sPD-1与淋巴细胞亚群变化预测脓毒症患者预后的前瞻性队列研究

sPD-1 and changes of lymphocyte subsets in predicting the prognosis of patients with sepsis:a prospective cohort study

目的观察脓毒症及脓毒症休克患者可溶性程序性细胞死亡蛋白1(soluble programmed cell death protein 1,sPD-1)与细胞免疫和体液免疫的动态变化,探索sPD-1与脓毒症免疫抑制的关系。方法本研究为前瞻性队列研究,纳入2018年6月至2018年12月入住宁夏医科大学总医院ICU的脓毒症和脓毒症休克患者为研究对象,同期入住ICU的普通术后患者为非脓毒症组,并纳入年龄、性别与其他三组匹配的健康志愿者为健康对照组。检测患者入ICU后第1天、第3天和第7天外周血sPD-1、淋巴细胞计数、血清免疫球蛋白水平及淋巴细胞亚群分析,比较各组sPD-1及各项免疫指标变化,并进行相关分析。健康对照组和非脓毒症组仅取入组当日血标本。结果本研究共纳入研究对象90例,年龄(58.36±17.46)岁,男性58例,女性32例。其中脓毒症29例,脓毒症休克31例,非脓毒症15例,另招募志愿者15名作为健康对照组。脓毒症和脓毒症休克组患者28 d病死率为28.3%。患者入ICU第1天,sPD-1水平(pg/mL)脓毒症休克组和脓毒症组显著高于非脓毒症组和健康对照组[512.64(216.85,1039.41)vs.261.90(191.96,421.99)vs.191.56(151.26,232.66)vs.200.51(162.14,241.26),均P<0.05],脓毒症休克组sPD-1高于脓毒症组,且一周内持续处于高水平(均P<0.05)。脓毒症和脓毒症休克组淋巴细胞计数第1天显著低于健康对照组和非脓毒症组(均P<0.05),且脓毒症休克组淋巴细胞计数减低持续至第7天(均P<0.05)。淋巴细胞百分比和总T淋巴细胞,脓毒症和脓毒症休克组显著低于健康对照组和非脓毒症组(均P<0.05),而总B淋巴细胞差异无统计学意义(均P>0.05)。脓毒症休克组第7天CD8+T淋巴细胞仍显著低于脓毒症组[(18.36±2.23)%vs.(28.28±2.97)%,P<0.05]。血清免疫球蛋白IgG、IgM水平,脓毒症和脓毒症休克组显著低于健康对照组和非脓毒症组(均P<0.05),第7天恢复。ROC曲线分析评估sPD-1对预后不良的预测价值,结果显示第7天的sPD-1对脓毒症及脓毒症休克患者28 d预后有预测价值,最佳截断值为286.52 pg/mL,其敏感度为100.00%,特异度为56.25%。结论脓毒症和脓毒症休克患者早期即出现免疫抑制,脓毒症休克患者免疫抑制时间长,早期以体液免疫抑制为主,后期以细胞免疫抑制为主。

Objective To observe the dynamic changes of soluble programmed cell death protein 1(sPD-1)and cellular immunity and humoral immunity in patients with sepsis and septic shock,and to explore the relationship between sPD-1 and immunosuppression in sepsis.Methods This study was a prospective cohort study.Patients with sepsis and septic shock admitted to the ICU of General Hospital of Ningxia Medical University from June 2018 to December 2018 were included as the study subjects,ordinary postoperative patients admitted to the ICU during the same period were included as the non-sepsis group,and healthy volunteers matched in age and sex were included as healthy controls.The sPD-1,lymphocyte count,serum immunoglobulin and lymphocyte subsets of peripheral blood on the first,third and seventh days after admission to the ICU were detected.The changes of sPD-1 and various immune indices in each group were compared,and the correlation between the indices was analyzed.For healthy controls and non-sepsis patients,only blood samples were tested on the day of inclusion.Results A total of 90 patients[58 males and 32 females,aged(58.36±17.46)years]were included in this study,including 29 cases of sepsis,31 cases of septic shock,15 cases of non-sepsis,and 15 volunteers were recruited as healthy control group.The 28-day fatality rate of patients in the sepsis and septic shock groups was 28.3%.On the first day of ICU admission,the sPD-1 concentration were significantly higher in the septic shock group and sepsis group than those in the non-sepsis group and healthy control group[512.64(216.85,1039.41)pg/mL vs.261.90(191.96,421.99)pg/mL vs.191.56(151.26,232.66)pg/mL vs.200.51(162.14,241.26)pg/mL,all P<0.05].The sPD-1 concentration in the septic shock group was significantly higher than that in the sepsis group,and this phenomenon persisted for at least one week(P<0.05).The lymphocyte count on the first day in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups(all P<0.05),and the lymphocyte count in the septic shock group remained lower levels until the seventh day of ICU admission(all P<0.05).The percentage of lymphocytes and total T lymphocytes in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups(all P<0.05),while the percentage of total B lymphocytes did not differ between groups(all P>0.05).The percentage of CD8+T lymphocytes on the seventh day of ICU admission in the septic shock group was still significantly lower than that in the sepsis group[(18.36±2.23)%vs.(28.28±2.97)%,P<0.05].The levels of serum immunoglobulin IgG and IgM were significantly lower in the sepsis and septic shock group than those in the healthy control and non-sepsis groups(all P<0.05),and the IgG and IgM in the sepsis and septic shock groups returned to normal on the seventh day of ICU admission.The area under the ROC curve was used to evaluate the predictive value of sPD-1 on poor prognosis,and the results showed that sPD-1 on the seventh day of ICU had a good predictive value for 28-day prognosis in patients with sepsis and septic shock,and the best cut-off value was 286.52 pg/mL,with a sensitivity of 100.00%and specificity of 56.25%.Conclusions Immunosuppression occurs in patients with sepsis and septic shock in the early stage,and the duration of immunosuppression in patients with septic shock is prolonged,but humoral immunosuppression plays a major defense in the early stage,and cellular immunosuppression is dominant in the later stage.