胸腺肽α1用于新型冠状病毒肺炎的辅助治疗——一项回顾性队列研究

Thymosin alpha 1 for the adjuvant treatment of coronavirus disease 2019:a retrospective cohort study

目的评估胸腺肽α1辅助治疗对新型冠状病毒肺炎(新冠肺炎)患者预后的影响。方法采用回顾性队列研究方法,收集2020年1月31日至3月4日上海援鄂医疗队在武汉市第三医院收治的95例新冠肺炎确诊患者的临床资料。根据入院后是否使用胸腺肽α1治疗分为胸腺肽组和非胸腺肽组,比较两组的28 d病死率(主要结局)及入院28 d无呼吸机天数、入院后淋巴细胞计数(LYM)、C-反应蛋白(CRP)水平(次要结局)。使用Kaplan-Meier生存曲线进行28 d生存分析;采用Cox回归模型计算胸腺肽α1对患者28 d生存情况的影响。结果95例患者中,胸腺肽组31例,非胸腺肽组64例;入院28 d死亡29例,其中胸腺肽组死亡11例(35.5%),非胸腺肽组死亡18例(28.1%)。Kaplan-Meier生存曲线结果提示,入院后使用胸腺肽α1可以改善新冠肺炎患者28 d生存情况,但单因素Cox模型分析显示差异无统计学意义〔风险比(HR)=0.48,95%可信区间(95%CI)为0.20~1.14,P=0.098〕;多因素Cox模型分析显示,使用胸腺肽α1是改善28 d病死率的因素(HR=0.15,95%CI为0.04~0.55,P=0.004),同时高龄(HR=1.10,95%CI为1.05~1.15,P<0.001)、合并肾功能不全(HR=42.35,95%CI为2.77~648.64,P=0.007)、入院时LYM降低(HR=0.15,95%CI为0.04~0.60,P=0.007)及使用甲泼尼龙(HR=4.59,95%CI为1.26~16.67,P=0.021)也是28 d病死率增加的危险因素;而免疫球蛋白及抗病毒药物阿比多尔、更昔洛韦的使用并不影响28 d病死率。经年龄、性别、LYM等因素调整后,多因素Cox权重分析模型进一步显示,胸腺肽α1能够显著改善新冠肺炎患者28 d生存情况(HR=0.45,95%CI为0.25~0.84,P=0.012)。在次要结局方面,胸腺肽组与非胸腺肽组入院28 d无呼吸机天数(d:17.97±13.56比20.09±12.67)和入院7 d后LYM上升幅度〔×10^(9)/L:-0.07(-0.23,0.43)比0.12(-0.54,0.41)〕比较差异均无统计学意义(均P>0.05);但胸腺肽组入院7 d后CRP下降幅度明显大于非胸腺肽组〔mg/L:39.99(8.44,82.22)比0.53(-7.78,22.93),P<0.05〕。结论胸腺肽α1辅助治疗可能会改善新冠肺炎患者28 d病死率及炎症反应。

Objective To evaluate the effect of thymosin alpha 1 on the prognosis of patients with coronavirus disease 2019(COVID-19).Methods A retrospective cohort study was performed to collect clinical data of 95 patients treated by Shanghai Aid Medical Team in Wuhan Third Hospital during January 31,2020 and March 4,2020,who were confirmed COVID-19.They were divided into two groups according to whether they were treated with thymosin alpha 1 after admission.The 28-day mortality(primary outcome),and 28-ventilator-free-day,lymphocyte count(LYM)level,C-reactive protein(CRP)level(secondary outcomes)were compared between two groups.Survival analysis was performed using the Kaplan-Meier curve.The effect of thymosin alpha 1 on 28-day survival was evaluated with Cox regression model.Results Among the 95 patients,there were 31 cases in thymosin group and 64 cases in non-thymosin group;29 patients died 28 days after admission,including 11 cases(35.5%)in thymosin group and 18 cases(28.1%)in non-thymosin group.Kaplan-Meier survival curve showed that thymosin alpha 1 could improve the 28-day survival of patients with COVID-19,but the univariate Cox model analysis showed that the difference was not statistically significant[hazard ratio(HR)=0.48,95%confidence interval(95%CI)was 0.20-1.14,P=0.098];multivariate Cox model analysis showed that thymosin alpha 1 was the factor to improve the 28-day mortality(HR=0.15,95%CI was 0.04-0.55,P=0.004),old age(HR=1.10,95%CI was 1.05-1.15,P<0.001),accompanied by chronic renal dysfunction(HR=42.35,95%CI was 2.77-648.64,P=0.007),decrease of LYM at admission(HR=0.15,95%CI was 0.04-0.60,P=0.007)and the use of methylprednisolone(HR=4.59,95%CI was 1.26-16.67,P=0.021)were also risk factors for the increase of 28-day mortality.The use of immunoglobulin and antiviral drugs abidol and ganciclovir did not affect the 28-day mortality.After adjustment for age,gender,LYM and other factors,weighted multivariate Cox analysis model showed thymosin alpha 1 could significantly improve the 28-day survival of COVID-19 patients(HR=0.45,95%CI was 0.25-0.84,P=0.012).In terms of secondary outcomes,no statistical difference(all P>0.05)was found between two groups in days without ventilator at 28 days after admission(days:17.97±13.56 vs.20.09±12.67)and the increase of LYM at 7 days after admission[×10^(9)/L:-0.07(-0.23,0.43)vs.0.12(-0.54,0.41)].But the decrease of CRP at 7 days after admission in thymosin alpha group was significantly greater than that in non-thymosin group[mg/L:39.99(8.44,82.22)vs.0.53(-7.78,22.93),P<0.05].Conclusion Thymosin alpha 1 may improve 28-day mortality and inflammation state in COVID-19 patients.