严重大流行 2009 年 H1N1 流感和季节性流感住院成人的细胞因子反应模式。

Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults.

机构信息

Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China.

出版信息

PLoS One. 2011;6(10):e26050. doi: 10.1371/journal.pone.0026050. Epub 2011 Oct 13.

DOI:10.1371/journal.pone.0026050

PMID:22022504

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3192778/

Abstract

BACKGROUND

Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis.

METHODS

Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed.

RESULTS

63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course.

CONCLUSIONS

A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.

摘要

背景

研究不同病毒亚型引起的严重流感感染中的细胞因子/趋化因子反应可能有助于了解发病机制。

方法

研究了因实验室确诊的季节性和大流行性 2009 年 A/H1N1（pH1N1）流感而住院的成年人。在出现时以及随后连续使用流式细胞术和 ELISA 进行细胞因子/趋化因子的检测，使用流式细胞术的细胞因子/趋化因子的检测。使用体外培养（全血测定，±PHA/LPS 刺激）研究流感患者的 PBMCs 中的细胞因子/趋化因子表达。前瞻性地记录并分析临床变量。

结果

研究了 63 例 pH1N1 和 53 例季节性流感患者。pH1N1 患者更年轻（平均±S.D. 42.8±19.2 岁 vs 70.5±16.7 岁），合并症较少。两组均常见呼吸道/心血管并发症（71.4% vs 81.1%），但 pH1N1 患者发生严重肺炎伴低氧血症（54.0% vs 28.3%）和 ICU 入院（25.4% vs 1.9%）更为频繁。在 pH1N1 肺炎（2-15 倍正常）和复杂的季节性流感中发现促炎细胞因子 IL-6、CXCL8/IL-8、CCL2/MCP-1 和 sTNFR-1 的过度激活，但在轻度 pH1N1 感染中则没有。然而，与季节性流感相比，适应性免疫（Th1/Th17）相关的 CXCL10/IP-10、CXCL9/MIG 和 IL-17A 则明显受到抑制（2-27 倍；P 值<0.01）。这一模式通过连续测量进一步得到证实。pH1N1 肺炎中的细胞因子血症趋于持续，与病毒清除较慢有关[PCR 阴性：第 3-4 天，55% vs 85%；第 6-7 天，67% vs 100%]。升高的促炎细胞因子，尤其是 IL-6，预测 ICU 入院（调整后的 OR 12.6，95%CI 2.6-61.5，每对数（10）单位增加；P = 0.002），并与流感感染中的发热、呼吸急促、低氧血症和住院时间（Spearman 的 rho，P 值<0.01）相关。季节性流感患者的 PBMCs 在体外被激活并表达细胞因子（例如 IL-6、CXCL8/IL-8、CCL2/MCP-1、CXCL10/IP-10、CXCL9/MIG）；它们对刺激的“反应性”在疾病过程中表现出动态变化。