Rondina Matthew T, Tatsumi Kohei, Bastarache Julie A, Mackman Nigel
1Divisions of General Internal Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT. 2Molecular Medicine Program at the University of Utah School of Medicine, Salt Lake City, UT. 3Department of Internal Medicine at the George E. Wahlen Salt Lake City VAMC, Salt Lake City, UT. 4Division of Hematology/Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, NC. 5Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN.
Crit Care Med. 2016 Jul;44(7):e574-8. doi: 10.1097/CCM.0000000000001584.
To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1.
A prospective, multicenter, case-cohort pilot study.
Three academic ICUs.
Fifteen patients with primary influenza A/H1N1 that included seven survivors and eight nonsurvivors. For comparison, age- and gender-matched healthy controls (n = 27) were also studied.
Plasma was prepared from whole blood drawn on ICU admission in patients with influenza (ICU day 1). Microvesicle tissue factor activity, thrombin-antithrombin complexes, and D-dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 patients with influenza using the Luminex Multi-Analyte Profiling system (Luminex Corporation, DeSoto, TX). Patients were followed up for the primary outcome of 28-day mortality.
The average admission Acute Physiology and Chronic Health Evaluation II score of the patients was 25.5 ± 9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n = 8/15). Patients with influenza had dysregulated indices of coagulation and inflammation compared with controls. Among the markers of activation of coagulation measured on ICU day 1, only increased microvesicle tissue factor activity was significantly associated with subsequent influenza-related mortality (5.6 ± 1.2 pg/mL in nonsurvivors vs 1.8 ± 0.8 pg/mL in survivors; p < 0.05). Interleukin-8 was significantly higher in nonsurvivors compared with survivors (71.8 ± 29.1 pg/mL, n = 5 vs 17.3 ± 3.7 pg/mL, n = 7; p < 0.05). In addition, microvesicle tissue factor activity and interleukin-8 levels were significantly and positively correlated (r = 0.60; p = 0.003). Other cytokines, thrombin-antithrombin complexes, and D-dimer were not different between nonsurvivors and survivors and did not correlate with illness severity or mortality.
This study identifies an association between plasma interleukin-8 and microvesicle tissue factor activity measured on admission in patients with severe, primary influenza A/H1N1 infection and subsequent mortality. Thus, these biomarkers may serve as very early prognostic markers for patients with influenza A/H1N1.
识别可作为甲型H1N1流感危重症患者死亡早期预测指标的血浆生物标志物。
一项前瞻性、多中心、病例队列试点研究。
三家学术重症监护病房。
15例甲型H1N1流感初发患者，其中7例存活，8例死亡。为作比较，还研究了年龄和性别匹配的健康对照者（n = 27）。
流感患者在重症监护病房入院时（重症监护病房第1天）采集全血制备血浆。检测微泡组织因子活性、凝血酶 - 抗凝血酶复合物和D - 二聚体作为促凝标志物和凝血激活标志物。使用Luminex多分析物检测系统（Luminex公司，得克萨斯州迪索托）对12例流感患者亚组的相同血样检测血浆细胞因子水平。对患者进行随访，以观察28天死亡率这一主要结局。
患者入院时急性生理与慢性健康状况评估II（APACHE II）评分的平均值为25.5±9.3，60%的患者发生休克，28天死亡率为53.3%（n = 8/15）。与对照组相比，流感患者的凝血和炎症指标失调。在重症监护病房第1天检测的凝血激活标志物中，只有微泡组织因子活性升高与随后的流感相关死亡率显著相关（死亡患者为5.6±1.2 pg/mL，存活患者为1.8±0.8 pg/mL；p < 0.05）。与存活患者相比，死亡患者的白细胞介素 - 8显著更高（71.8±29.1 pg/mL，n = 5 vs 17.3±3.7 pg/mL，n = 7；p < 0.05）。此外，微泡组织因子活性与白细胞介素 - 8水平显著正相关（r = 0.60；p = 0.003）。其他细胞因子、凝血酶 - 抗凝血酶复合物和D - 二聚体在死亡患者和存活患者之间无差异，且与疾病严重程度或死亡率无关。
本研究发现，重症甲型H1N1流感初发患者入院时检测的血浆白细胞介素 - 8与微泡组织因子活性之间存在关联，并与随后的死亡率相关。因此，这些生物标志物可能作为甲型H1N1流感患者的极早期预后标志物。
