白细胞介素- 6联合CD4^+T淋巴细胞检测对评估新型冠状病毒肺炎严重程度及预后的价值

Value of interleukin-6 and CD4^+T-lymphocytopenia in assessing the severity and prognosis of coronavirus disease 2019

目的探讨白细胞介素-6(IL-6)与CD4^+T淋巴细胞联合检测在评估新型冠状病毒肺炎(简称新冠肺炎)严重程度和预后中的价值。方法采用前瞻性观察性研究方法,选择2020年1月13日至3月13日河南省人民医院收治的45例新冠肺炎患者,按疾病严重程度分为普通型(13例)、重型(20例)、危重型(12例)组;以同期15例健康志愿者作为健康对照组。收集患者临床资料,比较不同疾病严重程度组与健康对照组临床特征、一般检验结果、IL-6、CD4+水平的差异;绘制受试者工作特征曲线(ROC),评价各指标对新冠肺炎病情严重程度的预测价值;采用多因素Cox回归分析影响新冠肺炎患者预后的危险因素,并进行Kaplan-Meier生存曲线分析。结果危重型组患者年龄明显大于重型和普通型组(岁:66.91±17.01比59.35±18.07、40.23±12.61,均P<0.05),2019新型冠状病毒(2019-nCoV)转阴时间较重型和普通型组明显延长(d:19.00±10.66比18.00±7.18、9.31±3.49,均P<0.05)。随着疾病严重程度增加,患者白细胞计数(WBC)、C-反应蛋白(CRP)、降钙素原(PCT)、总胆红素(TBil)、肌钙蛋白I(TnI)、IL-6、D-二聚体等指标均明显升高,淋巴细胞计数(LYM)、血小板计数(PLT)、CD4+、CD8+、氧合指数(PaO2/FiO2)则明显下降(均P<0.01)。ROC曲线分析显示:PaO2/FiO2、IL-6、CD4+对新冠肺炎患者疾病严重程度均有一定预测价值,ROC曲线下面积(AUC)分别为0.903、0.871、0.689,95%可信区间(95%CI)分别为0.806~0.949、0.769~0.974、0.542~0.853,最佳截断值分别为196.00 mmHg(1 mmHg=0.133 kPa)、6.02 ng/L、355.00个/μL,敏感度分别为73.3%、99.3%、73.3%,特异度分别为96.6%、62.1%、65.5%。多因素Cox回归分析显示,年龄、PaO2/FiO2、高IL-6低CD4+(IL-6≥6.02 ng/L且CD4+<355个/μL)是影响新冠肺炎患者预后的独立危险因素〔风险比(HR)分别为1.077、0.053、3.490,均P<0.05〕。Kaplan-Meier生存分析显示,当同时出现高IL-6、低CD4+(IL-6≥6.02 ng/L且CD4+<355个/μL)时,发生不良预后的时间为(20.53±5.71)d;IL-6升高或CD4+下降不同时出现时,发生不良预后的时间为(53.21±3.16)d。结论IL-6、CD4+水平与新冠肺炎疾病严重程度密切相关,当出现IL-6≥6.02 ng/L且CD4+<355个/μL时提示预后不佳。

Objective To evaluate the role of interleukin-6(IL-6)and CD4^+T-lymphocytopenia in assessing the severity and prognosis of coronavirus disease 2019(COVID-19).Methods A prospective observational study was conducted.Forty-five patients with COVID-19 admitted to Henan Provincial People's Hospital from January 13 to March 13,2020 were enrolled and divided into normal group(13 cases),severe group(20 cases),critically severe group(12 cases)according to the severity of the disease.A total of 15 healthy subjects receiving physical examinations during the same period were collected as the healthy control group.Clinical data were collected to compare the clinical characteristics,general test results,IL-6 and CD4^+T-lymphocytopenia levels of patients in different disease severity groups and healthy control group.The receiver operating characteristic(ROC)curve was drawn to evaluate the predictive value of each indicator for the severity of COVID-19.Multivariate Cox regression analysis was used to analyze the risk factors affecting the prognosis of COVID-19 patients,and Kaplan-Meier survival curve analysis was performed.Results The age of the critically severe group was significantly higher than that of the severe and normal groups(years old:66.91±17.01 vs.59.35±18.07,40.23±12.61,both P<0.05),and the negative conversion time of the 2019 novel coronavirus(2019-nCoV)was significantly longer than that of the severe and normal groups(days:19.00±10.66 vs.18.00±7.18,9.31±3.49,both P<0.05).With the increase of the severity of disease,white blood cell count(WBC),C-reactive protein(CRP),calcitonin(PCT),total bilirubin(TBil),troponin I(TnI),IL-6,D-dimer and other indicators were significantly increased,while lymphocyte count(LYM),platelet count(PLT),CD4+,CD8+,oxygenation index(PaO2/FiO2)were significantly decreased(all P<0.01).ROC curve showed that PaO2/FiO2,IL-6 and CD4+had certain predictive value for disease severity of COVID-19,the area under the ROC curve(AUC)of them were 0.903,0.871,0.689,and the 95%confidence interval(95%CI)were 0.806-0.949,0.769-0.974,0.542-0.853;the best cut-off values were 196.00 mmHg(1 mmHg=0.133 kPa),6.02 ng/L,355 cells/μL,respectively;the sensitivity were 73.3%,99.3%,73.3%,and the specificity were 96.6%,62.1%,65.5%,respectively.Multivariate Cox regression analysis showed that age,PaO2/FiO2,high IL-6 and low CD4+(IL-6≥6.02 ng/L and CD4+<355 cells/μL)were independent risk factors affecting the prognosis of COVID-19[hazard ratio(HR)was 1.077,0.053 and 3.490,respectively,all P<0.05].Kaplan-Meier survival analysis showed that when both high IL-6 and low CD4+(IL-6≥6.02 ng/L and CD4+<355 cells/μL)were present,the mean time of adverse prognosis was(20.53±5.71)days;when increased IL-6 and decreased CD4+were inconsistent,the mean time of adverse prognosis was(53.21±3.16)days.Conclusions The levels of IL-6 and CD4^+T-lymphocytopenia are closely related to the severity of COVID-19 disease.When IL-6≥6.02 ng/L and CD4+<355 cells/μL occur simultaneously,the prognosis is poor.