Serum Cytokine Profiling Differentiates Underlying Diseases in Cytokine Storm Syndrome

Shuya Kaneko; Maho Hatano; Asami Shimbo; Futaba Miyaoka; Hitoshi Irabu; Yuko Akutsu; Yuko Hayashi; Mao Mizuta; Yasuo Nakagishi; Keiji Akamine; Naomi Iwata; Kenji Furuno; Takayuki Tanaka; Kazuyuki Ueno; Shuhei Fujita; Koji Yokoyama; Toshinori Minato; Kazushi Izawa; Takahiro Yasumi; Tadashi Matsubayashi; Tadashi Hosoya; Hiroki Nishikawa; Junya Fujimura; Ryoko Asano; Yuko Sugita; Kenichi Watanabe; Anna Kobayashi; Takuya Endo; Katsuhide Eguchi; Ryuta Nishikomori; Ryuhei Yasuoka; Takaki Asano; Miyako Kanno; Kazuya Hamada; Yuji Fujita; Daisuke Hayashi; Shojiro Watanabe; Takeshi Shiba; Shinsuke Yasuda; Masaaki Mori; Hirokazu Kanegane; Masatoshi Takagi; Masaki Shimizu

doi:10.1002/art.43349

Serum Cytokine Profiling Differentiates Underlying Diseases in Cytokine Storm Syndrome

Arthritis Rheumatol. 2026 Feb;78(2):463-474. doi: 10.1002/art.43349. Epub 2025 Nov 30.

Authors

Shuya Kaneko¹, Maho Hatano¹, Asami Shimbo¹, Futaba Miyaoka¹, Hitoshi Irabu¹, Yuko Akutsu¹, Yuko Hayashi², Mao Mizuta³, Yasuo Nakagishi³, Keiji Akamine⁴, Naomi Iwata⁵, Kenji Furuno⁶, Takayuki Tanaka⁷, Kazuyuki Ueno⁸, Shuhei Fujita⁸, Koji Yokoyama⁹, Toshinori Minato¹⁰, Kazushi Izawa¹¹, Takahiro Yasumi¹², Tadashi Matsubayashi¹³, Tadashi Hosoya¹⁴, Hiroki Nishikawa¹⁵, Junya Fujimura¹⁶, Ryoko Asano¹⁷, Yuko Sugita¹⁸, Kenichi Watanabe¹⁹, Anna Kobayashi²⁰, Takuya Endo²¹, Katsuhide Eguchi²², Ryuta Nishikomori²³, Ryuhei Yasuoka²⁴, Takaki Asano²⁵, Miyako Kanno²⁶, Kazuya Hamada²⁷, Yuji Fujita²⁸, Daisuke Hayashi²⁹, Shojiro Watanabe³⁰, Takeshi Shiba³¹, Shinsuke Yasuda¹⁴, Masaaki Mori³², Hirokazu Kanegane³³, Masatoshi Takagi¹, Masaki Shimizu²

Affiliations

¹ Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
² Department of Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
³ Department of Pediatric Rheumatology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.
⁴ Department of Nephrology and Rheumatology, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
⁵ Department of Immunology and Infectious Diseases, Aichi Children's Health and Medical Center, Obu, Japan.
⁶ (current address: Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan): Department of General Pediatrics and Interdisciplinary Medicine, Fukuoka Children's Hospital, Fukuoka, Japan.
⁷ Department of Pediatrics, Japanese Red Cross Otsu Hospital, Otsu, Japan.
⁸ Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Japan.
⁹ Department of Pediatrics, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
¹⁰ Department of Pediatrics, Toyooka Hospital, Toyooka, Japan.
¹¹ Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
¹² Department of Pediatrics, Kyoto University Graduate School of Medicine, and Japan Environment and Children's Study Kyoto Regional Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
¹³ Department of Pediatrics, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
¹⁴ Department of Rheumatology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
¹⁵ Department of Pediatrics, Nara Prefecture General Medical Center, Nara, Japan.
¹⁶ Department of Pediatrics, Kakogawa Central City Hospital, Kakogawa, Japan.
¹⁷ First Department of Internal Medicine, University of Toyama, Toyama, Japan.
¹⁸ Department of Pediatrics, School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
¹⁹ Department of Pediatrics, Japanese Red Cross Nagaoka Hospital, Nagaoka, Japan.
²⁰ Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.
²¹ Department of Pediatrics, Saitama Medical University, Kawagoe, Japan.
²² Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²³ Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
²⁴ Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
²⁵ Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences and Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
²⁶ Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
²⁷ Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nakagami-gun, Japan.
²⁸ Department of Pediatrics, Dokkyo Medical University, Shimotsuga-gun, Japan.
²⁹ Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan.
³⁰ Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.
³¹ Department of Pediatrics, Tenri Hospital, Tenri, Japan.
³² Joint Research Department of Lifelong Immunotherapy, Institute of Science Tokyo, Tokyo, Japan, and Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
³³ Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.

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.

Grants and funding

Medical and Biological Laboratories Co., Ltd.