DOI: 10.1002/jmv.71191 ISSN: 0146-6615

Early Risk Stratification of COVID‐19 Associated Cytokine Storm Using a Four‐Cytokine Cumulative Score: A Retrospective Cohort Study

Junyu Yin, Xianxu Huang, Xin Ou, Shilin Xu, Jiaying Zhang, Shuo Wang, Jianping Sun, Jiangping Wu, Guifang Qiao, Yu Cao, Qingkun Song
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ABSTRACT

Cytokine storm (CS) is a major immunopathological driver of severe illness and death in COVID‐19, yet practical tools for its early identification remain limited. This study aimed to identify early predictive biomarkers, characterize their lead times and develop a cumulative cytokine score for early risk stratification of COVID‐19‐associated CS. In this single‐center retrospective cohort study, 295 hospitalized patients with COVID‐19 were included. Admission cytokines and inflammatory markers were analyzed. Cox proportional hazards models were used to identify predictors of CS and in‐hospital mortality. Receiver operating characteristic analysis was performed to determine optimal cut‐offs, and the interval between biomarker elevation above the cut‐off and CS onset was defined as the early warning interval. A four‐cytokine cumulative score (0–4 points; IL‐6, IL‐8, IL‐10, TNF‐α) was constructed. Internal validation was performed using 2,000 bootstrap resamples. Cytokines increased approximately 4–5 days prior to CS onset, earlier than CRP and

d
‐dimer. In the multivariable model integrating clinical variables, a cumulative cytokine score of 3–4 was independently associated with increased CS risk (HR = 4.078, 95% CI: 1.180–14.101, p  = 0.026) and higher in‐hospital mortality (HR = 22.026, 95% CI: 2.569–188.846, p  = 0.005). The score demonstrated good discriminative performance for CS prediction (AUC = 0.795). A cumulative cytokine score integrating multiple inflammatory pathways may offer a theoretical basis for the early auxiliary diagnosis and risk stratification of COVID‐19–associated CS.

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