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据世界卫生组织最新数据,截至2023年3月7日,全球已报告新型冠状病毒肺炎(COVID-19)确诊病例约7.6亿例,死亡超过686万例[1]。目前,抗病毒治疗可以抑制病毒复制,加快病毒清除,减轻炎症及免疫反应等,被认为是降低COVID-19重症率、住院率及死亡率的重要手段之一[2]。2021年12月,美国食品药品监督管理局批准奈玛特韦片/利托那韦片组合包装(Paxlovid)的紧急使用授权申请,使其成为治疗COVID-19的新型口服药物。2022年2月,国家药品监督管理局附条件批准Paxlovid进口注册[3],用于成人伴有进展为重症高风险因素的轻至中度COVID-19患者。国外多项研究已经证实,Paxlovid能显著降低COVID-19患者的病毒载量、全因住院率、重症率和死亡率等[4-5]。然而,目前罕见报道中国人群使用Paxlovid的疗效等相关数据。鉴于人种差异及病毒变异,开展此类研究十分必要。本研究旨在探索中国人群中Paxlovid对COVID-19患者早期预后不良的危险因素,并构建预测模型,以期为提高该类患者的救治效果提供参考。
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2023年1月至2023年3月于闽南地区3家军队三甲医院使用Paxlovid治疗的COVID-19住院患者共129例,经筛选最终纳入92例进行分析。其中,男69例(75.00%),女23例(25.00%),平均年龄(76.26±15.81)岁,体重(62.86±10.69)kg,发病天数(8.60±5.94)d,核酸检测CT值(27.84±5.52)。
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92例Paxlovid治疗的COVID-19患者中,早期预后不良者有31例(33.70%),其中,死亡11例(35.48%),危重型17例(54.84%),重型3例(9.68%)。
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比较早期预后不良组与非早期预后不良组的患者一般资料、发病天数、检查指标、合并疾病、合用药及辅助治疗等情况,结果显示两组在发病天数、淋巴细胞计数、AST、CRP、PCT、D-二聚体等12项临床指标有相关性(P<0.05),见表1。
表 1 两组患者临床资料的单因素分析
项目 非早期预后不良组(n=61) 早期预后不良组(n=31) 统计量 P值 年龄(岁,$ \bar{x} $±s) 77.16±16.47 74.42±14.52 0.785 0.434 性别[女,n(%)] 16(26.23) 7(22.58) 0.146 0.702 体重(m/kg,$ \bar{x} $±s) 63.99±10.09 60.63±11.63 1.430 0.156 发病天数(t/d,$ \bar{x} $±s) 7.72±5.46 12.48±6.56 −3.693 <0.001 血氧饱和度(%,$ \bar{x} $±s) 94.01±4.97 90.91±10.76 1.894 0.061 核酸检测CT值($ \bar{x} $±s) 28.31±5.64 26.90±5.24 1.158 0.250 淋巴细胞计数(×109/L,$ \bar{x} $±s) 0.98±0.59 0.62±0.44 2.992 0.040 eGFR[ml/(min·1.73 m2),$ \bar{x} $±s] 68.29±30.56 57.20±38.44 1.505 0.136 ALT[U/L,M(P25,P75)] 22.90(9.00,121.00) 23.00(6.00,237.20) −0.450 0.653a AST[U/L,M(P25,P75)] 31.00(13.50,88.00) 37.40(21.00,306.20) 2.747 0.006a TG(mmol/L,$ \bar{x} $±s) 1.36±0.87 1.50±0.76 −0.782 0.436 TC(mmol/L,$ \bar{x} $±s) 3.95±0.94 3.59±1.19 1.555 0.123 LDL-C(mmol/L,$ \bar{x} $±s) 2.19±0.69 2.01±0.97 0.998 0.321 HDL-C(mmol/L,$ \bar{x} $±s) 1.14±0.32 1.00±0.44 1.664 0.100 CK(U/L,$ \bar{x} $±s) 145.23±253.51 148.21±107.09 −0.062 0.950 CRP(mg/L,$ \bar{x} $±s) 52.41±46.71 118.72±82.74 −4.918 <0.001 PCT[ng/ml,M(P25,P75)] 0.07(0.01,27.60) 1.40(0.01,42.95) 4.366 <0.001a D−二聚体[μg/ml,M(P25,P75)] 0.79(0.19,11.39) 2.17(0.36,41.83) 4.254 <0.001a 用药前已使用其他抗新冠病毒药物治疗[n(%)] 1(1.64) 5(16.13) 7.079 0.008 用药前已行呼吸机辅助通气[n(%)] 10(16.39) 19(61.29) 19.194 <0.001 合并疾病 高血压[n(%)] 39(63.93) 20(64.52) 0.003 0.956 糖尿病[n(%)] 16(26.23) 14(45.16) 3.352 0.067 ASCVD[n(%)] 29(47.54) 15(48.39) 0.006 0.939 慢性肺病[n(%)] 19(31.15) 5(16.13) 2.404 0.121 治疗方案 Paxlovid疗程(t/d,$ \bar{x} $±s) 4.74±0.68 5.26±2.05 −1.805 0.074 联合免疫抑制剂[n(%)] 42(68.85) 29(93.55) 7.116 0.008 联合抗凝药[n(%)] 36(59.02) 29(93.55) 11.821 0.001 联合抗菌药物[n(%)] 46(75.41) 30(96.77) 6.530 0.011 联合俯卧位治疗[n(%)] 8(13.11) 9(29.03) 3.457 0.088 联合呼吸机辅助通气[n(%)] 11(18.03) 25(80.65) 33.831 <0.001 注:a表示Mann-Whitney U检验。 -
采用二元Logistic回归分析,结果显示其中发病天数、淋巴细胞计数、AST、CRP和联合呼吸机辅助通气等5项临床指标是Paxlovid早期预后不良的独立危险因素,见表2。上述5项独立危险因素构建Logistic模型方程,Logit(P)=−8.371+0.126X发病天数+2.019X淋巴细胞计数+0.023XAST+0.016XCRP+3.528X联合呼吸机辅助通气。采用H-L法(Hosmerand-Lemeshow test)对模型的拟合度进行检验,结果显示模型拟合良好(χ2值=10.480,P=0.233),模型的理论准确度为89.10%。
表 2 Paxlovid早期预后不良多因素logistic分析
项目 回归系数B 标准误S.E 卡方值Waldχ2 自由度df 比值比OR 95%CI置信区间 P值 发病天数(t/d) 0.126 0.061 4.237 1 1.135 1.006~1.279 0.040 淋巴细胞计数 2.019 0.892 5.126 1 7.527 1.311~43.208 0.024 AST 0.023 0.009 6.578 1 1.023 1.005~1.041 0.010 CRP 0.016 0.007 5.744 1 1.016 1.003~1.029 0.017 联合呼吸机辅助通气 3.528 1.054 11.194 1 34.051 4.311~268.936 0.001 常量 −8.371 2.080 16.195 1 <0.001 -
将上述回归方程转换后得出联合预测因子的计算公式,Y联合预测因子=7.875X发病天数+126.188X淋巴细胞计数+1.438XAST+XCRP+220.500X联合呼吸机辅助通气,计算92例患者的Y联合预测因子值,绘制ROC曲线,见图1。分别计算发病天数、淋巴细胞计数、AST、CRP和联合呼吸机辅助通气和联合预测因子AUC,其中联合预测因子AUC最大为0.939(P<0.001),预测价值最优。取约登(Youden)指数最大时即0.756,最佳临界值447.920,敏感度0.903,特异性0.852,见表3。
表 3 各危险因素对Paxlovid早期预后不良的预测价值
项目 最佳临界值 敏感度 特异性 约登指数 AUC(95%CI) P值 发病天数(t/d) 14.500 0.387 0.951 0.338 0.722(0.614~0.831) 0.001 淋巴细胞计数 1.685 0.355 0.934 0.289 0.582(0.449~0.715) 0.202 AST 31.950 0.839 0.557 0.396 0.676(0.566~0.786) 0.006 CRP 104.500 0.548 0.869 0.417 0.772(0.672~0.871) <0.001 联合呼吸机辅助通气 0.500 0.806 0.820 0.626 0.813(0.715~0.911) <0.001 联合预测因子 447.920 0.903 0.852 0.756 0.939(0.885~0.993) <0.001
Risk factors of poor early prognosis in the treatment of COVID-19 with nematevir and ritonavir tablets and the establishment of prediction model
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摘要:
目的 探讨奈玛特韦片/利托那韦片(Paxlovid)对新型冠状病毒肺炎(COVID-19)患者早期预后不良的危险因素并构建预测模型,以期为提高该类患者的救治效果提供参考。 方法 回顾性分析2023年1月至2023年3月于闽南地区3家军队三甲医院使用Paxlovid治疗的COVID-19住院患者92例,收集临床指标进行单因素和多因素分析,筛选出Paxlovid早期预后不良的独立危险因素,对Logistic模型方程进行转换建立联合预测因子,采用ROC曲线确定联合预测因子的曲线下面积(AUC)及最佳临界值。 结果 92例患者中,早期预后不良者31例(33.70%),其中,死亡11例(35.48%),危重型17例(54.84%),重型3例(9.68%)。多因素Logistic回归分析结果显示,发病天数、淋巴细胞计数、天门冬氨酸氨基转移酶(AST)、C反应蛋白(CRP)和联合呼吸机辅助通气是使用Paxlovid早期预后不良的独立危险因素。以上述独立危险因素构建联合预测因子(Y)的计算公式,Y联合预测因子=7.875X发病天数+126.188X淋巴细胞计数+1.438XAST+XCRP+220.500X联合呼吸机辅助通气,绘制ROC曲线,联合预测因子的ROC曲线下面积最大为0.939,预测价值最优,约登指数(Youden)最大时(0.756)对应ROC曲线最佳临界值为447.920,模型的理论准确度为89.10%。 结论 发病天数、淋巴细胞计数、AST、CRP和联合呼吸机辅助通气是使用Paxlovid早期预后不良的独立危险因素,用药前可通过上述各危险因素计算联合预测因子,当预测结果大于447.920时,应采取更积极的治疗措施包括联合其他抗COVID-19药物等,以提高患者的救治效果。 Abstract:Objective To explore risk factors of poor early prognosis in the treatment of COVID-19 by nematevir and ritonavir tablets Paxlovid and establish the prediction model to provide reference for improving the effect of such patients. Methods 92 inpatients of COVID-19 treated with Paxlovid in three military tertiary hospital in southern Fujian from January 2023 to March 2023 were retrospectively analyzed. The clinical indicators of 92 inpatients were collected for univariate and multivariate analysis by single factor and multiple factors and the independent risk factors of poor early prognosis in Paxlovid were screened out. Logistic model equation was transformed to construct the combined predictors, and ROC curve was used to determine the area under the curve (AUC) and the optimal critical value of the combined predictors. Results Among 92 patients, 31 (33.70%) developed poor early prognosis, including 11 deaths (35.48%), 17 critical cases (54.84%) and 3 severe cases (9.68%). Multi-factor Logistic regression analysis showed that the disease days, lymphocyte count, aspartate aminotransferase(AST), C reactive protein(CRP) and ventilator-assisted ventilation were independent risk factors for poor early prognosis in Paxlovid. A formula for calculating the combined predictors (Y) was established as Ycombinedpredictors=7.875Xdisease days+126.188Xlymphocyte count+1.438XAST+XCRP+220.500Xventilator-assisted ventilation based on the above independent risk factors, and the ROC curve was drawn. With the maximum area under the ROC curve of the combined predictors being 0.939, the prediction value was best, and the optimal critical value of the ROC curve corresponding to the maximum Youden index (0.756) was 447.920.Theoretical accuracy of the model was 89.10%. Conclusion The disease days, lymphocyte count, AST, CRP and ventilator-assisted ventilation were independent risk factors for poor early prognosis in Paxlovid. Combined predictors could be calculated by the above risk factors before medication. The efficiency should be improved by taking more active treatment, including combining with other anti-COVID-19 drugs when the prediction result exceeds 447.920. -
Key words:
- Naimatwe/Litonavir /
- COVID-19 /
- poor prognosis /
- risk factor /
- prediction model
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表 1 两组患者临床资料的单因素分析
项目 非早期预后不良组(n=61) 早期预后不良组(n=31) 统计量 P值 年龄(岁, $ \bar{x} $ ±s)77.16±16.47 74.42±14.52 0.785 0.434 性别[女,n(%)] 16(26.23) 7(22.58) 0.146 0.702 体重(m/kg, $ \bar{x} $ ±s)63.99±10.09 60.63±11.63 1.430 0.156 发病天数(t/d, $ \bar{x} $ ±s)7.72±5.46 12.48±6.56 −3.693 <0.001 血氧饱和度(%, $ \bar{x} $ ±s)94.01±4.97 90.91±10.76 1.894 0.061 核酸检测CT值( $ \bar{x} $ ±s)28.31±5.64 26.90±5.24 1.158 0.250 淋巴细胞计数(×109/L, $ \bar{x} $ ±s)0.98±0.59 0.62±0.44 2.992 0.040 eGFR[ml/(min·1.73 m2), $ \bar{x} $ ±s]68.29±30.56 57.20±38.44 1.505 0.136 ALT[U/L,M(P25,P75)] 22.90(9.00,121.00) 23.00(6.00,237.20) −0.450 0.653a AST[U/L,M(P25,P75)] 31.00(13.50,88.00) 37.40(21.00,306.20) 2.747 0.006a TG(mmol/L, $ \bar{x} $ ±s)1.36±0.87 1.50±0.76 −0.782 0.436 TC(mmol/L, $ \bar{x} $ ±s)3.95±0.94 3.59±1.19 1.555 0.123 LDL-C(mmol/L, $ \bar{x} $ ±s)2.19±0.69 2.01±0.97 0.998 0.321 HDL-C(mmol/L, $ \bar{x} $ ±s)1.14±0.32 1.00±0.44 1.664 0.100 CK(U/L, $ \bar{x} $ ±s)145.23±253.51 148.21±107.09 −0.062 0.950 CRP(mg/L, $ \bar{x} $ ±s)52.41±46.71 118.72±82.74 −4.918 <0.001 PCT[ng/ml,M(P25,P75)] 0.07(0.01,27.60) 1.40(0.01,42.95) 4.366 <0.001a D−二聚体[μg/ml,M(P25,P75)] 0.79(0.19,11.39) 2.17(0.36,41.83) 4.254 <0.001a 用药前已使用其他抗新冠病毒药物治疗[n(%)] 1(1.64) 5(16.13) 7.079 0.008 用药前已行呼吸机辅助通气[n(%)] 10(16.39) 19(61.29) 19.194 <0.001 合并疾病 高血压[n(%)] 39(63.93) 20(64.52) 0.003 0.956 糖尿病[n(%)] 16(26.23) 14(45.16) 3.352 0.067 ASCVD[n(%)] 29(47.54) 15(48.39) 0.006 0.939 慢性肺病[n(%)] 19(31.15) 5(16.13) 2.404 0.121 治疗方案 Paxlovid疗程(t/d, $ \bar{x} $ ±s)4.74±0.68 5.26±2.05 −1.805 0.074 联合免疫抑制剂[n(%)] 42(68.85) 29(93.55) 7.116 0.008 联合抗凝药[n(%)] 36(59.02) 29(93.55) 11.821 0.001 联合抗菌药物[n(%)] 46(75.41) 30(96.77) 6.530 0.011 联合俯卧位治疗[n(%)] 8(13.11) 9(29.03) 3.457 0.088 联合呼吸机辅助通气[n(%)] 11(18.03) 25(80.65) 33.831 <0.001 注:a表示Mann-Whitney U检验。 表 2 Paxlovid早期预后不良多因素logistic分析
项目 回归系数B 标准误S.E 卡方值Waldχ2 自由度df 比值比OR 95%CI置信区间 P值 发病天数(t/d) 0.126 0.061 4.237 1 1.135 1.006~1.279 0.040 淋巴细胞计数 2.019 0.892 5.126 1 7.527 1.311~43.208 0.024 AST 0.023 0.009 6.578 1 1.023 1.005~1.041 0.010 CRP 0.016 0.007 5.744 1 1.016 1.003~1.029 0.017 联合呼吸机辅助通气 3.528 1.054 11.194 1 34.051 4.311~268.936 0.001 常量 −8.371 2.080 16.195 1 <0.001 表 3 各危险因素对Paxlovid早期预后不良的预测价值
项目 最佳临界值 敏感度 特异性 约登指数 AUC(95%CI) P值 发病天数(t/d) 14.500 0.387 0.951 0.338 0.722(0.614~0.831) 0.001 淋巴细胞计数 1.685 0.355 0.934 0.289 0.582(0.449~0.715) 0.202 AST 31.950 0.839 0.557 0.396 0.676(0.566~0.786) 0.006 CRP 104.500 0.548 0.869 0.417 0.772(0.672~0.871) <0.001 联合呼吸机辅助通气 0.500 0.806 0.820 0.626 0.813(0.715~0.911) <0.001 联合预测因子 447.920 0.903 0.852 0.756 0.939(0.885~0.993) <0.001 -
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