Canny Susan P, Stanaway Ian B, Holton Sarah E, Mitchem Mallorie, O'Rourke Allison R, Pribitzer Stephan, Baxter Sarah K, Wurfel Mark M, Malhotra Uma, Buckner Jane H, Bhatraju Pavan K, Morrell Eric D, Speake Cate, Mikacenic Carmen, Hamerman Jessica A
Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA.
Department of Pediatrics, University of Washington, Seattle, WA.
Crit Care Explor. 2025 Jan 31;7(2):e1203. doi: 10.1097/CCE.0000000000001203. eCollection 2025 Feb 1.
COVID-19 has been associated with features of a cytokine storm syndrome with some patients sharing features with the hyperinflammatory disorder, secondary hemophagocytic lymphohistiocytosis (sHLH).
We hypothesized that proteins associated with sHLH from other causes will be associated with COVID-sHLH and that subjects with fatal COVID-sHLH would have defects in immune-related pathways.
We identified two cohorts of adult patients presenting with COVID-19 at two tertiary care hospitals in Seattle, Washington in 2020 and 2021. In this observational study, we assessed clinical laboratory values and plasma proteomics. Subjects identified as having sHLH (ferritin > 1000 plus cytopenias in two or more lineages [WBC < 5000 odds ratio [OR] ANC (absolute neutrophil count) < 1000, hemoglobin < 9 or hematocrit < 27, platelets < 100,000], and elevated transaminases [either AST (aspartate aminotransferase) or ALT (alanine aminotransferase) > 30] OR subjects with a ferritin > 3000) were compared with those with COVID-19 without sHLH. We identified 264 patients with COVID-19 of whom 24 met our sHLH definition. Eight patients who died of COVID-sHLH underwent genomic sequencing to identify variants in immune-related genes.
Nine percent of enrolled COVID-19 subjects met our defined criteria for sHLH (n = 24/264). Using broad serum proteomic approaches (O-link and SomaScan), we identified three proteins increased in subjects with COVID-19-associated sHLH (soluble PD-L1 [sPD-L1], tumor necrosis factor-R1, and interleukin [IL]-18BP, p < 0.05 for O-link and false discovery rate < 0.05 for SomaScan), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and soluble tumor necrosis factor receptor 1). We also identified candidate proteins and pathways associated with COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected pathogenic variants in DOCK8 and TMPRSS15 in deceased individuals with COVID-sHLH, further suggesting that alterations in immune-related processes may contribute to hyperinflammation and fatal outcomes in COVID-19.
Proteins increased in COVID-19-associated sHLH, such as sPD-L1, and pathways, such as the syntaxin pathway, suggest important roles for the immune response in driving sHLH in the context of COVID-19.
新冠病毒病（COVID-19）与细胞因子风暴综合征相关，一些患者具有与高炎症性疾病继发性噬血细胞性淋巴组织细胞增生症（sHLH）相同的特征。
我们假设，其他病因所致sHLH相关蛋白也会与COVID-sHLH相关，且死于COVID-sHLH的患者在免疫相关途径存在缺陷。
我们确定了2020年和2021年在华盛顿州西雅图市两家三级护理医院就诊的成年COVID-19患者队列。在这项观察性研究中，我们评估了临床实验室值和血浆蛋白质组学。将被确定为患有sHLH的受试者（铁蛋白>1000且两个或更多谱系血细胞减少[白细胞<5000比值比（OR）中性粒细胞绝对计数（ANC）<1000、血红蛋白<9或血细胞比容<27、血小板<100,000]，以及转氨酶升高[天冬氨酸转氨酶（AST）或丙氨酸转氨酶（ALT）>30]）或铁蛋白>3000的受试者与未患sHLH的COVID-19患者进行比较。我们确定了264例COVID-19患者，其中24例符合我们的sHLH定义。8例死于COVID-sHLH的患者接受了基因测序，以确定免疫相关基因中的变异。
9%的入组COVID-19受试者符合我们定义的sHLH标准（n = 24/264）。使用广泛的血清蛋白质组学方法（O-link和SomaScan），我们确定了三种在COVID-19相关sHLH受试者中增加的蛋白质（可溶性程序性死亡配体1[sPD-L1]、肿瘤坏死因子受体1和白细胞介素[IL]-18结合蛋白，O-link检测中p<0.05，SomaScan检测中错误发现率<0.05），支持了先前与其他形式sHLH相关的蛋白质（IL-18结合蛋白和可溶性肿瘤坏死因子受体1）的作用。我们还确定了与COVID-sHLH相关的候选蛋白质和途径，包括sPD-L1和 syntaxin途径。我们在死于COVID-sHLH的个体中检测到DOCK8和TMPRSS15中的致病变异，进一步表明免疫相关过程的改变可能导致COVID-19中的高炎症和致命结局。
COVID-19相关sHLH中增加的蛋白质，如sPD-L1，以及途径，如 syntaxin途径，表明免疫反应在COVID-19背景下驱动sHLH中起重要作用。
