Abstract
目的
新型冠状病毒肺炎(corona virus disease 2019,COVID-19)相关心肌损伤的发病机制尚不清楚,对结局的影响证据尚不充分,本研究旨在探讨合并高血压、冠心病、糖尿病的COVID-19患者发生病死的可能危险因素。
方法
本研究为单中心回顾性研究,分析了北京大学援鄂国家医疗队于2020年1月29日至2020年3月10日在武汉华中科技大学同济医学院附属同济医院中法新城院区收治的COVID-19患者。鼻咽拭子标本检测COVID-19病毒核酸阳性以及合并高血压和/或糖尿病和/或冠心病为纳入标准,收集符合条件的患者的临床资料和实验室检查结果,评估COVID-19患者发生病死的相关因素。
结果
共有94例患者纳入本研究中,其中存活患者81例,病死患者13例,平均年龄 66.7 岁。入院生命体征:与存活组患者相比,病死组患者基础心率较快(103.2次/min vs. 88.4次/min, P=0.004), 呼吸急促(29.0次/min vs. 20.0次/min, P<0.001)。血常规提示:病死组患者中性粒细胞计数较高(9.2×109/L vs. 3.8×109/L, P<0.001), 淋巴细胞计数较低(0.5×109/L vs. 1.1×109/L, P<0.001)。心肌损伤标记物提示:病死组患者肌酸激酶同工酶MB(creatine kinase MB,CK-MB;3.2 μg/L vs. 0.8 μg/L, P<0.001)、高敏肌钙蛋白Ⅰ (high sensitivity cardiac troponinⅠ,hs-cTNⅠ; 217.2 ng/L vs. 4.9 ng/L, P<0.001)、N末端B型利钠肽原(N-terminal pro brain natriuretic peptide,NT-proBNP; 945.0 μg/L vs. 154.0 μg/L, P <0.001)较高。炎症因子提示:病死组患者铁蛋白(770.2 μg/L vs. 622.8 μg/L, P =0.050)、白细胞介素-2受体(interleukin-2 recepter,IL-2R;1 586.0 U/mL vs. 694.0 U/mL, P <0.001)、白细胞介素-6(interleukin-6,IL-6; 82.3 ng/L vs. 13.0 ng/L, P <0.001)、白细胞介素-10(interleukin-10,IL-10; 9.8 ng/L vs. 5.0 ng/L, P <0.001)较高。单因素Logistic回归分析发现:高龄、不吸氧血氧饱和度低、淋巴细胞计数低、发生心肌损伤、IL-2R、IL-6、IL-10指标异常升高是COVID-19患者合并高血压、冠心病、糖尿病病死的相关因素。多因素Logistic回归分析发现:高龄(OR=1.11, 95%CI =1.03~1.19, P =0.026)、不吸氧血氧饱和度低(OR=0.85, 95% CI =0.72~0.99, P =0.041)、IL-10异常(>9.1 ng/L;OR=101.93, 95%CI =4.74~2190.71, P =0.003)是COVID-19患者合并高血压、冠心病、糖尿病病死的独立危险因素。
结论
高龄、不吸氧血氧饱和度低、淋巴细胞计数低、发生心肌损伤、IL-2R、IL-6、IL-10指标异常升高是COVID-19患者合并高血压、冠心病、糖尿病病死的相关因素;高龄、不吸氧血氧饱和度低、IL-10异常(>9.1 ng/L)是COVID-19患者合并高血压、冠心病、糖尿病病死的独立危险因素。
Keywords: 新型冠状病毒肺炎, 高血压, 糖尿病, 冠心病, 危险因素
Abstract
Objective
The pathogenesis of myocardial injury upon corona virus disease 2019 (COVID-19) infection remain unknown,evidence of impact on outcome is insufficient, therefore, we aim to investigate the risk factors for death among COVID-19 patients combined with hypertension, coronary heart disease or diabetes in this study.
Methods
This was a single-centered, retrospective, observational study. Patients of Sino-French Eco-City section of Tongji Hospital, Wuhan, China attended by Peking University Supporting Medical Team and admitted from Jan. 29, 2020 to Mar. 20, 2020 were included. The positive nucleic acid of COVID-19 virus and combination with hypertension, coronary heart disease or diabetes were in the standard. We collected the clinical data and laboratory examination results of the eligible patients to evaluate the related factors of death.
Results
In the study, 94 COVID-19 patients enrolled were divided into the group of death (13 cases) and the group of survivors (81 cases), the average age was 66.7 years. Compared with the survival group, the death group had faster basal heart rate(103.2 beats/min vs. 88.4 beats /min, P=0.004), shortness of breath(29.0 beats /min vs. 20.0 beats /min, P<0.001), higher neutrophil count(9.2×109/L vs. 3.8×109/L, P<0.001), lower lymphocyte count(0.5×109/L vs. 1.1×109/L, P<0.001), creatine kinase MB(CK-MB, 3.2 μg/L vs. 0.8 μg/L, P<0.001), high sensitivity cardiac troponin Ⅰ(hs-cTnⅠ, 217.2 ng/L vs. 4.9 ng/L, P<0.001), N-terminal pro brain natriuretic peptide(NT-proBNP; 945.0 μg/L vs. 154.0 μg/L, P<0.001), inflammatory factor ferritin(770.2 μg/L vs. 622.8 μg/L , P=0.050), interleukin-2 recepter(IL-2R, 1 586.0 U/mL vs. 694.0 U/mL, P<0.001), interleukin-6(IL-6, 82.3 ng/L vs. 13.0 ng/L, P<0.001), interleukin-10(IL-10, 9.8 ng/L vs. 5.0 ng/L, P<0.001)were higher than those in the survival group. Univariate logistic regression analysis showed that the risk factors for death were old age, low non oxygen saturation, low lymphocyte count, myocardial injury, abnormal increase of IL 2R, IL-6, and IL-10. Multivariate regression showed that old age (OR=1.11, 95%CI=1.03-1.19, P=0.026), low non oxygen saturation(OR=0.85, 95%CI=0.72-0.99, P=0.041), and abnormal increase of IL-10(>9.1 ng/L, OR=101.93, 95%CI=4.74-2190.71, P=0.003)were independent risk factors for COVID-19 patients combined with hypertension, coronary heart disease or diabetes.
Conclusion
In COVID-19 patients combined with hypertension, coronary heart disease or diabetes, the risk factors for death were old age, low non oxygen saturation, low lymphocyte count, myocardial injury, and abnormal increase of IL-2R, IL-6, and IL-10. Old age, low non oxygen saturation and abnormal increase of IL-10 were independent risk factors.
Keywords: COVID-19, Hypertension, Coronary heart disease, Diabetes, Risk factors
新型冠状病毒肺炎(corona virus disease 2019,COVID-19)是一种有包膜的β属冠状病毒[1],感染主要影响呼吸系统,表现为发热、咳嗽、乏力、呼吸困难等典型症状,严重者可出现低氧血症、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)[2]。COVID-19患者常患有高血压、冠心病、糖尿病,合并这些慢性疾病患者的COVID-19感染率较高,重症率高,病死率高,但其机制仍不明确[3,4]。本研究通过分析合并高血压、冠心病、糖尿病的COVID-19患者的临床特点和病死危险因素,为高危患者的早期识别与诊断提供依据。
1. 资料与方法
回顾性分析了北京大学援鄂国家医疗队于2020年1月29日至2020年3月10日在武汉华中科技大学同济医学院附属同济医院中法新城院区收治的COVID-19患者。
1.1. 资料采集
患者入院后进行完整的病史采集,测量生命体征以及不吸氧状态下的血氧饱和度,按照病情分为危重型及非危重型,入院后完善各项化验检查,采集距住院日期最近一次血常规、血肌酐、心肌损伤标记物 [包括肌酸激酶同工酶MB(creatine kinase MB,CK-MB)、高敏肌钙蛋白Ⅰ (high sensitivity cardiac troponin Ⅰ,hs-cTNⅠ)、N末端B型利钠肽原(N-terminal pro brain natriuretic peptide,NT-proBNP) ]、炎症细胞因子[包括铁蛋白、白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-2受体(interleukin-2 recepter,IL-2R)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-8(interleukin-8,IL-8)、白细胞介素-10(interleukin-10,IL-10)、肿瘤坏死因子-α(tumor necrosis factor -α,TNF-α)], 由于超过85%患者白细胞介素 1β值小于5 μg/L,因此未纳入统计。是否存在心肌损伤根据欧洲心脏病学会于2018年9月发布的第四个心肌梗死通用定义标准[5]:hs-cTnⅠ高于参考水平的99%,即hs-cTNI>34.2 ng/L。所有患者均常规进行鼻咽或口咽拭子COVID-19病毒核酸检测。
1.2. 纳入及排除标准
纳入标准:年龄大于等于18周岁;至少一次鼻咽或口咽拭子COVID-19病毒核酸检测为阳性;完整采集病史,合并有高血压、糖尿病、冠心病其中任意一种或多种疾病的患者。合并高血压定义为:既往明确高血压病史正在使用降压药,或住院期间未使用降压药物的情况下,非同日3次测量血压,收缩压≥140 mmHg和(或)舒张压≥90 mmHg;合并糖尿病定义为:既往明确糖尿病病史正在使用降糖药或胰岛素,或住院期间连续两次空腹血糖≥7.8 mmol/L;合并冠心病定义为:既往冠脉造影或冠脉CT提示冠脉狭窄超过50%,或既往典型心绞痛临床症状,或明确的急性心梗或陈旧性心梗病史。
排除标准:未能完善心肌损伤标记物或炎症细胞因子检查的患者;孕妇;合并严重的自身免疫性疾病、血液病、恶性肿瘤患者。
1.3. 统计学分析
采用SPSS 23.0软件进行统计分析,分类数据按率(百分比)显示,组间比较采用Pearson卡方检验或Fisher精确检验。正态分布的连续数据表示为均数±标准差;非正态分布的连续数据表示为中位数(IQR)。采用独立样本t检验或Mann-Whitney U检验对两组进行比较。使用单因素以及多因素Logistic回归进行危险因素分析,结果表示为优势比(OR)以及95%CI,P<0.05为差异有统计学意义。
2. 结果
总共有94例患者纳入本研究中,截至2020年4月6日医疗队撤离,存活患者共81例,病死患者13例,平均年龄66.7岁,危重型患者19人,非危重症患者75人。病死的13例患者中1例患者出现缺血性胸痛、急性心肌梗死,最终心源性休克病死,1例患者病死原因可疑为应激性心肌病,其他患者病死原因考虑为低氧血症相关的多脏器功能衰竭。入组患者合并疾病具体情况请见表1。
1.
COVID-19患者合并症情况
Distribution of COVID-19 patients combined with hypertension, coronary heart disease or diabetes
| Items | Death group (n=13) |
Survival group (n=81) |
| CHD, coronary heart disease. | ||
| Hypertension | 7 | 47 |
| Diabetes | 2 | 3 |
| CHD | 0 | 6 |
| Hypertension & diabetes | 1 | 13 |
| Hypertension & CHD | 1 | 4 |
| Diabetes & CHD | 1 | 1 |
| Hypertension & diabetes & CHD | 1 | 7 |
将患者分为存活组和病死组进行分析,入院生命体征提示,病死组患者入院时基础心率较快(P=0.004),呼吸急促(P<0.001);血常规结果提示,病死组中性粒细胞计数较高(P<0.001),淋巴细胞计数较低(P<0.001);心肌损伤标记物提示,病死组的CK-MB、hs-cTNⅠ、NT-proBNP均较存活组更高,差异具有统计学意义(P<0.001);炎症因子指标提示,病死组较存活组明显升高的炎症因子有铁蛋白(P=0.050)、IL-2R(P<0.001)、IL-6(P<0.001)、IL-10(P<0.001), 具体详见表2。
2.
人口统计学信息和基本资料
Demographic and baseline informations
| Items | Death group(n=13) | Survival group(n=81) | t/Z/χ2 | P |
| SpO2, non oxygen saturation; WBC, white blood cell; CK-MB, creatine kinase MB; hs-cTnⅠ, high sensitivity cardiac troponin Ⅰ; NT-proBNP, N-terminal pro brain natriuretic peptide; IL-2R, interleukin-2 recepter; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α. | ||||
| General information | ||||
| Age/years, M(IQR) | 77.0 (67.5, 83.0) | 66.0 (59.0, 72.5) | -2.894 | 0.731 |
| Male, n(%) | 8 (61.5) | 37 (45.7) | 1.129 | 0.288 |
| Vital signs on admission | ||||
| Heart rate/(beats/min), x±s | 103.2±15.8 | 88.4±16.7 | 2.997 | 0.004 |
| Systolic pressure/mmHg, M(IQR) | 135.0 (109.0, 161.5) | 140.0 (125.0, 149.5) | -0.526 | 0.599 |
| Diastolic pressure (mmHg), x±s | 84.6±15.7 | 84.0±13.1 | 0.156 | 0.876 |
| Respiratory rate/(beats/min), M(IQR) | 29.0 (24.0, 30.0) | 20.0 (20.0, 24.0) | -3.689 | <0.001 |
| SpO2/%, M(IQR) | 89.0 (78.5, 94.5) | 96.0 (94.0, 98.0) | -3.232 | 1.000 |
| Complete blood count | ||||
| WBC (×109/L), M(IQR) | 10.2 (6.3, 14.7) | 5.6 (4.5, 7.8) | -3.242 | 1.000 |
| Neutrophil (×109/L), M(IQR) | 9.2 (5.5, 13.9) | 3.8 (2.7, 5.9) | -3.510 | <0.001 |
| Lymphocyte (×109/L), M(IQR) | 0.5 (0.3, 0.7) | 1.1 (0.7, 1.5) | -3.719 | <0.001 |
| Creatinine/(μmol/L), M(IQR) | 86.0 (73.5, 112.5) | 74.0 (57.0, 92.0) | -1.807 | 0.073 |
| Biomarkers of myocardial injury | ||||
| CK-MB/(μg/L), M(IQR) | 3.2 (2.3, 6.9) | 0.8 (0.5, 1.0) | -4.196 | <0.001 |
| hs-cTNⅠ/(ng/L), M(IQR) | 217.2 (34.4, 4037.4) | 4.9 (2.5, 13.9) | -4.513 | <0.001 |
| NT-proBNP/(μg/L), M(IQR) | 945.0 (518.5, 3 464.0) | 154.0 (75.0, 415.3) | -4.111 | <0.001 |
| Myocardial injury, n(%) | 10 (76.9) | 13 (16.0) | 22.461 | <0.001 |
| Cytokines | ||||
| Ferritin/(μg/L), M(IQR) | 770.2 (598.0, 2 172.0) | 622.8 (385.3, 1 162.7) | -2.180 | 0.050 |
| IL-2R/(U/mL), M(IQR) | 1 586.0 (1 253.0, 2 364.0) | 694.0 (425.0, 1 054.5) | -3.740 | <0.001 |
| IL-6/(ng/L), M(IQR) | 82.3 (37.8, 164.8) | 13.0 (4.0, 39.4) | -3.960 | <0.001 |
| IL-8/(ng/L), M(IQR) | 29.1 (16.2, 52.4) | 12.4 (7.0, 21.3) | -2.551 | 0.160 |
| IL-10/(ng/L), M(IQR) | 9.8 (6.8, 17.9) | 5.0 (5.0, 5.5) | -4.376 | <0.001 |
| TNF-α/(ng/L), M(IQR) | 13.3 (7.2, 17.4) | 8.8 (5.7, 12.3) | -2.202 | 0.051 |
结合表2中P<0.05的变量以及临床经验,筛选可能影响COVID-19患者预后的不同类型变量纳入Logistic回归模型,包括年龄、性别、是否合并高血压、是否合并糖尿病、是否合并冠心病、不吸氧血氧饱和度、中性粒细胞计数、淋巴细胞计数、血肌酐值、是否存在心肌损伤、铁蛋白异常升高(>400 μg/L)、IL-2R异常升高(>710 U/mL)、IL-6异常升高(>35 ng/L)、IL-8异常升高(>62 ng/L)、IL-10异常升高(>9.1 ng/L)、TNF-α异常升高(>8.1 ng/L)。通过单因素Logistic回归分析,发现高龄、不吸氧血氧饱和度低、淋巴细胞计数低、发生心肌损伤、IL-2R、IL-6、IL-10指标异常升高是COVID-19患者合并高血压、冠心病、糖尿病病死的相关因素。
使用后退法筛选多因素回归模型变量,根据筛选结果纳入性别、年龄、不吸氧血氧饱和度、存在心肌损伤以及IL-10异常进入多因素Logistic回归分析,发现高龄(OR=1.11, 95%CI =1.03~1.19, P =0.026)、不吸氧血氧饱和度低(OR=0.85, 95% CI =0.72~0.99, P =0.041)、IL-10异常(>9.1 ng/L,OR=101.93, 95%CI =4.74~2 190.71, P =0.003)是COVID-19患者合并高血压、冠心病、糖尿病病死的独立危险因素(表3)。
3.
病死因素的Logistic回归分析
Logistic regression analysis of factors of death
| Items | Univariate analysis | Multivariate analysis | |||
| OR(95%CI) | P | OR(95%CI) | P | ||
| CHD, coronary heart disease; SpO2, non oxygen saturation; IL-2R, interleukin-2 recepter; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α. | |||||
| Age/years | 1.11 (1.03, 1.19) | 0.004 | 1.18 (1.02, 1.36) | 0.026 | |
| Male | 1.90 (0.57, 6.32) | 0.293 | 0.16 (0.02, 1.55) | 0.113 | |
| Hypertension (No vs. Yes) | 0.47 (0.11, 2.00) | 0.307 | |||
| Diabetes (No vs. Yes) | 1.48 (0.44, 5.00) | 0.524 | |||
| CHD (No vs. Yes) | 1.05 (0.26, 4.23) | 0.945 | |||
| SpO2/% | 0.89 (0.83, 0.96) | 0.001 | 0.85 (0.72, 0.99) | 0.041 | |
| Neutrophil (×109/L) | 1.05 (0.98, 1.11) | 0.155 | |||
| Lymphocyte (×109/L) | 0.03 (0.00, 0.30) | 0.003 | |||
| Creatinine/(μmol/L) | 1.00 (0.99, 1.01) | 0.897 | |||
| Myocardial injury | 17.44 (4.21, 72.1) | <0.001 | 11.77 (0.93, 148.87) | 0.057 | |
| Ferritin>400 μg/L | 5.36 (0.66, 43.48) | 0.116 | |||
| IL-2R>710 U/mL | 5.64 (1.18, 27.05) | 0.031 | |||
| IL-6>35 ng/L | 8.40 (2.12, 33.33) | 0.002 | |||
| IL-8>62 ng/L | 4.73 (0.71, 31.52) | 0.109 | |||
| IL-10>9.1 ng/L | 14.60 (3.84, 55.46) | <0.001 | 101.93 (4.74, 2 190.71) | 0.003 | |
| TNF-α>8.1 ng/L | 1.71 (0.49, 6.02) | 0.402 | |||
3. 讨论
在冠状病毒患者中,心血管疾病是常见的合并症,冠状病毒患者合并心血管疾病的发病率和病死率都高。非典型冠状病毒(severe acute respiratory syndrome coronavirus,SARS-CoV)患者中,糖尿病和冠心病的患病率分别为11%和8%,合并糖尿病和心血管疾病是导致患者死亡或其他不良结局的独立危险因素[6,7],中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus,MERS-CoV)患者中约有50%合并高血压和糖尿病[8],关于COVID-19病例临床特点的一些早期报道中,约有将近50%的患者合并心血管系统合并症[3,4],其具体机制尚不明确。COVID-19感染是由病毒表面spike蛋白与人血管紧张素转换酶2(angiotensin converting enzyme,ACE2)受体结合引起的[9],ACE2主要在肺泡上皮中大量存在[10],因此,COVID-19患者肺部表现最为典型和显著。ACE2在心脏也高度表达,其作用是抵消高血压、充血性心力衰竭和动脉粥样硬化等因素导致的血管紧张素Ⅱ在肾素-血管紧张素系统中的过度激活,对心血管系统具有一定保护作用[11]。心血管疾病患者的ACE2水平相对较高,有学者认为这是心血管疾病患者COVID-19患病率高的可能机制之一[12]。
COVID-19相关的心脏损伤也十分常见,大部分表现为心肌损伤标记物的升高,Zhou等[3]研究指出,7.2%的COVID-19住院患者存在心脏损伤(hs-cTnⅠ升高或新出现心电图或超声心动异常),病死组患者与存活组相比hs-cTnⅠ有进行性升高趋势。另一项1 099例COVID-19的多中心回顾性研究[13]显示,与无终点事件的患者相比,有重症加强护理病房(intensive care unit,ICU)入院、机械通气和病死等复合终点事件的患者心肌损伤标志物升高的比例更大(P=0.021)。也有少数COVID-19相关的心脏损伤表现为心源性休克或者应激性心肌病[14,15]。目前,COVID-19患者心肌损伤的确切机制尚不清楚,推测心肌损伤可能是病毒直接破坏心肌细胞、严重低氧血症和高炎症反应所致。我们的研究同样提示,对于COVID合并心血管疾病患者,心肌损伤是不可忽视的问题。
IL-10是一种ARDS早期阶段广泛表达的促炎细胞因子,是重要的肺疾病诱导介质[16]。在ARDS早期,SARS-CoV和MERS-CoV的感染可引起炎症反应,激活树突状细胞、单核巨噬细胞和其他外周血单核细胞,上调TNF-α、IL-6等促炎因子,这些炎症因子在重症病例中的水平高于轻症病例[17]。COVID-19患者同样存在细胞因子风暴,血液中IL-4、IL-6和IL-10水平显著升高[18]。现有研究也表明,缺氧状态与炎症过程之间存在双向信号通路,二者可能相互促进,加重缺氧以及炎症反应[19,20]。我们的研究同样发现病死组的多种细胞因子水平明显高于存活组,缺氧(不吸氧血氧饱和度低)及IL-10异常(>9.1 ng/L)是COVID-19患者合并糖尿病及心血管疾病病死的独立危险因素,这一结果提示在缺氧以及高炎症反应共同作用下,可能最终影响COVID-19患者预后,但损伤的具体机制还需要更多的基础实验进一步研究。
本研究存在一定的局限性,为单中心回顾性研究,样本量较小,终点事件数较少,可能影响统计模型效率;只有一部分患者接受了凝血功能测试,因此我们没有将凝血功能指标纳入统计学分析;另外,我们没有进行随访,还需要关注这部分患者长期的预后。
综上,我们的研究结果显示,高龄、不吸氧血氧饱和度低、淋巴细胞计数低、发生心肌损伤、IL-2R、IL-6、IL-10指标异常升高是COVID-19患者合并高血压、冠心病、糖尿病病死的相关因素;高龄、不吸氧血氧饱和度低、IL-10异常(>9.1 ng/L)是COVID-19患者合并高血压、冠心病、糖尿病病死的独立危险因素。
Contributor Information
凌 云鹏 (Yun-peng LING), Email: micsling@163.com.
葛 庆岗 (Qing-gang GE), Email: qingganggelin@126.com.
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