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. 2021 Oct 15;23(1):260.
doi: 10.1186/s13075-021-02644-2.

Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis

Tomohiro Koga  1   2 , Kaori Furukawa  3 , Kiyoshi Migita  4 , Shimpei Morimoto  5 , Toshimasa Shimizu  3   5 , Shoichi Fukui  3 , Masataka Umeda  3   6 , Yushiro Endo  3   5 , Remi Sumiyoshi  3   5 , Shin-Ya Kawashiri  3   7 , Naoki Iwamoto  3 , Kunihiro Ichinose  3 , Mami Tamai  3 , Tomoki Origuchi  3 , Takahiro Maeda  6   7 , Akihiro Yachie  8 , Atsushi Kawakami  3
Affiliations

Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis

Tomohiro Koga et al. Arthritis Res Ther. .

Abstract

Objective: To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis.

Method: We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis.

Results: Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%).

Conclusion: Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.

Keywords: Cytokine profile; Familial Mediterranean fever; GM-CSF; TNF-α; sepsis.

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Conflict of interest statement

The authors declare that there are no competing interests

Figures

Fig. 1
Fig. 1
A multiplex cytokine bead assay of GM-CSF, TNF-α, VEGF, MIP-1β, FGF-2, and IL-17A in the serum of patients with FMF and sepsis. Data are presented as individual plots (median, interquartile range). ***p < 0.001, **p < 0.01. GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; MIP-1β, macrophage inflammatory protein-1b; FGF-2, fibroblast growth factor 2; IL-17A, interleukin-17; FMF, familial Mediterranean fever
Fig. 2
Fig. 2
Cytokine networks in the patients with FMF and sepsis. Hierarchical clustering with a Spearman’s rank correlation heatmap of serum cytokine levels among patients with A sepsis and B FMF. Serum circular network layouts in C sepsis and D FMF. Significant correlations (p < 0.0033) were represented by connecting edges to underscore strong positive (ρ > 0.50; thick black line), moderate positive (0.3 < ρ < 0.5; thin black line). E Cytokines ranked by their relative importance for discriminating FMF from sepsis. The horizontal axis represents the average decrease in classification accuracy. FMF, familial Mediterranean fever
Fig. 3
Fig. 3
ROC curve analysis for the prediction of FMF by a specific set of cytokines. A The combined measurement of GM-CSF and TNF-α. B The combined measurement of GM-CSF and VEGF. C The combined measurement of TNF-α and VEGF. GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor
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