Utility of Cytokine Biomarkers for the Diagnosis of Pediatric Pyogenic Musculoskeletal Infections

Abstract

Background: Pyogenic musculoskeletal infections, such as septic arthritis and osteomyelitis, require prompt recognition and treatment but can be challenging to distinguish from Lyme or inflammatory arthritis. Our goal was to identify cytokine biomarkers of musculoskeletal infections.

Methods: Using 2 multicenter prospective cohorts of children undergoing emergency department evaluation for musculoskeletal infection, we selected children ≤21 years of age with a musculoskeletal infection (cases) matched by age and sex to children with Lyme and inflammatory arthritis (controls). We performed a 45-cytokine/chemokine panel using the Olink proximity extension assay platform and used receiver operator curve analysis to evaluate the discriminative ability of each cytokine. Using forward stepwise logistic regression, we derived a 3-cytokine panel and compared the accuracy with 5 commonly available plasma biomarkers.

Results: We included 47 children with musculoskeletal infection, 48 with Lyme arthritis, and 49 with inflammatory arthritis. Interleukin-6 had the highest accuracy for musculoskeletal infection (area under the curve [AUC], 0.84; 95% CI, 0.77-0.91). A 3-cytokine biosignature panel (interleukin-6, interleukin-17A, and colony stimulating factor-1) had the highest overall accuracy (AUC, 0.90; 95% CI, 0.84-0.96) and performed better than 5 common plasma biomarkers (white blood cell count, absolute neutrophil count, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin; P < .05 for all comparisons).

Conclusions: Plasma cytokines can distinguish musculoskeletal infections from Lyme or inflammatory arthritis and may assist initial decision-making for children undergoing evaluation for musculoskeletal infection.

Keywords: Lyme arthritis; cytokines; diagnostic biomarkers; pediatric musculoskeletal infection; prediction modeling.

Figure 1.

Boxplot showing the median (IQR) levels (pg/mL) for the 11 cytokines that differed between children with and without a pyogenic musculoskeletal infection. Y-axis is logarithmic. The median appears higher in children with pyogenic musculoskeletal infection for all cytokines as compared with children without pyogenic musculoskeletal infection. Abbreviations: CSF-1, colony-stimulating factor-1; CSF-3, colony-stimulating factor-3; HGF, hepatocyte growth factor; IFNG, interferon-gamma; IL-1B, interleukin-1B; IL-6, interleukin-6; IL-15, interleukin-15; IL-17A, interleukin-17A; IL-27, interleukin-27; IQR, interquartile range; MSKI, musculoskeletal infection; OSM, oncostatin M; VEGFA, vascular endothelial growth factor A.

Figure 2.

Receiver operating characteristics curves demonstrating the performance of the 3-cytokine panel (IL-6 + CSF-1 + IL-17A) compared with IL-6 alone, CSF-1 alone, and IL-17A alone. IL-6 + CSF-1 + IL-17A: AUC, 0.90; 95% CI, 0.84–0.96. IL-6: AUC, 0.83; 95% CI, 0.76–0.90. CSF-1: AUC, 0.82; 95% CI, 0.75–0.89. IL-17A: AUC, 0.76; 95% CI, 0.67–0.85. Abbreviations: AUC, area under the curve; CSF-1, colony-stimulating factor 1; IL-6, interleukin 6; IL-17A, interleukin 17A.