Immunosuppression in patients who die of sepsis and multiple organ failure.
Immunosuppression in patients who die of sepsis and multiple organ failure.
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DOI：
10.1001/jama.2011.1829
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发表时间：
2011-12-21
影响因子：
120.7
通讯作者：
Hotchkiss, Richard S.
中科院分区：
文献类型：
--
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
严重脓毒症的典型特征是初始的精氨酸介导的过度炎症。这一高炎症阶段是否伴随免疫抑制仍有争议。动物研究表明，败血症发生多种免疫缺陷，但人类的数据仍然相互矛盾。确定脓毒症与宿主先天性和适应性免疫变化的关系，并检查可能的免疫抑制机制。在学术医学中心重症监护室（ICU）死亡的40例活动性严重脓毒症患者的床边进行快速尸检脾脏和肺组织收获，以表征其死亡时的免疫状态（2009-2011）。对照脾（n=29）从被宣布脑死亡或由于创伤而进行紧急脾切除术的患者获得;对照肺（n=20）从移植供体或从肺癌切除术获得。进行细胞因子分泌测定和细胞表面受体-配体表达谱的免疫表型分析，以确定免疫功能障碍的潜在机制。进行免疫组织化学染色以评价免疫效应细胞的损失。脓毒症患者和对照组的平均年龄分别为71.7（SD，15.9）和52.7（SD，15.0）岁。脓毒症患者的ICU天数中位数为8天（范围1-195天），而对照组患者在ICU的天数为4天或更少。脓毒症的中位持续时间为4天（范围，1-40天）。与对照组相比，抗CD 3/抗CD 28刺激的脓毒症患者脾细胞在5小时时细胞因子分泌显著减少：肿瘤坏死因子，5361（95% CI，3327-7485）pg/mL vs 418（95% CI，98-738）pg/mL;干扰素γ，1374（95% CI，550-2197）pg/mL vs 37.5（95% CI，−5至80）pg/mL;白细胞介素6，3691（95% CI，2313-5070）vs 365（95% CI，87-642）pg/mL;白细胞介素10，633（95% CI，−269至1534）vs 58（95% CI，−39至156）pg/mL;（所有P<0.001）。5小时内脂多糖刺激的细胞因子分泌也有类似的减少。脓毒症患者的细胞因子分泌通常低于对照组的10%，与年龄、脓毒症持续时间、皮质类固醇使用和营养状况无关。虽然脾和肺之间存在差异，流式细胞术分析表明，增加了选定的抑制性受体和配体的表达和抑制细胞群在这两个器官的扩张。从脓毒症患者与癌症患者和移植供体的肺分离的免疫细胞中存在细胞抑制分子表达的独特差异。免疫组织化学染色显示脾CD 4、CD 8和HLA-DR细胞大量减少，肺上皮细胞上抑制性受体配体表达。脓毒症后死于ICU的患者与非脓毒症病因死亡的患者相比，其生化、流式细胞术和免疫组化结果与免疫抑制一致。靶向免疫增强治疗可能是一种有效的方法，在选定的脓毒症患者。
Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009–2011). Control spleens (n=29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n=20) were obtained from transplant donors or from lung cancer resections. Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1–195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1–40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327–7485) pg/mL vs 418 (95% CI, 98–738) pg/mL; interferon γ, 1374 (95% CI, 550–2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313–5070) vs 365 (95% CI, 87–642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P<.001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.
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DOI：
10.1073/pnas.0809422106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Huang, Xin;Venet, Fabienne;Ayala, Alfred
通讯作者：
Ayala, Alfred
影响因子：
9.6
作者：
Kollef, Katherhie E.;Schramm, Garrett E.;Kollef, Marin H.
通讯作者：
Kollef, Marin H.
影响因子：
38.9
作者：
Levy, Mitchell M.;Dellinger, R. Phillip;Angus, Derek C.
通讯作者：
Angus, Derek C.
影响因子：
120.7
作者：
Limaye, Ajit P.;Kirby, Katharine A.;Rubenfeld, Gordon D.;Leisenring, Wendy M.;Bulger, Eileen M.;Neff, Margaret J.;Gibran, Nicole S.;Huang, Meei-Li;Hayes, Tracy K. Santo;Corey, Lawrence;Boeckh, Michael
通讯作者：
Boeckh, Michael
影响因子：
8.8
作者：
Abraham, Edward;Singer, Mervyn
通讯作者：
Singer, Mervyn