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. 2025 Aug 8.
doi: 10.1002/art.43349. Online ahead of print.

Serum Cytokine Profiling Differentiates Underlying Diseases in Cytokine Storm Syndrome

Shuya Kaneko  1 , Maho Hatano  1 , Asami Shimbo  1 , Futaba Miyaoka  1 , Hitoshi Irabu  1 , Yuko Akutsu  1 , Yuko Hayashi  2 , Mao Mizuta  3 , Yasuo Nakagishi  3 , Keiji Akamine  4 , Naomi Iwata  5 , Kenji Furuno  6 , Takayuki Tanaka  7 , Kazuyuki Ueno  8 , Shuhei Fujita  8 , Koji Yokoyama  9 , Toshinori Minato  10 , Kazushi Izawa  11 , Takahiro Yasumi  12 , Tadashi Matsubayashi  13 , Tadashi Hosoya  14 , Hiroki Nishikawa  15 , Junya Fujimura  16 , Ryoko Asano  17 , Yuko Sugita  18 , Kenichi Watanabe  19 , Anna Kobayashi  20 , Takuya Endo  21 , Katsuhide Eguchi  22 , Ryuta Nishikomori  23 , Ryuhei Yasuoka  24 , Takaki Asano  25 , Miyako Kanno  26 , Kazuya Hamada  27 , Yuji Fujita  28 , Daisuke Hayashi  29 , Shojiro Watanabe  30 , Takeshi Shiba  31 , Shinsuke Yasuda  14 , Masaaki Mori  32 , Hirokazu Kanegane  33 , Masatoshi Takagi  1 , Masaki Shimizu  2
Affiliations

Serum Cytokine Profiling Differentiates Underlying Diseases in Cytokine Storm Syndrome

Shuya Kaneko et al. Arthritis Rheumatol. .

Abstract

Objective: Cytokine storm syndrome (CSS), commonly associated with hemophagocytic lymphohistiocytosis (HLH), is a fatal hyperinflammatory syndrome. Differentiating the underlying diseases responsible for CSS is essential for timely therapeutic decisions. This study explored the clinical usefulness of serum cytokine profiling in distinguishing underlying diseases in patients with CSS.

Methods: Serum samples were collected from 143 adult and pediatric patients with CSS and 22 healthy controls. The cohort included patients with various diagnoses of primary and secondary HLH and Kawasaki disease (KD)-like hyperinflammatory syndromes. Serum levels of 48 cytokines were analyzed in 97 patients using a bead-based multiplex immunoassay (Luminex assay). Serum levels of interferon alpha (IFN-α), interleukin-18 (IL-18), IL-6, CXCL9, and soluble tumor necrosis factor receptor II (sTNF-RII) were measured in 165 participants using enzyme-linked immunosorbent assay (ELISA).

Results: Luminex assay categorized patients with CSS into five clusters based on serum cytokine patterns. ELISA revealed distinct cytokine patterns, wherein patients with histiocytic necrotizing lymphadenitis-associated HLH and systemic lupus erythematosus-associated macrophage activation syndrome (MAS) showed elevated IFN-α; systemic juvenile idiopathic arthritis-associated and adult-onset Still's disease-associated MAS, X-linked inhibitor of apoptosis protein deficiency with HLH, and NLRC4-associated autoinflammatory disorder exhibited higher IL-18 levels. Additionally, KD shock syndrome had higher IL-6 levels than the other groups. CXCL9 was significantly elevated in patients with virus-associated HLH, familial HLH, malignant lymphoma-associated HLH, and KD-MAS. Multisystem inflammatory syndrome in children and toxic shock syndrome also showed moderate elevations of CXCL9 and IL-6 levels.

Conclusion: Serum cytokine profiling effectively differentiates CSS subtypes, facilitating better diagnosis and personalized treatment strategies based on specific disease backgrounds.

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References

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