elevated levels of D-dimer, C-reactive protein (CRP), and interleukin-6 (IL-6), higher rates of multilobar involvement and pleural effusion, and more frequent use of systemic glucocorticoids, intravenous immunoglobulin (IVIG), fiberoptic bronchoscopy with bronchoalveolar lavage, and second-line antimicrobial agents (all p < 0.05). Serum CIRP and CXCL5 levels were significantly higher in the poor-prognosis group (both p < 0.001). Multivariable logistic regression analysis demonstrated that neutrophil percentage, MP antibody titer, D-dimer, CRP, IL-6, extent of pulmonary involvement, pleural effusion, CIRP, and CXCL5 were independent risk factors for poor prognosis (all p < 0.05). ROC analysis showed areas under the curve (AUCs) of 0.733 for CIRP, 0.752 for CXCL5, and 0.796 for their combination in predicting poor prognosis, with the combination showing superior predictive performance. Levels of NET markers were significantly elevated in the poor-prognosis group (both p < 0.001), and both CIRP and CXCL5 were positively correlated with MPO-DNA and CitH3. Elevated serum CIRP and CXCL5 levels are associated with poor prognosis in children with MPP and correlate with NET markers. Combined detection may facilitate early identification of high-risk patients; however, whether these biomarkers influence disease progression through modulation of NET requires further investigation.
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