Purpose

Sepsis is a heterogeneous syndrome. Identification of sepsis subphenotypes with distinct immune profiles could lead to targeted therapies. This study investigates the immune profiles of patients with sepsis following distinct body temperature patterns (i.e., temperature trajectory subphenotypes).

Methods

Hospitalized patients from four hospitals between 2018 and 2022 with suspicion of infection were included. A previously validated temperature trajectory algorithm was used to classify study patients into temperature trajectory subphenotypes. Microbiological profiles, clinical outcomes, and levels of 31 biomarkers were compared between these subphenotypes.

Results

The 3576 study patients were classified into four temperature trajectory subphenotypes: hyperthermic slow resolvers (N = 563, 16%), hyperthermic fast resolvers (N = 805, 23%), normothermic (N = 1693, 47%), hypothermic (N = 515, 14%). The mortality rate was significantly different between subphenotypes, with the highest rate in hypothermics (14.2%), followed by hyperthermic slow resolvers 6%, normothermic 5.5%, and lowest in hyperthermic fast resolvers 3.6% (p < 0.001). After multiple testing correction for the 31 biomarkers tested, 20 biomarkers remained significantly different between temperature trajectories: angiopoietin-1 (Ang-1), C-reactive protein (CRP), feline McDonough sarcoma-like tyrosine kinase 3 ligand (Flt-3l), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-15, IL-1 receptor antagonist (RA), IL-2, IL-6, IL-7, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), human macrophage inflammatory protein 3 alpha (MIP-3a), neutrophil gelatinase-associated lipocalin (NGAL), pentraxin-3, thrombomodulin, tissue factor, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and vascular cellular adhesion molecule-1 (vCAM-1).The hyperthermic fast and slow resolvers had the highest levels of most pro- and anti-inflammatory cytokines. Hypothermics had suppressed levels of most cytokines but the highest levels of several coagulation markers (Ang-1, thrombomodulin, tissue factor).

Conclusion

Sepsis subphenotypes identified using the universally available measurement of body temperature had distinct immune profiles. Hypothermic patients, who had the highest mortality rate, also had the lowest levels of most pro- and anti-inflammatory cytokines.

中文翻译：

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基于温度轨迹的脓毒症亚表型的不同免疫特征和临床结果

 目的

脓毒症是一种异质性综合征。鉴定具有不同免疫特征的脓毒症亚表型可能导致靶向治疗。本研究调查了遵循不同体温模式（即温度轨迹亚表型）的脓毒症患者的免疫特征。

 方法

纳入了 2018 年至 2022 年间来自 4 家医院的疑似感染住院患者。使用先前验证的温度轨迹算法将研究患者分类为温度轨迹亚表型。比较这些亚表型之间的微生物学特征、临床结果和 31 种生物标志物的水平。

 结果

将 3576 名研究患者分为四种温度轨迹亚表型：热疗慢消退器 （N = 563， 16%）、热疗快速消退器 （N = 805， 23%）、常温性 （N = 1693， 47%）、低温 （N = 515， 14%）。亚表型之间的死亡率存在显著差异，低温患者死亡率最高 （14.2%），其次是热疗慢消退者 6%，常温慢消退者 5.5%，热疗快速消退者最低 3.6% （p < 0.001）。在对测试的 31 种生物标志物进行多次测试校正后，20 种生物标志物在温度轨迹之间仍存在显著差异：血管生成素-1 （Ang-1）、C 反应蛋白 （CRP）、猫麦克唐纳肉瘤样酪氨酸激酶 3 配体 （Flt-3l）、粒细胞集落刺激因子 （G-CSF）、粒细胞-巨噬细胞集落刺激因子 （GM-CSF）、白细胞介素 （IL）-15、IL-1 受体拮抗剂 （RA）、IL-2、IL-6、IL-7、干扰素 γ 诱导蛋白 10 （IP-10）、单核细胞趋化蛋白-1 （MCP-1）、人巨噬细胞炎症蛋白 3 α （MIP-3a）、中性粒细胞明胶酶相关脂质运载蛋白 （NGAL）、五聚蛋白-3、血栓调节蛋白、组织因子、髓系细胞表达的可溶性触发受体-1 （sTREM-1） 和血管细胞粘附分子-1 （vCAM-1）。热疗快速和慢速消解器具有最高水平的大多数促炎和抗炎细胞因子。低温治疗抑制了大多数细胞因子的水平，但抑制了几种凝血标志物 （Ang-1 、 血栓调节蛋白、组织因子） 的水平最高。

 结论

使用普遍可用的体温测量法鉴定的脓毒症亚表型具有不同的免疫特征。死亡率最高的低温患者也具有最低的促炎和抗炎细胞因子水平。