重型、危重型新型冠状病毒肺炎患者合并心肌损伤特点及其对转归的影响

引用本文

卢青, 王九龙, 张波, 李志刚, 孔德娜, 熊诗强, 丁世芳. 重型、危重型新型冠状病毒肺炎患者合并心肌损伤特点及其对转归的影响[J]. 第二军医大学学报, 2020, 41(6): 596-603

LU Qing, WANG Jiu-long, ZHANG Bo, LI Zhi-gang, KONG De-na, XIONG Shi-qiang, DING Shi-fang. Characteristics of myocardial injury in severe and critical coronavirus disease 2019 patients and its effect on prognosis[J]. Academic Journal of Second Military Medical University, 2020, 41(6): 596-603 (in Chinese with English abstract)

重型、危重型新型冠状病毒肺炎患者合并心肌损伤特点及其对转归的影响

卢青¹, 王九龙², 张波³, 李志刚¹, 孔德娜³, 熊诗强¹, 丁世芳¹

1. 解放军中部战区总医院心血管内科, 武汉 430070;
2. 南方医科大学第一临床医学院, 广州 510515;
3. 解放军中部战区总医院感染内科, 武汉 430070

收稿日期: 2020-04-29 接受日期: 2020-05-21

作者简介: 卢青, 博士, 副主任医师.E-mail:luqingluoli@163.com.

通信作者(Corresponding author): 丁世芳.Tel:027-50772018, E-mail:dsfmdwh@163.com.

摘要: 目的分析重型、危重型新型冠状病毒肺炎（COVID-19）患者合并心肌损伤的特点、危险因素及其与转归的关系。方法收集2020年1月至3月于解放军中部战区总医院诊治的重型、危重型COVID-19患者的临床资料。根据病程中是否发生心肌损伤将患者分为非心肌损伤组和心肌损伤组，比较两组患者基线资料、临床表现、辅助检查、治疗和转归情况，分析重型、危重型COVID-19患者发生心肌损伤的危险因素及其对转归的影响。结果纳入56例重型、危重型COVID-19患者，其中非心肌损伤组22例、心肌损伤组34例。两组患者均以男性多见，性别构成在两组间差异无统计学意义（P>0.05）。与非心肌损伤组相比，心肌损伤组患者年龄更大[78.5（70.8，89.0）岁vs 56.5（50.3，68.3）岁，P < 0.01]，≥65岁患者占比较高[85.3%（29/34）vs 31.8%（7/22），P < 0.01]，合并冠心病的患者占比较高[38.2%（13/34）vs 9.1%（2/22），P < 0.05]。就诊症状均以发热（87.5%，49/56）、咳嗽（64.3%，36/56）和乏力（46.4%，26/56）等常见，两组间各症状发生率差异均无统计学意义（P均>0.05）。非心肌损伤组肺部CT表现为片样/斑片样影和磨玻璃影的患者比例高于心肌损伤组[72.7%（16/22）vs 38.2%（13/34），P < 0.05]，其余征象在两组间差异均无统计学意义（P均>0.05）。与非心肌损伤组相比，心肌损伤组患者氨基末端B型钠尿肽原、D-二聚体、降钙素原和IL-6水平均较高[4 939.5（1 817.0，9 450.3）pg/mL vs 612.5（301.0，1 029.5）pg/mL、4 386.5（2 309.5，9 635.3）ng/mL vs 850.5（343.5，2 333.8）ng/mL、0.46（0.23，3.79）ng/mL vs 0.18（0.13，0.39）ng/mL、138.6（41.9，464.8）pg/mL vs 65.1（34.7，99.3）pg/mL]，差异均有统计学意义（P均 < 0.01）。多因素logistic回归模型分析显示，年龄≥65岁（OR=18.62，95% CI 1.61~215.96，P < 0.05）和D-二聚体水平≥ 3 000 ng/mL（OR=15.48，95% CI 1.45~164.77，P < 0.05）是重型、危重型COVID-19患者并发心肌损伤的独立危险因素。在治疗和转归方面，两组患者在抗病毒、抗细菌、糖皮质激素等药物的使用方面差异均无统计学意义（P均>0.05）；心肌损伤组患者死亡率与非心肌损伤组相比更高[58.8%（20/34）vs 9.1%（2/22），P < 0.01]，且接受气管插管、体外膜肺氧合、连续性血液净化治疗等有创生命支持者均为心肌损伤组患者。结论高龄，男性，合并冠心病和（或）心功能不全，以及D-二聚体、降钙素原和IL-6异常升高是重型、危重型COVID-19患者并发心肌损伤的危险因素；重型、危重型COVID-19患者发生心肌损伤时病情将进一步加重，部分患者甚至需要有创循环呼吸支持，且预后不良，死亡率高，需要更严密、动态地观察上述指标，并针对相关因素积极治疗。

关键词: 新型冠状病毒肺炎重型危重型心肌损伤危险因素治疗结果

Characteristics of myocardial injury in severe and critical coronavirus disease 2019 patients and its effect on prognosis

LU Qing¹, WANG Jiu-long², ZHANG Bo³, LI Zhi-gang¹, KONG De-na³, XIONG Shi-qiang¹, DING Shi-fang¹

1. Department of Cardiology, General Hospital of Central Theater Command of PLA, Wuhan 430070, Hubei, China;
2. The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, China;
3. Department of Infection, General Hospital of Central Theater Command of PLA, Wuhan 430070, Hubei, China

Abstract: Objective To analyze the characteristics and related risk factors of myocardial injury in severe and critical coronavirus disease 2019 (COVID-19) patients and their relationship with the prognosis. Methods The clinical data of severe and critical COVID-19 patients treated in General Hospital of Central Theater Command of PLA from Jan. 2020 to Mar. 2020 were collected. The patients were divided into non-myocardial injury group and myocardial injury group. The baseline data, clinical characteristics, auxiliary examination, treatment and prognosis were compared between the two groups, and the risk factors of myocardial injury and the effect on the prognosis of the severe and critical COVID-19 patients were analyzed. Results A total of 56 patients were included, with 22 in the non-myocardial injury group and 34 in the myocardial injury group. Patients were mostly male in both groups, and there was no significant difference in gender composition between the two groups (P>0.05). Compared with the non-myocardial injury group, the age of onset was significantly higher in the myocardial injury group (78.5[70.8, 89.0] years vs 56.5[50.3, 68.3] years, P < 0.01), and the proportions of patients over 65 years old and combined with coronary heart disease were significantly greater (85.3%[29/34] vs 31.8%[7/22] and 38.2%[13/34] vs 9.1%[2/22], both P < 0.05). In terms of symptoms, fever (87.5%, 49/56), cough (64.3%, 36/56) and fatigue (46.4%, 26/56) were the most common ones, and there were no significant differences between the two groups (all P>0.05). For the CT findings of the lungs, the proportion of patients having patch-like/plaque-like shadows and ground-glass opacities was significantly greater in the non-myocardial injury group versus the myocardial injury group (72.7%[16/22] vs 38.2%[13/34], χ²=6.364, P < 0.05), and other signs were not significantly different between the two groups (P>0.05). Compared with the non-myocardial injury group, the levels of N-terminal pro-B-type natriuretic peptide, D-dimer, procalcitonin and IL-6 were significantly higher in the myocardial injury group (4 939.5[1 817.0, 9 450.3] pg/mL vs 612.5[301.0, 1 029.5] pg/mL, 4 386.5[2 309.5, 9 635.3] ng/mL vs 850.5[343.5, 2 333.8] ng/mL, 0.46[0.23, 3.79] ng/mL vs 0.18[0.13, 0.39] ng/mL, and 138.6[41.9, 464.8] pg/mL vs 65.1[34.7, 99.3] pg/mL, respectively), and the differences were significant (all P < 0.01). Multivariate logistic regression analysis showed that age ≥ 65 years old (odds ratio[OR]=18.62, 95% confidence interval[CI] 1.61-215.96, P < 0.05) and D-dimer level ≥ 3 000 ng/mL (OR=15.48, 95% CI 1.45-164.77, P < 0.05) were the independent risk factors for myocardial injury in severe and critical COVID-19 patients. There were no significant differences in the use of antiviral drugs, antibacterial drugs, or glucocorticoids between the two groups (all P>0.05). The mortality rate was significantly higher in the myocardial injury than that in the non-myocardial injury group (58.8%[20/34] vs 9.1%[2/22], P < 0.01). Patients who received tracheal intubation, extracorporeal membrane oxygenation, continuous renal replacement therapy (CRRT) and other invasive life support measures were all in the myocardial injury group. Conclusion Older age, male gender, coronary heart disease and (or) cardiac insufficiency, and elevated D-dimer, procalcitonin and IL-6 are the risk factors of myocardial injury in severe and critical COVID-19 patients. Myocardial injury can aggravate the condition and some patients need invasive circulating breathing support, with poor prognosis and high mortality. Therefore, the above indicators need to be observed more closely and dynamically and active treatment should be given according to related factors.

Key words: coronavirus disease 2019 severe type critical type myocardial injury risk factors outcomes

2019年12月新型冠状病毒肺炎(coronavirus disease 2019, COVID-19)疫情暴发, 严重威胁人类健康和生命安全。中华人民共和国国家卫生健康委员会和WHO统计数据显示, 截至2020年4月28日全球累计确诊人数达287万, 死亡人数超过19万^[1-2]。研究显示, COVID-19患者, 尤其是重型、危重型患者在病程中常伴发心肌损伤和心功能不全^[3-4]。目前关于重型、危重型COVID-19患者发生心肌损伤的特点和相关因素及其与转归关系的研究较少, 本研究就此进行初步探讨。

1 资料和方法 1.1 一般资料

选择于2020年1月至3月于解放军中部战区总医院诊治的重型、危重型COVID-19患者。纳入标准:诊断和治疗均按《新型冠状病毒肺炎诊疗方案(试行第七版)》^[5]执行。排除标准:(1)非重型、危重型COVID-19患者；(2)发生急性冠状动脉综合征者；(3)临床资料不完整者。

1.2 方法

通过电子病历管理系统收集患者临床资料, 包括基线资料(性别、年龄和基础疾病等)、临床表现、辅助检查、治疗和转归情况。根据患者病情变化动态复查相关辅助检查, 记录中性粒细胞绝对值、丙氨酸转氨酶(alanine aminotransferase, ALT)、心脏肌钙蛋白T(cardiac troponin T, cTnT)、氨基末端B型钠尿肽原(N-terminal pro-B-type natriuretic peptide, NT-proBNP)、D-二聚体、CRP、降钙素原和IL-6的最高值, 以及血红蛋白和淋巴细胞绝对值的最低值。以病程中是否发生心肌损伤将COVID-19患者分为心肌损伤组和非心肌损伤组, 比较两组患者上述指标的差异, 分析重型、危重型COVID-19患者发生心肌损伤的危险因素及其与预后转归的关系。本研究以血清学病原体IgM阳性作为近期有呼吸道病原体感染的诊断依据；心肌损伤定义为cTnT水平＞我院实验室cTnT正常参考值上限的99%, 且患者无明显胸痛等心肌缺血证据^[6]。

1.3 统计学处理

应用SPSS 26.0软件进行统计学分析。呈偏态分布的计量资料以中位数(下四分位数, 上四分位数)表示, 两组间比较采用非参数秩和检验；计数资料以例数和百分数表示, 两组间比较采用χ²检验或Fisher确切概率法；将两组间差异有统计学意义的变量纳入单因素和多因素logistic回归模型, 分析重型、危重型COVID-19患者发生心肌损伤的危险因素。采用双侧检验, 检验水准(α)为0.05。

2 结果 2.1 基线资料分析

纳入56例重型、危重型COVID-19患者, 其中非心肌损伤组22例(39.3%)、心肌损伤组34例(60.7%)。两组患者均以男性多见, 性别构成在两组间差异无统计学意义(P＞0.05)。与非心肌损伤组相比, 心肌损伤组患者年龄较大[78.5(70.8, 89.0)岁vs 56.5(50.3, 68.3)岁, P＜0.01], ≥65岁患者占比较高[85.3%(29/34)vs 31.8%(7/22), P＜0.01]。两组患者在合并高血压、糖尿病、慢性肝病、慢性肾病、恶性肿瘤及血管紧张素转换酶抑制剂/血管紧张素受体拮抗剂(angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, ACEI/ARB)药物史方面差异均无统计学意义(P均＞0.05), 但心肌损伤组患者合并冠心病的比例高于非心肌损伤组[38.2%(13/34)vs 9.1%(2/22)]且差异有统计学意义(P＜0.05)。就诊症状均以发热(87.5%, 49/56)、咳嗽(64.3%, 36/56)和乏力(46.4%, 26/56)等多见, 其余症状少见, 两组患者各症状发生率差异均无统计学意义(P均＞0.05)。两组患者入院时(未吸氧状态下)动脉血氧饱和度(arterial oxygen saturation, SaO₂)差异无统计学意义(P＞0.05)；心肌损伤组SaO₂＜93%的患者比例高于非心肌损伤组[44.1%(15/34)vs 18.2%(4/22)], 但差异无统计学意义(P＝0.082)。见表 1。

表 1 两组重型、危重型COVID-19患者基线资料比较 Tab 1 Comparison of baseline data of severe and critical COVID-19 patients between two groups

Parameter	Total N＝56	Non-myocardial injury N＝22	Myocardial injury N＝34	Statistic	P value
Gender n (%)				χ²＝0.898	0.529
Male	42 (75.0)	15 (68.2)	27 (79.4)
Female	14 (25.0)	7 (31.8)	7 (20.6)
Age (year), M (Q_L, Q_U)	71.5 (56.3, 85.8)	56.5 (50.3, 68.3)	78.5 (70.8, 89.0)	Z＝－4.464	＜0.01
≥65 n (%)	36 (64.3)	7 (31.8)	29 (85.3)	χ²＝16.637	＜0.01
＜65 n (%)	20 (35.7)	15 (68.2)	5 (14.7)
Basic disease n (%)
Hypertension	29 (51.8)	9 (40.9)	20 (58.8)	χ²＝1.714	0.274
CHD	15 (26.8)	2 (9.1)	13 (38.2)	χ²＝5.785	0.029
Diabetes	20 (35.7)	5 (22.7)	15 (44.1)	χ²＝2.662	0.154
CKD	6 (10.7)	0 (	6 (17.6)	Fisher exact test	0.071
CLD	7 (12.5)	3 (13.6)	4 (11.8)	Fisher exact test	1.000
Malignant tumor	4 (7.1)	1 (4.5)	3 (8.8)	Fisher exact test	1.000
ACEI/ARB history n (%)	15 (26.8)	4 (18.2)	11 (32.4)	χ²＝1.368	0.356
Symptom n (%)
Fever	49 (87.5)	21 (95.5)	28 (82.4)	Fisher exact test	0.226
Cough	36 (64.3)	14 (63.6)	22 (64.7)	χ²＝0.007	1.000
Expectoration	20 (35.7)	6 (27.3)	14 (41.2)	χ²＝1.125	0.394
Dyspnea	15 (26.8)	7 (31.8)	8 (23.5)	χ²＝0.468	0.547
Fatigue	26 (46.4)	8 (36.4)	18 (52.9)	χ²＝1.476	0.279
Muscle ache	14 (25.0)	6 (27.3)	8 (23.5)	χ²＝0.100	1.000
Diarrhea	5 (8.9)	3 (13.6)	2 (5.9)	Fisher exact test	0.371
SaO₂ (%), M (Q_L, Q_U)	94.6 (88.5, 98.0)	95.0 (93.3, 98.0)	94.0 (88.1, 98.2)	Z＝－1.017	0.315
SaO₂＜93% n (%)	19 (33.9)	4 (18.2)	15 (44.1)	Fisher exact test	0.082
COVID-19: Coronavirus disease 2019; CHD: Coronary heart disease; CKD: Chronic kidney disease; CLD: Chronic liver disease; ACEI/ARB: Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; SaO₂: Arterial oxygen saturation; M (Q_L, Q_U): Median (lower quartile, upper quartile)

表 1 两组重型、危重型COVID-19患者基线资料比较 Tab 1 Comparison of baseline data of severe and critical COVID-19 patients between two groups

2.2 肺部影像学和病原体检查结果

肺部CT检查显示52例(92.9%)患者病变累及双肺, 51例(91.1%)为多发/弥漫性病变, 29例(51.8%)为片样/斑片样影, 22例(39.3%)为典型磨玻璃影, 3例(5.4%)为实变影。非心肌损伤组CT表现为片样/斑片样影和磨玻璃影的患者比例高于心肌损伤组[72.7%(16/22)vs 38.2%(13/34)], 差异有统计学意义(χ²＝6.364, P＜0.05), 其余征象在两组间差异均无统计学意义(P均＞0.05)。入院早期有12例(21.4%)患者合并其他病原体感染。合并其他病毒感染者5例(8.9%), 其中2例合并柯萨奇病毒感染, 1例合并腺病毒感染, 1例为乙型流感病毒和副流感病毒混合感染, 1例为甲型流感病毒、乙型流感病毒、副流感病毒和腺病毒混合感染。合并非典型病原体感染者10例(17.9%), 其中7例合并支原体感染, 2例合并军团菌感染, 1例合并Q热立克次体感染。其他病毒和非典型病原体混合感染者3例, 其中1例为乙型流感病毒、副流感病毒、支原体的混合感染, 1例为柯萨奇病毒合并支原体感染, 1例为甲型流感病毒、乙型流感病毒、腺病毒、副流感病毒和支原体的混合感染。两组患者在合并其他病原体感染方面差异均无统计学意义(P均＞0.05)。

2.3 实验室检查结果

在病程中, 43例(76.8%)患者存在血红蛋白水平降低和中性粒细胞绝对值升高, 49例(87.5%)患者淋巴细胞绝对值降低；两组患者血红蛋白水平、中性粒细胞绝对值和淋巴细胞绝对值差异均无统计学意义(P均＞0.05)。40例(71.4%)患者ALT水平升高, 两组间ALT水平差异无统计学意义(P＞0.05)。51例(91.1%)患者D-二聚体水平升高, 56例(100.0%)患者IL-6、CRP水平均升高, 29例(51.8%)患者NT-proBNP水平升高, 20例(35.7%)患者降钙素原水平升高。与非心肌损伤组相比, 心肌损伤组患者NT-proBNP、D-二聚体、降钙素原和IL-6水平均较高[4 939.5 (1 817.0, 9 450.3)pg/mL vs 612.5 (301.0, 1 029.5)pg/mL、4 386.5(2 309.5, 9 635.3)ng/mL vs 850.5(343.5, 2 333.8)ng/mL、0.46(0.23, 3.79)ng/mL vs 0.18(0.13, 0.39)ng/mL、138.6(41.9, 464.8)pg/mL vs 65.1(34.7, 99.3)pg/mL], 差异均有统计学意义(P均＜0.01)；但两组患者CRP水平差异无统计学意义(P＞0.05)。进一步将实验室检查结果中位数的整数或近似整数(血红蛋白、中性粒细胞绝对值、淋巴细胞绝对值、D-二聚体、CRP和IL-6)或正常参考值上限(ALT、NT-proBNP和降钙素原)作为截断值, 分析两组患者分布情况, 结果显示, 两组血红蛋白＜90 g/L、中性粒细胞绝对值≥12×10⁹/L、淋巴细胞绝对值＜0.4×10⁹/L、ALT水平升高及CRP水平≥100 mg/L的患者比例差异均无统计学意义(P均＞0.05)；与非心肌损伤组相比, 心肌损伤组NT-proBNP水平升高、D-二聚体水平≥3 000 ng/mL、降钙素原水平升高、IL-6水平≥100 pg/mL的患者比例均较高[76.5%(26/34)vs 13.6%(3/22)、58.8%(20/34)vs 18.2%(4/22)、47.1%(16/34)vs 18.2%(4/22)、61.8%(21/34)vs 22.7%(5/22)], 差异均有统计学意义(P均＜0.05)。见表 2。

表 2 两组重型、危重型COVID-19患者实验室检查结果比较 Tab 2 Comparison of laboratory test results of severe and critical COVID-19 patients between two groups

Parameter	Total N＝56	Non-myocardial injury N＝22	Myocardial injury N＝34	Statistic	P value
Hb (g·L^－1), M (Q_L, Q_U)	94.5 (83.0, 108.0)	97.5 (86.0, 110.5)	90.5 (80.3, 107.3)	Z＝－0.990	0.327
＜90 n (%)	23 (41.1)	8 (36.4)	15 (44.1)	χ²＝0.332	0.592
≥90 n (%)	33 (58.9)	14 (63.6)	19 (55.9)
Neutrophil (L^－1, ×10⁹), M (Q_L, Q_U)	12.29 (7.63, 16.05)	11.91 (8.55, 14.42)	12.49 (6.55, 18.00)	Z＝－0.520	0.612
≥12 n (%)	29 (51.8)	11 (50.0)	18 (52.9)	χ²＝0.046	1.000
＜12 n (%)	27 (48.2)	11 (50.0)	16 (47.1)
Lymphocyte (L^－1, ×10⁹), M (Q_L, Q_U)	0.38 (0.24, 0.60)	0.39 (0.28, 0.50)	0.37 (0.22, 0.71)	Z＝－0.235	0.819
＜0.4 n (%)	30 (53.6)	12 (54.5)	18 (52.9)	χ²＝0.010	1.000
≥0.4 n (%)	26 (46.4)	10 (45.5)	16 (47.1)
ALT (U·L^－1), M (Q_L, Q_U)	73.0 (34.3, 166.5)	87.5 (49.8, 124.0)	55.0 (30.8, 188.7)	Z＝－0.487	0.632
Increased n (%)	40 (71.4)	18 (81.8)	22 (64.7)	χ²＝1.917	0.230
Normal n (%)	16 (28.6)	4 (18.2)	12 (35.3)
NT-proBNP (pg·mL^－1), M (Q_L, Q_U)	1 962.0 (580.3, 6 260.3)	612.5 (301.0, 1 029.5)	4 939.5 (1 817.0, 9 450.3)	Z＝－4.832	＜0.01
Increased n (%)	29 (51.8)	3 (13.6)	26 (76.5)	χ²＝21.120	＜0.01
Normal n (%)	27 (48.2)	19 (86.4)	8 (23.5)
D-dimer (ng·mL^－1), M (Q_L, Q_U)	2 819.0 (911.8, 5 850.0)	850.5 (343.5, 2 333.8)	4 386.5 (2 309.5, 9 635.3)	Z＝－4.370	＜0.01
≥3 000 n (%)	24 (42.9)	4 (18.2)	20 (58.8)	χ²＝9.009	＜0.01
＜3 000 n (%)	32 (57.1)	18 (81.8)	14 (41.2)
CRP (mg·L^－1), M (Q_L, Q_U)	104.5 (47.5, 149.5)	91.3 (51.4, 130.6)	114.0 (45.4, 171.6)	Z＝－0.822	0.419
≥100 n (%)	30 (53.6)	10 (45.5)	20 (58.8)	χ²＝0.960	0.414
＜100 n (%)	26 (46.4)	12 (54.5)	14 (41.2)
PCT (ng·mL^－1), M (Q_L, Q_U)	0.33 (0.17, 0.96)	0.18 (0.13, 0.39)	0.46 (0.23, 3.79)	Z＝－2.585	＜0.01
Increased n (%)	20 (35.7)	4 (18.2)	16 (47.1)	χ²＝4.851	0.045
Normal n (%)	36 (64.3)	18 (81.8)	18 (52.9)
IL-6 (pg·mL^－1), M (Q_L, Q_U)	88.3 (39.1, 202.1)	65.1 (34.7, 99.3)	138.6 (41.9, 464.8)	Z＝－2.600	＜0.01
≥100 n (%)	26 (46.4)	5 (22.7)	21 (61.8)	χ²＝8.184	＜0.01
＜100 n (%)	30 (53.6)	17 (77.3)	13 (38.2)
COVID-19: Coronavirus disease 2019; Hb: Hemoglobin; ALT: Alanine aminotransferase; NT-proBNP: N-terminal pro-B-type natriuretic peptide; CRP: C-reactive protein; PCT: Procalcitonin; IL-6: Interleukin 6; M (Q_L, Q_U): Median (lower quartile, upper quartile)

表 2 两组重型、危重型COVID-19患者实验室检查结果比较 Tab 2 Comparison of laboratory test results of severe and critical COVID-19 patients between two groups

2.4 重型、危重型COVID-19患者发生心肌损伤危险因素分析

将两组间差异有统计学意义的变量纳入logistic回归模型进行单因素分析, 结果显示, 年龄≥65岁、合并冠心病、NT-proBNP水平升高、D-二聚体水平≥3 000 ng/mL、降钙素原水平升高、IL-6水平≥100 pg/mL是重型、危重型COVID-19患者并发心肌损伤的危险因素(P均＜0.05)。进一步多因素分析结果显示, 年龄≥65岁和D-二聚体水平≥3 000 ng/mL是预测重型、危重型COVID-19患者并发心肌损伤的独立危险因素(P均＜0.05)。见表 3。

表 3 Logistic回归模型分析重型、危重型COVID-19患者合并心肌损伤的危险因素 Tab 3 Logistic regression model analysis of risk factors for myocardial injury in severe and critical COVID-19 patients

2.5 治疗和转归

病程中, 56例患者(100.0%)均予抗病毒治疗；55例(98.2%)予抗细菌治疗；14例(25.0%)予抗真菌治疗；50例(89.3%)予Ig治疗；48例(85.7%)予糖皮质激素治疗, 单日最大糖皮质激素使用剂量中位数为120 mg。两组患者在药物治疗方面差异均无统计学意义(P均＞0.05)。17例患者予无创辅助通气, 其中非心肌损伤组7例(31.8%)、心肌损伤组10例(29.4%), 两组间差异无统计学意义(P＞0.05)。行气管插管、体外膜肺氧合(extracorporeal membrane oxygenation, ECMO)和连续性血液净化治疗(continuous renal replacement therapy, CRRT)等有创生命支持者均为心肌损伤组患者, 患者例数分别为13例(38.2%)、4例(11.8%)、2例(5.9%)。见表 4。

表 4 两组重型、危重型COVID-19患者治疗和转归情况比较 Tab 4 Comparison of treatment measures and outcomes of severe and critical COVID-19 patients between two groups

Parameter	Total N＝56	Non-myocardial injury N＝22	Myocardial injury N＝34	Statistic	P value
Drug treatment n (%)
Antiviral treatment	56 (100.0)	22 (100.0)	34 (100.0)	Fisher exact test	1.000
Antibacterial treatment	55 (98.2)	22 (100.0)	33 (97.1)	Fisher exact test	1.000
Antifungal treatment	14 (25.0)	5 (22.7)	9 (26.5)	χ²＝0.100	1.000
Immunoglobulin	50 (89.3)	22 (100.0)	28 (82.4)	Fisher exact test	0.071
GCs	48 (85.7)	21 (95.5)	27 (79.4)	Fisher exact test	0.130
Dosage of GCs^a (mg), M (Q_L , Q_U )	120 (80, 195)	160 (80, 320)	80 (40, 160)	Z＝－1.914	0.056
Special treatment n (%)
Non-invasive ventilation	17 (30.4)	7 (31.8)	10 (29.4)	χ²＝0.037	1.000
Tracheal intubation	13 (23.2)	0 (	13 (38.2)	χ²＝10.955	＜0.01
ECMO	4 (7.1)	0 (	4 (11.8)	Fisher exact test	0.146
CRRT	2 (3.6)	0 (	2 (5.9)	Fisher exact test	0.514
Outcome
Time 1 (d), M (Q_L , Q_U )	16.0 (10.5, 22.5)	16.0 (14.0, 20.0)	13.5 (7.5, 29.5)	Z＝－0.852	0.403
Time 2 (d), M (Q_L , Q_U )	24.0 (19.0, 40.0)	24.0 (20.0, 33.0)	27.0 (16.5, 43.5)	Z＝－0.426	0.679
Hospital stay (d), M (Q_L , Q_U )	28.0 (15.5, 36.5)	30.0 (21.8, 44.8)	19.0 (14.0, 34.0)	Z＝－2.375	0.017
Total disease course (d), M (Q_L , Q_U )	36.0 (23.8, 48.3)	40.5 (27.3, 53.3)	32.5 (20.0, 43.8)	Z＝－1.682	0.094
Death n (%)	22 (39.3)	2 (9.1)	20 (58.8)	χ²＝13.851	＜0.01
^a: Maximum dose of GCs on the given day. COVID-19: Coronavirus disease 2019; GCs: Glucocorticoids; ECMO: Extracorporeal membrane oxygenation; CRRT: Continuous renal replacement therapy; Time 1: Time from treatment to nucleic acid negative; Time 2: Time from onset to nucleic acid negative; M (Q_L, Q_U): Median (lower quartile, upper quartile)

表 4 两组重型、危重型COVID-19患者治疗和转归情况比较 Tab 4 Comparison of treatment measures and outcomes of severe and critical COVID-19 patients between two groups

在转归方面, 与非心肌损伤组相比, 心肌损伤组患者住院时间较短[19.0(14.0, 34.0)d vs 30.0(21.8, 44.8)d, P＜0.05], 死亡率较高[58.8%(20/34)vs 9.1%(2/22), P＜0.01]；而两组患者治疗后核酸转阴时间(治疗后转阴时间)、从发病至核酸转阴时间(总转阴时间)差异均无统计学意义(P均＞0.05)。相较于心肌损伤组, 非心肌损伤组患者从发病至出院(死亡)时间(总病程)更长, 但差异无统计学意义(P＞0.05)。见表 4。

累计死亡22例患者, 其中心肌损伤组20例(90.9%)。22例死亡患者中, 8例(36.4%)死于急性呼吸循环功能衰竭, 6例(27.3%)死于急性呼吸衰竭, 5例(22.7%)死于多器官(心、肺、肝和肾等)功能衰竭, 2例(9.1%)死于感染性休克, 1例(4.5%)死于失血性休克；因心肺功能衰竭死亡者占86.4%(19例)。

3 讨论

研究证实, 引起此次COVID-19疫情的病原体是一种新型冠状病毒——严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), 该病毒是迄今为止发现的第7种可以引起人类感染的冠状病毒^[7]。目前认为, SARS-CoV-2通过刺突蛋白(spike protein, S蛋白)与血管紧张素转换酶2(angiotensin-converting enzyme 2, ACE2)结合侵入肺泡上皮细胞, 造成机体感染^[8]。ACE2在肺、心脏、肾脏等组织中广泛表达, 但目前关于SARS-CoV-2是否会直接侵袭心脏仍无定论。通过尸体解剖发现, COVID-19患者心肌细胞变性坏死, 心肌间质内可见单核细胞、淋巴细胞或中性粒细胞浸润, 部分血管内皮脱落, 以及内膜炎症和血栓形成^{[5, 9]}。目前认为COVID-19患者伴发心肌损伤的机制主要是:(1)通过S蛋白-ACE2途径直接侵袭心肌组织；(2)应激状态、脓毒血症、炎症反应和细胞因子风暴；(3)缺血缺氧性损伤；(4)抗病毒、抗细菌等药物的不良反应；(5)血管炎、心肌微循环功能障碍^[10-11]。具体机制有待进一步明确。

本研究结果显示, 重型、危重型COVID-19患者以中老年男性患者为主, 常合并高血压、糖尿病、冠心病等基础疾病, 多以发热、咳嗽、乏力和咳痰等症状就诊, 与其他研究结果^[12]类似。本研究中, 心肌损伤组患者年龄更大, 高龄患者更多, 合并冠心病的比例更高；入院时心肌损伤组SaO₂＜93%的患者占比亦更高[44.1%(15/34)vs 18.2%(4/22)], 但可能由于样本量较小, 两组间差异无统计学意义(P＝0.082)。说明老年患者, 尤其是合并冠心病者, 由于冠状动脉血流储备、心功能储备更低, 更易在SARS-CoV-2急性感染时发生缺血缺氧、酸中毒而导致心肌损伤。对于合并冠心病的COVID-19患者, 除常规治疗外, 须格外注意SaO₂, 使其维持在95%以上可能更为合理。当无创辅助通气支持下SaO₂无法维持时, 应及早予有创呼吸支持, 甚至ECMO等有创呼吸循环支持。另外, 给予盐酸曲美他嗪等药物可改善缺氧时心肌细胞的能量代谢, 或许能减少缺血缺氧导致心肌损伤的发生和发展。

本研究心肌损伤组D-二聚体水平异常患者比例高于非心肌损伤组。可能的原因是:重型、危重型COVID-19患者需长时间卧床, 血流缓慢, 导致机体处于高凝状态；SARS-CoV-2直接侵袭及其引发的炎性因子风暴损害凝血系统和心血管系统, 引发“凝血瀑布”持续异常激活、微血管血栓形成, 最终导致微循环功能障碍。当冠状动脉微血管血栓形成时, 心肌缺血缺氧和心肌损伤将加重。2020年4月1日发布的《新型冠状病毒肺炎重型、危重型病例诊疗方案(试行第二版)》^[13]指出, 需注意COVID-19患者发生凝血功能异常和血栓风险, 酌情给予抗凝治疗或许能减少心肌损伤的发生和发展。

在炎性因子方面, 本组56例患者CRP和IL-6水平均升高。Chen等^[14]研究显示, COVID-19患者常伴有CRP、红细胞沉降率、血清铁蛋白和IL-6等炎症指标异常升高。与严重急性呼吸综合征(severe acute respiratory syndrome, SARS)类似, COVID-19患者IL-1、IL-6和IFN-γ等细胞因子水平亦显著升高^{[4, 15]}。本研究中, 心肌损伤组患者IL-6水平比非心肌损伤组更高；本组患者中虽仅有少部分降钙素原水平升高, 但心肌损伤组患者降钙素原水平高于非心肌损伤组, 异常患者比例更高。这进一步佐证了COVID-19并发心肌损伤的机制之一是脓毒血症引起炎症反应和细胞因子风暴导致IL-6大量释放, 诱发血管炎和心肌炎症, 进而直接或间接造成心肌损伤。因此, 在诊治过程中, 及时复查炎症指标和病原学指标, 尽早予糖皮质激素抗炎治疗和抗细菌治疗, 必要时给予托珠单抗(IL-6受体拮抗剂)抑制炎症反应和细胞因子风暴, 或许能减少心肌损伤的发生, 改善患者预后。

本研究中, 相较于非心肌损伤组, 心肌损伤组患者NT-proBNP水平较高。NT-proBNP主要表达于心室肌细胞, 其分泌量随心室内压力增高而增加^[16]。心肌损伤组NT-proBNP水平升高明显, 提示患者可能存在心室内压显著增高和心功能不全。一方面, 如前所述, 心肌损伤组老年患者更多, 合并冠心病等心血管疾病比例更高, 基础心功能较差；在急性感染时心肌耗氧量增加而冠状动脉血供不会同时增加, 发生心肌能量代谢障碍, 导致心肌损伤。另一方面, 在缺血缺氧、病毒直接侵袭等多种因素作用下, 心肌损伤加重, 心肌收缩力减弱, NT-proBNP水平随之增高。因此, 若不及时纠正心肌损伤和心功能不全任何一项, 将可能陷入恶性循环。故在重型、危重型COVID-19患者治疗过程中, 应动态复查相关指标并及时予保护心肌和抗心力衰竭治疗。

本研究显示, 高龄、合并冠心病、NT-proBNP水平升高、D-二聚体水平≥3 000 ng/mL、降钙素原水平升高和IL-6水平≥100 pg/mL均是重型、危重型COVID-19患者并发心肌损伤的危险因素, 而年龄≥65岁和D-二聚体水平≥3 000 ng/mL则是预测合并心肌损伤的独立危险因素。因此在COVID-19患者诊治过程中, 应动态复查凝血功能、心肌标志物和炎性因子等指标；当D-二聚体水平≥3 000 ng/mL, 尤其是老年患者, 须警惕心肌损伤的发生。

抗病毒药物对心肌损伤的作用尚不完全明确, 但本研究中两组患者在药物治疗方面差异均无统计学意义。已有共识提出, 氯喹、阿比多尔和利巴韦林可诱发心律失常或心肌损伤, 对于既往有缓慢性心律失常、心脏传导阻滞或严重心绞痛的患者, 应慎用^[17]。本研究中行气管插管、ECMO、CRRT进行呼吸支持者皆为心肌损伤组患者, 且心肌损伤组死亡率更高。这说明在相似的药物治疗方案下, 心肌损伤组重型、危重型COVID-19患者病情更重, 进展更快, 常需有创呼吸循环支持, 但尽管如此, 其预后仍不良。

综上所述, 高龄、男性重型、危重型COVID-19患者合并冠心病及D-二聚体、降钙素原和IL-6和NT-proBNP异常升高时, 更易并发心肌损伤, 且病情较重, 常需有创生命支持, 但预后仍不良。其中, 年龄≥65岁和D-二聚体水平≥3 000 ng/mL是重型、危重型COVID-19患者并发心肌损伤的独立危险因素。据此, 在诊治过程中须动态监测上述指标、评估病情进展、预警心肌损伤的发生, 并指导针对性治疗。尽早和更充分的氧合治疗, 酌情加用盐酸曲美他嗪, 当IL-6水平≥100 pg/mL时予IL-6受体拮抗剂治疗, 以及当D-二聚体水平≥3 000 ng/mL时予抗凝治疗, 或许有助于降低重型、危重型COVID-19患者心肌损伤的发生率, 提高治疗成功率, 降低病死率。

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第二军医大学学报 2020, Vol. 41 Issue (6): 596-603	PDF