Department of Surgery, Boston Medical Center, Boston University, Boston, Massachusetts.
Department of Pathology and Laboratory Medicine, Boston University, Boston, Massachusetts.
Shock. 2021 Nov 1;56(5):667-672. doi: 10.1097/SHK.0000000000001769.
BACKGROUND: "Cytokine storm" has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a "cytokine storm" resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a "cytokine storm" has yet to be defined. METHODS: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. RESULTS: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 = 34 pg/mL; Crohn's disease, IL-6 = 5 pg/mL), yet respond dramatically to cytokine inhibitors. CONCLUSION: The misleading term "cytokine storm" implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term "cytokine storm". "Cytokine storm" should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.
背景:“细胞因子风暴”被用来暗示严重临床病症中细胞因子水平的增加。与严重急性呼吸系统综合征冠状病毒 2 型(SARS-CoV-2)和 2012 年中东呼吸系统综合征的相似之处促使早期研究人员怀疑存在“细胞因子风暴”,导致不受调节的炎症反应与 SARS-CoV-2 引起的显著发病率和死亡率相关。将血液细胞因子作为“细胞因子风暴”的阈值尚未确定。
方法:进行文献回顾,以确定 11 种不同临床病症或疾病期间释放的细胞因子水平。通过将论文中的患者人数乘以每种细胞因子的平均浓度,计算出各种细胞因子的加权平均值。使用皮尔逊相关系数评估个体病症或疾病之间细胞因子水平的相关性。
结果:对文献进行了回顾,以确定广泛的临床病症中细胞因子的血液水平。这些病症的范围从运动和自身免疫性疾病到感染性休克和嵌合抗原受体 T 细胞治疗。最常测量的细胞因子是白细胞介素 6(IL-6),其在感染性休克中的范围为 24123pg/mL,在运动后为 11pg/mL。在严重 SARS-CoV-2 感染的患者中,IL-6 的血液水平仅为 43pg/mL,比感染性休克患者的 IL-6 水平低三个数量级。这些不同疾病的临床表现与细胞因子的血液水平不相关。此外,不同疾病之间细胞因子的浓度之间相关性较差。具体来说,IL-6 的血液水平与 IL-8、IL-10 或 TNF 不相关。感染性休克具有最高浓度的细胞因子,但多种细胞因子抑制剂未能在多项临床试验中显示出改善的结果。患有自身免疫性疾病的患者血液细胞因子水平非常低(类风湿关节炎,IL-6=34pg/mL;克罗恩病,IL-6=5pg/mL),但对细胞因子抑制剂反应剧烈。
结论:误导性术语“细胞因子风暴”暗示增加的血液细胞因子水平是导致严重临床病症的原因。并非所有导致疾病恶化的炎症病症都与显著升高的细胞因子水平相关,尽管与“细胞因子风暴”有关。“细胞因子风暴”应该从医学词汇中删除,因为它既不能反映驱动疾病的介质,也不能预测哪些疾病将对细胞因子抑制剂有反应。
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