重型新型冠状病毒肺炎早期治疗效果的影响因素分析

引用本文

郑楷炼, 宁方政, 徐莹, 陈怡, 赵志越, 孔祥毓, 董宇超, 赵峰, 万小健. 重型新型冠状病毒肺炎早期治疗效果的影响因素分析[J]. 第二军医大学学报, 2020, 41(4): 371-377

ZHENG Kai-lian, NING Fang-zheng, XU Ying, CHEN Yi, ZHAO Zhi-yue, KONG Xiang-yu, DONG Yu-chao, ZHAO Feng, WAN Xiao-jian. Risk factors affecting the early treatment effect of patients with severe coronavirus disease 2019[J]. Academic Journal of Second Military Medical University, 2020, 41(4): 371-377 (in Chinese with English abstract)

重型新型冠状病毒肺炎早期治疗效果的影响因素分析

郑楷炼^1,2^△, 宁方政³^△, 徐莹⁴, 陈怡^1,5, 赵志越³, 孔祥毓^1,6, 董宇超^1,7, 赵峰^1,8, 万小健^1,9

1. 湖北省武汉市火神山医院, 武汉 430100;
2. 海军军医大学(第二军医大学)长海医院普通外科, 上海 200433;
3. 海军军医大学(第二军医大学)基础医学院, 上海 200433;
4. 湖北省武汉市汉口医院消化科, 武汉 430014;
5. 海军军医大学(第二军医大学)长海医院感染科, 上海 200433;
6. 海军军医大学(第二军医大学)长海医院消化内科, 上海 200433;
7. 海军军医大学(第二军医大学)长海医院呼吸与危重症医学科, 上海 200433;
8. 海军军医大学(第二军医大学)长海医院心血管内科, 上海 200433;
9. 海军军医大学(第二军医大学)长海医院麻醉学部, 上海 200433

收稿日期: 2020-03-21 接受日期: 2020-04-11

作者简介: 郑楷炼, 硕士, 主治医师.E-mail:zhengkl828@126.com;
宁方政, 海军军医大学(第二军医大学)临床医学专业2015级五年制本科学员.E-mail:570662131@qq.com.

通信作者(Corresponding author): 万小健.Tel:021-31161629, E-mail:15800995488@163.com.

^△共同第一作者

摘要: 目的探讨影响重型新型冠状病毒肺炎（COVID-19）早期治疗效果的相关危险因素。方法回顾性分析2020年1月至2月在湖北省武汉市汉口医院住院的71例严重急性呼吸综合征冠状病毒2（SARS-CoV-2）核酸检测阳性的重型COVID-19患者资料。收集患者入院早期生命体征、临床表现、静息状态下脉搏氧饱和度、血常规、肝功能、肾功能、血生物化学、电解质、超敏肌钙蛋白T、凝血功能、脑钠肽前体、肺部CT表现、序贯器官功能衰竭评分（SOFA），以及治疗方式和早期治疗转归等资料。根据治疗2周后的治疗效果分为临床改善组和临床进展组，比较两组患者各项指标的差异，分析影响早期治疗效果的危险因素。结果临床缓解组患者43例，经治疗后均转为普通型；临床进展组患者28例，10例死亡，15例进展至危重型，3例治疗后无明显改善。两组患者发病前均存在武汉疫区居住史。临床进展组患者中吸烟者所占比例（75.0%，21/28）高于临床缓解组患者（46.5%，20/43），差异有统计学意义（P=0.033）。与临床缓解组患者相比，临床进展组患者淋巴细胞计数[0.80（0.70，0.90）×10⁹/L vs 0.70（0.60，0.70）×10⁹/L]、血小板计数[222（174，310）×10⁹/L vs 193（152，232）×10⁹/L]、纤维蛋白原水平[4.22（3.71，4.80）g/L vs 3.81（2.96，4.38）g/L]降低，差异均有统计学意义（P均 < 0.05）。两组患者常见临床症状、生命体征、静息状态下脉搏氧饱和度、其余实验室检查指标、SOFA评分、治疗方式等差异均无统计学意义（P均>0.05）。多因素logistic回归分析结果显示，吸烟（OR=4.88，95% CI 1.33~25.00，P=0.020）、白细胞计数≤3.5×10⁹/L（OR=10.00，95% CI 1.47~100.00，P=0.008）、淋巴细胞计数 < 0.1×10⁹/L（OR=16.67，95% CI 3.33~100.00，P < 0.001）是影响患者早期治疗效果的危险因素。结论有吸烟史、白细胞计数≤3.5×10⁹/L及淋巴细胞计数 < 0.1×10⁹/L的重型COVID-19患者早期治疗效果不佳的风险较高，建议临床上对有上述危险因素的重型COVID-19患者进行重点诊疗，及早采取有效治疗措施进行干预，以改善预后。

关键词: 新型冠状病毒肺炎重型肺炎治疗效果危险因素

Risk factors affecting the early treatment effect of patients with severe coronavirus disease 2019

ZHENG Kai-lian^1,2^△, NING Fang-zheng³^△, XU Ying⁴, CHEN Yi^1,5, ZHAO Zhi-yue³, KONG Xiang-yu^1,6, DONG Yu-chao^1,7, ZHAO Feng^1,8, WAN Xiao-jian^1,9

1. Huoshenshan Hospital, Wuhan 430100, Hubei, China;
2. Department of General Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
3. College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
4. Department of Gastroenterology, Hankou Hospital, Wuhan 430014, Hubei, China;
5. Department of Infectious Disease, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
6. Department of Gastroenterology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
7. Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
8. Department of Cardiovasology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
9. Department of Anesthesia, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China

^△Co-first authors

Abstract: Objective To explore the relevant risk factors that affect the early treatment effect of severe coronavirus disease 2019 (COVID-19). Methods A retrospective analysis was performed on the data of 71 severe COVID-19 patients who were admitted to Hankou Hospital, Wuhan, Hubei from Jan. to Feb. 2020 with positive in nucleic acid test of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The early vital signs, clinical manifestations, resting oxygen saturation, blood routine, liver function, blood biochemistry, electrolyte, high-sensitivity troponin, coagulation function, pro-brain natriuretic peptide, lung CT manifestations and sequential organ failure assessment (SOFA) at admission, as well as treatment regimens and early treatment outcomes were collected. According to the treatment effect after 2 weeks, the patients were divided into clinical remission group and clinical deterioration group. The differences of each index between the two groups were compared, and the risk factors affecting the early treatment effect were analyzed. Results Forty-three patients in the clinical remission group turned into non-severe cases after treatment. Among the 28 patients in the clinical deterioration group, 10 died, 15 had disease progression to critically ill status, and three had no significant improvement after treatment. The patients in both groups had a history of staying in Wuhan before the onset of the disease. The proportion of smokers in the clinical deterioration group was significantly higher than that in the clinical remission group (75.0% [21/28] vs 46.5% [20/43], P=0.033). Compared with the patients in the clinical remission group, the patients in the clinical deterioration group were more likely to have different degrees of reductions in lymphocyte counts (0.80 [0.70, 0.90]×10⁹/L vs 0.70 [0.60, 0.70]×10⁹/L), platelet counts (222 [174, 310]×10⁹/L vs 193 [152, 232]×10⁹/L) and fibrinogen level (4.22 [3.71, 4.80] g/L vs 3.81 [2.96, 4.38] g/L) (all P < 0.05). There were no significant differences in common clinical symptoms, vital signs, resting oxygen saturation, other laboratory indicators, SOFA score, or treatment regimens between the two groups (all P>0.05). Multivariate logistic regression analysis revealed that smoking (odds ratio [OR]=4.88, 95% confidence interval [CI] 1.33-25.00, P=0.020), white blood cell (WBC) count ≤3.5×10⁹/L (OR=10.00, 95% CI 1.47-100.00, P=0.008), and lymphocyte count < 0.1×10⁹/L (OR=16.67, 95% CI 3.33-100.00, P < 0.001), were the independent risk factors affecting the early treatment effect of severe COVID-19 patients. Conclusion The severe COVID-19 patients with smoking history, WBC count ≤3.5×10⁹/L or lymphocyte count < 0.1×10⁹/L have a higher risk of poor early treatment, and more attention should be paid in clinical diagnosis and treatment of these patients to improve the prognosis.

Key words: coronavirus disease 2019 severe pneumonia treatment effect risk factors

新型冠状病毒肺炎（coronavirus disease 2019，COVID-19）是由严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）感染引起的急性呼吸道传染病，其传染性强，具有人群普遍易感性，被我国列为按甲类传染病管理的乙类传染病。根据WHO报告，约13.8%为重型患者，6.1%为危重型患者^[1]，部分重型患者治疗不力或延误治疗可进展为危重型。部分重型及危重型患者病情进展快，可发生严重急性呼吸窘迫综合征^[2]，预后差，病死率高。本研究通过分析重型COVID-19患者早期的临床特征及实验室指标，寻找影响早期治疗效果的相关因素，为重型患者的临床早期识别和个体化干预提供参考。

1 资料和方法 1.1 一般资料

回顾性分析2020年1月至2月湖北省武汉市汉口医院咽拭子SARS-CoV-2核酸检测阳性的重型COVID-19患者71例，男35例、女36例，中位年龄为62岁。71例患者均符合国家卫生健康委员会颁布的《新型冠状病毒肺炎诊疗方案（试行第六版）》的诊断和分型标准^[3]。

1.2 COVID-19临床分型标准^[3]

普通型：具有发热、呼吸道等症状，影像学可见肺炎表现。重型：（1）出现气促，呼吸频率≥30/min；（2）静息状态下指氧饱和度≤93%；（3）动脉血氧分压（arterial partial pressure of oxygen，PaO₂）/吸入气氧分数（fraction of inspiration oxygan，FiO₂）≤300 mmHg（1 mmHg＝0.133 kPa）；（4）肺部影像学显示24~48 h内病灶明显进展＞50%者按重型管理。危重型（符合以下情况之一）：（1）出现呼吸衰竭，且需要机械通气；（2）出现休克；（3）合并其他器官功能衰竭需ICU监护治疗。

1.3 观察指标

观察并记录患者一般资料及入院早期的临床症状、生命体征、静息状态下脉搏氧饱和度（pulse oxygen saturation，SpO₂）、血常规、肝功能、肾功能、血生物化学、电解质、降钙素原、超敏C-反应蛋白（hypersensitive C-reactive protein，hs-CRP）、超敏肌钙蛋白T（hypersensitive troponin T，hs-TNT）、凝血功能、脑钠肽前体（pro-brain natriuretic peptide，ProBNP）、CT表现、序贯器官功能衰竭评分（sequential organ failure assessment，SOFA）等资料，并评估患者早期（2周）治疗效果。

1.4 疗效评估和分组

早期（2周）治疗效果转归评估由1名高年资影像科医师和1名呼吸科医师共同完成。临床缓解：呼吸道症状及SpO₂较入院时好转，且肺部影像学显示急性渗出病灶改善；临床进展：呼吸道症状及SpO₂较入院时无改善或恶化，肺部影像学显示急性渗出病灶进展，或患者死亡。根据治疗2周后的效果，将患者分为临床缓解组和临床进展组，其中临床缓解组患者43例，临床进展组患者28例。

1.5 统计学处理

应用SPSS 22.0软件进行统计学分析。计数资料以例数和百分数表示，组间比较采用χ²检验。计量资料使用Shapiro-Wilk法进行正态性检验，呈正态分布的计量资料以x±s表示，组间比较采用独立样本t检验；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，组间比较采用u检验。采用logistic回归模型分析影响患者早期治疗效果的危险因素。检验水准（α）为0.05。

2 结果 2.1 两组患者的一般资料比较

临床缓解组患者43例，经治疗后均转为普通型；临床进展组患者28例，其中10例死亡，15例进展至危重型，3例治疗后无明显改善。两组患者发病前均存在武汉疫区居住史。由表 1可见，临床进展组患者中吸烟者所占比例（75.0%，21/28）高于临床缓解组患者（46.5%，20/43），差异有统计学意义（P＝0.033）；两组患者性别、年龄、发病到入院时间、基础疾病（高血压、糖尿病、冠心病、心律失常）等差异均无统计学意义（P均＞0.05）。

表 1 两组重型COVID-19患者一般资料比较 Tab 1 General information of severe COVID-19 patients in two groups

2.2 两组患者入院早期相关指标的比较

由表 2可见，临床进展组患者出现发热症状的患者比例低于临床缓解组[85.7%（24/28）vs 97.62%（42/43）]，但差异无统计学意义（P＝0.075）；两组患者其他常见临床症状（咳嗽、气促、腹泻、头痛、乏力、流涕、胸痛及肌肉酸痛）及入院时体温、静息状态下SpO₂、心率差异均无统计学意义（P均＞0.05）。

表 2 两组重型COVID-19患者临床症状、生命体征及静息状态下SpO₂等指标比较 Tab 2 Clinical symptoms, vital signs and resting SpO₂ of severe COVID-19 patients in two groups

Parameter	Total N＝71	Clinical remission N＝43	Clinical deterioration N＝28	P value
Fever n (%)				0.075
No	5 (7.0)	1 (2.4)	4 (14.3)
Yes	66 (93.0)	42 (97.6)	24 (85.7)
Cough n (%)				0.249
No	8 (11.3)	3 (7.0)	5 (17.9)
Yes	63 (88.7)	40 (93.0)	23 (82.1)
Shortness of breath n (%)				0.527
No	36 (50.7)	20 (46.5)	16 (57.1)
Yes	35 (49.3)	23 (53.5)	12 (42.9)
Diarrhoea n (%)				0.644
No	67 (94.4)	41 (95.3)	26 (92.9)
Yes	4 (5.6)	2 (4.7)	2 (7.1)
Headache n (%)				1.000
No	65 (91.5)	39 (90.7)	26 (92.9)
Yes	6 (8.5)	4 (9.3)	2 (7.1)
Fatigue n (%)				1.000
No	42 (59.2)	25 (58.1)	17 (60.7)
Yes	29 (40.8)	18 (41.9)	11 (39.3)
Nasal discharge n (%)				0.152
No	69 (97.2)	43 (100.0)	26 (92.9)
Yes	2 (2.8)	0	2 (7.1)
Chest ache n (%)				0.400
No	56 (78.9)	32 (74.4)	24 (85.7)
Yes	15 (21.1)	11 (25.6)	4 (14.3)
Muscle ache n (%)				0.558
No	68 (95.8)	42 (97.7)	26 (92.9)
Yes	3 (4.2)	1 (2.3)	2 (7.1)
Temperature (℃), M (Q_L, Q_U)	38.0 (36.9, 38.8)	38.2 (36.8, 38.7)	38.0 (37.0, 38.9)	0.962
SpO₂ (%), M (Q_L, Q_U)	90.0 (84.0, 91.0)	89.0 (83.5, 91.0)	90.0 (84.8, 92.0)	0.459
Heart rate (min^－1), M (Q_L, Q_U)	90.0 (86.0, 98.0)	90.5 (88.0, 98.0)	90.0 (86.0, 98.8)	0.810
COVID-19: Coronavirus disease 2019; SpO₂: Pulse oxygen saturation; M (Q_L, Q_U): Median (lower quartile, upper quartile)

表 2 两组重型COVID-19患者临床症状、生命体征及静息状态下SpO₂等指标比较 Tab 2 Clinical symptoms, vital signs and resting SpO₂ of severe COVID-19 patients in two groups

由表 3可见，与临床缓解组患者相比，临床进展组患者入院早期淋巴细胞计数[0.70（0.60，0.70）×10⁹/L vs 0.80（0.70，0.90）×10⁹/L]、血小板计数[193（152，232）×10⁹/L vs 222（174，310）×10⁹/L]、纤维蛋白原水平[3.81（2.96，4.38）g/L vs 4.22（3.71，4.80）g/L]降低，差异均有统计学意义（P均＜0.05）；两组患者其他实验室指标、CT肺部累及情况、SOFA评分差异无统计学意义（P均＞0.05）。

表 3 两组重型COVID-19患者实验室检查结果、CT表现和SOFA评分比较 Tab 3 Laboratory indices, CT characteristics and SOFA scores of severe COVID-19 patients in two groups

Parameter	Total N＝71	Clinical remission N＝43	Clinical deterioration N＝28	P value
WBC (L^－1, ×10⁹), M (Q_L, Q_U)	6.30 (4.35, 8.30)	6.30 (4.45, 9.35)	5.40 (3.80, 7.67)	0.300
Neu (L^－1, ×10⁹), M (Q_L, Q_U)	4.80 (3.05, 7.20)	5.10 (3.55, 7.65)	4.25 (2.40, 7.15)	0.298
Lym (L^－1, ×10⁹), M (Q_L, Q_U)	0.70 (0.60, 0.90)	0.80 (0.70, 0.90)	0.70 (0.60, 0.70)	0.008
Neu/Lym M (Q_L, Q_U)	6.86 (3.82, 12.4)	7.29 (4.00, 11.7)	5.22 (3.60, 16.6)	0.659
PLT (L^－1, ×10⁹), M (Q_L, Q_U)	210 (161, 268)	222 (174, 310)	193 (152, 232)	0.031
TBil (μmol • L^－1), M (Q_L, Q_U)	9.40 (6.75, 14.0)	9.10 (6.75, 13.7)	9.55 (7.08, 14.5)	0.746
DBil (μmol • L^－1), M (Q_L, Q_U)	3.50 (2.85, 5.10)	3.50 (2.85, 4.85)	3.45 (2.82, 5.20)	0.733
TP (g • L^－1), M (Q_L, Q_U)	62.0 (58.6, 65.2)	61.1 (58.0, 64.5)	63.0 (59.9, 66.1)	0.154
ALB (g • L^－1), M (Q_L, Q_U)	31.6 (29.3, 34.3)	31.1 (28.6, 34.5)	31.9 (29.7, 34.0)	0.390
A/G M (Q_L, Q_U)	1.06 (0.90, 1.24)	1.05 (0.90, 1.25)	1.06 (0.92, 1.21)	0.832
ALT (U • L^－1), M (Q_L, Q_U)	26.0 (18.0, 44.0)	25.0 (15.5, 51.0)	27.5 (19.8, 43.0)	0.711
CO₂CP (mmol • L^－1), M (Q_L, Q_U)	25.6 (23.9, 28.4)	26.4 (24.6, 28.2)	24.6 (23.3, 28.4)	0.309
Creatine (μmol • L^－1), M (Q_L, Q_U)	68.0 (56.5, 79.5)	69.0 (56.5, 81.0)	65.0 (56.8, 78.0)	0.737
BUN (mmol • L^－1), M (Q_L, Q_U)	4.70 (3.64, 6.05)	4.48 (3.64, 5.73)	5.12 (3.95, 6.27)	0.353
Na (mmol • L^－1), M (Q_L, Q_U)	142 (140, 143)	141 (139, 143)	142 (140, 144)	0.136
K (mmol • L^－1), M (Q_L, Q_U)	3.90 (3.60, 4.50)	4.00 (3.70, 4.50)	3.70 (3.40, 4.25)	0.176
Ca (mmol • L^－1), M (Q_L, Q_U)	2.00 (2.00, 2.20)	2.00 (2.00, 2.15)	2.10 (2.00, 2.20)	0.560
hs-CRP (mg • L^－1), M (Q_L, Q_U)	35.9 (19.2, 43.4)	36.2 (22.3, 72.9)	26.4 (18.3, 37.2)	0.145
PCT (μg • L^－1), M (Q_L, Q_U)	0.11 (0.05, 0.20)	0.11 (0.05, 0.37)	0.11 (0.05, 0.13)	0.750
hs-TNT (ng • L^－1), M (Q_L, Q_U)	1.00 (1.00, 4.29)	1.00 (1.00, 2.19)	1.00 (1.00, 5.75)	0.531
ProBNP (ng • L^－1), M (Q_L, Q_U)	252 (108, 552)	252 (109, 554)	252 (102, 552)	0.654
Fibrinogen (g • L^－1), M (Q_L, Q_U)	4.10 (3.50, 4.62)	4.22 (3.71, 4.80)	3.81 (2.96, 4.38)	0.047
D-dimer (mg • L^－1), M (Q_L, Q_U)	0.63 (0.21, 1.98)	0.50 (0.19, 1.83)	0.83 (0.27, 6.72)	0.178
Prothrombin activity (%), M (Q_L, Q_U)	77.4 (65.5, 84.1)	77.9 (66.3, 86.2)	75.4 (64.7, 82.3)	0.571
CT positive n (%)				0.644
Bilateral lungs	67 (94.4)	41 (95.3)	26 (92.9)
Single lung	4 (5.6)	2 (4.7)	2 (7.1)
SOFA score M (Q_L, Q_U)	2 (1, 3)	2 (1, 3)	2 (2, 3)	0.397
COVID-19: Coronavirus disease 2019; CT: Computed tomography; SOFA: Sequential organ failure assessment; WBC: White blood cell; Neu: Neutrophil; Lym: Lymphocyte; PLT: Platelet; TBil: Total bilirubin; DBil: Direct bilirubin; TP: Total protein; ALB: Albumin; A/G: Albumin-globulin ratio; ALT: Alanine transaminase; CO2CP: Carbon dioxide combining power; BUN: Blood urea nitrogen; Na: Sodium; K: Potassium; Ca: Calcium; hs-CRP: Hypersensitive C-reactive protein; PCT: Procalcitonin; hs-TNT: Hypersensitive troponin T; ProBNP: Pro-brain natriuretic peptide; M (Q_L, Q_U): Median (lower quartile, upper quartile)

表 3 两组重型COVID-19患者实验室检查结果、CT表现和SOFA评分比较 Tab 3 Laboratory indices, CT characteristics and SOFA scores of severe COVID-19 patients in two groups

由表 4可见，两组接受糖皮质激素治疗、抗病毒治疗、抗细菌治疗及中医药治疗的患者比例差异均无统计学意义（P均＞0.05）。两组患者入院后早期均接受氧疗，43例临床缓解组患者中有40例（93.0%）接受过高流量氧疗，28例临床进展组患者中有26例（92.9%）接受过高流量氧疗，两组间差异无统计学意义（P＞0.05）。

表 4 两组重型COVID-19患者治疗情况分析 Tab 4 Treatment for severe COVID-19 patients in two groups

2.3 影响患者早期治疗效果的危险因素

单因素logistic回归分析结果显示，吸烟（OR＝3.45，95% CI 1.22~10.00，P＝0.020）、白细胞计数≤3.5×10⁹/L（OR＝4.35，95% CI 1.04~20.00，P＝0.034）、淋巴细胞计数＜0.1×10⁹/L（OR＝7.69，95% CI 2.44~25.00，P＜0.001）是影响重型COVID-19患者早期治疗效果的危险因素；多因素logistic回归分析结果显示，吸烟（OR＝4.88，95% CI 1.33~25.00，P＝0.020）、白细胞计数≤3.5×10⁹/L（OR＝10.00，95% CI 1.47~100.00，P＝0.008）、淋巴细胞计数＜0.1×10⁹/L（OR＝16.67，95% CI 3.33~100.00，P＜0.001）是影响患者早期治疗效果的独立危险因素。见表 5。

表 5 重型COVID-19患者早期治疗效果影响因素的logistic回归分析 Tab 5 Logistic regression analysis on risk fators of early treatment effect in severe COVID-19 patients

3 讨论

COVID-19患病初期，部分患者症状较轻，随着病情进展，病毒进一步累及肺实质，患者逐渐出现呼吸困难。Huang等^[4]对41例确诊COVID-19患者的数据分析显示，COVID-19自发病到病情进展的中位时间为5 d（1~8 d），到出现呼吸困难的中位时间为8 d（5~13 d）；患者病情进展越快，越易发展至危重型，预后差。因此，分析重型COVID-19患者的早期临床特征，寻找影响早期治疗效果的相关因素，对于高危患者尽早分类诊治和实施个体化治疗、改善患者预后具有重要意义。

本研究通过多因素分析发现，吸烟是重型COVID-19治疗效果的独立危险因素（OR＝4.88，95% CI 1.33~25.00，P＝0.020），提示有吸烟史的重型COVID-19患者早期治疗效果欠佳，容易出现疾病进展。香烟中的有毒有害颗粒及气体能引起肺部炎症反应，造成肺血管内皮细胞损伤^[5]；同时增加淋巴细胞和中性粒细胞的浸润，进一步加重肺实质破坏^[6]；此外，烟草中的有害物质可激活多种炎性因子，包括参与细胞因子风暴中的TNF-α，激活的炎性因子可加剧气道炎症反应^[7]。COVID-19死亡患者的病理解剖结果显示，其肺部表现为双侧弥漫性肺泡损伤伴细胞纤维黏液性渗出，具有高度促炎效应的CD4⁺ T细胞（CCR4⁺ CCR6⁺ Th17细胞）明显增加^[8]；同时，COVID-19危重型患者血清中的TNF-α水平明显升高^[4]。TNF-α能进一步调节Th17细胞分化，增加血管通透性^[9]。文献报道，Th17细胞参与了SARS-CoV-2感染中的细胞因子风暴导致组织损伤，促进肺水肿^[10]。吸烟所引起的一系列肺组织学基础损伤及炎性因子紊乱使肺部在受病毒侵袭时产生细胞因子风暴的风险大大增高，这可能是有吸烟史的重型COVID-19患者预后较差的原因。

淋巴细胞计数减少是COVID-19患者的常见临床特征，文献报道，各临床分型的COVID-19患者均会出现不同程度的淋巴细胞计数减少^{[4, 11-13]}，死亡病例的淋巴细胞减少更严重^[14]。首例COVID-19死亡患者的尸体解剖报告也证实，COVID-19死者体内淋巴细胞在减少的同时也被过度激活^[8]。本研究中，临床进展组患者的淋巴细胞计数比临床改善组更低，淋巴细胞计数＜0.1×10⁹/L是影响患者早期治疗效果的危险因素（OR＝16.67，95% CI 3.33~100.00，P＜0.001）。这提示SARS-CoV-2感染过度激活机体的免疫系统，并消耗大量的淋巴细胞，导致机体免疫调控系统失衡、多种细胞因子异常释放，触发细胞因子风暴；失调的免疫反应加重肺氧合功能损害，导致患者病情进一步恶化。有学者推测COVID-19患者淋巴细胞计数减少与疾病进展相关^[15]，可作为潜在的预后预测因子。

本研究发现，临床进展组和临床缓解组患者白细胞计数差异无统计学意义，但多因素logistic回归分析显示白细胞计数≤3.5×10⁹/L是影响患者早期治疗效果的危险因素（OR＝10.00，95% CI 1.47~100.00，P＝0.008）。此外，临床进展组患者的血小板计数也较临床缓解组减少（P＝0.031）。重型COVID-19疾病进展过程中是否存在病毒对人体骨髓造血系统的抑制，造成白细胞、淋巴细胞及血小板等减少，值得进行深入研究。

本研究还发现，糖皮质激素治疗、抗病毒治疗、抗菌治疗、高流量氧疗、中药治疗等五大常规治疗方式在两组患者中差异均无统计学意义。我们查阅文献并仔细分析，认为可能存在以下几方面原因：（1）本组研究样本量较小，可能需要进一步扩大样本量进行验证；（2）目前临床上对COVID-19疾病进展机制尚未完全掌握，常规的对症治疗措施不一定能逆转疾病的进展和预后；（3）疫情早期治疗经验和治疗手段有限，治疗的规范性和同质化不够。

综上所述，有吸烟史、白细胞计数≤3.5×10⁹/L及淋巴细胞计数＜0.1×10⁹/L是影响重型COVID-19患者早期治疗效果的危险因素，建议对于存在上述危险因素的重型COVID-19患者进行重点诊疗，及早采取更有效的治疗措施进行干预，以期改善患者预后，降低危重型转化率和死亡率。

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第二军医大学学报 2020, Vol. 41 Issue (4): 371-377	PDF