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SCIENTIA SINICA Vitae, Volume 50 , Issue 3 : 258-269(2020) https://doi.org/10.1360/SSV-2020-0037

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

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  • ReceivedFeb 5, 2020
  • AcceptedFeb 8, 2020
  • PublishedFeb 11, 2020

Abstract

The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. albumin (ALB) LYM, LYM(%), LDH, NEU(%) and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, ALB, CRP, LDH, LYM(%), LYM, and NEU(%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection.


Funded by

国家重大科技专项(2017ZX10103011,2017ZX10204401)

中国医学科学院医学创新基金(2017-I2M-1-009)

深圳市科技研发项目(JCYJ20180504165549581,JCYJ20170413141236906903)

中国博士后科学基金(2019T120147)


Acknowledgment

本文作者感谢一位坚持匿名的科学家. 感谢李顺旺和李晓芸在辅助数据分析和制作图表提供的帮助.


References

[1] Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in wuhan, China. Lancet, 2020, doi: 10.1016/S0140-6736(20)30183-5 CrossRef Google Scholar

[2] Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med, 2020, doi: 10.1056/NEJMoa2001316 CrossRef PubMed Google Scholar

[3] Tan W J, Zhao X, Ma X J, et al. A novel coronavirus genome identified in a cluster of pneumonia cases-wuhan, China 2019−2020. China CDC Weekly, 2020, 2: 61–62. Google Scholar

[4] Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med, 2020, doi 10.1056/NEJMoa2001017. Google Scholar

[5] Chan J F W, Yuan S, Kok K H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet, 2020, doi: 10.1016/S0140-6736(20)30154-9 CrossRef Google Scholar

[6] Jiang Y, Xu J, Zhou C, et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med, 2005, 171: 850-857 CrossRef PubMed Google Scholar

[7] Niu P, Zhao G, Deng Y, et al. A novel human mab (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice. Sci China Life Sci, 2018, 61: 1280-1282 CrossRef PubMed Google Scholar

[8] Bi Y, Tan S, Yang Y, et al. Clinical and immunological characteristics of human infections with h5n6 avian influenza virus. Clin Infect Dis, 2019, 68: 1100-1109 CrossRef PubMed Google Scholar

[9] Yang Y, Wong G, Yang L, et al. Comparison between human infections caused by highly and low pathogenic H7N9 avian influenza viruses in Wave Five: Clinical and virological findings. J Infection, 2019, 78: 241-248 CrossRef PubMed Google Scholar

[10] Vincent J L, Dubois M J, Navickis R J, et al. Hypoalbuminemia in acute illness: Is there a rationale for intervention?. Ann Surgery, 2003, 237: 319-334 CrossRef PubMed Google Scholar

[11] Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci, 2020, : doi: 10.1007/s11427-020-1637-5 CrossRef PubMed Google Scholar

[12] Huang F, Guo J, Zou Z, et al. Angiotensin ii plasma levels are linked to disease severity and predict fatal outcomes in h7n9-infected patients. Nat Commun, 2014, 5: 3595 CrossRef PubMed Google Scholar

[13] Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza a H5N1 infections. Nat Commun, 2014, 5: 3594 CrossRef PubMed Google Scholar

[14] Lin Y C, Lin J W, Wu M S, et al. Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta-analysis. PLoS ONE, 2017, 12: e0188975 CrossRef PubMed Google Scholar

[15] Forrester S J, Booz G W, Sigmund C D, et al. Angiotensin ii signal transduction: An update on mechanisms of physiology and pathophysiology. Physiol Rev, 2018, 98: 1627-1738 CrossRef PubMed Google Scholar

[16] Crackower M A, Sarao R, Oudit G Y, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature, 2002, 417: 822-828 CrossRef PubMed Google Scholar

[17] Packer M, McMurray J J V. Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure. Lancet, 2017, 389: 1831-1840 CrossRef Google Scholar

[18] Fröhlich H, Nelges C, Täger T, et al. Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease. Am Heart J, 2016, 178: 28-36 CrossRef PubMed Google Scholar

[19] Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med, 2005, 11: 875-879 CrossRef PubMed Google Scholar

[20] Damman K, Gori M, Claggett B, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC-Heart Failure, 2018, 6: 489-498 CrossRef PubMed Google Scholar

[21] Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature, 2005, 436: 112-116 CrossRef PubMed Google Scholar

[22] Rai A K, Sanjukta S, Jeyaram K. Production of angiotensin i converting enzyme inhibitory (ace-i) peptides during milk fermentation and their role in reducing hypertension. Critical Rev Food Sci Nutrition, 2017, 57: 2789-2800 CrossRef PubMed Google Scholar

[23] Torres V E, Abebe K Z, Chapman A B, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med, 2014, 371: 2267-2276 CrossRef PubMed Google Scholar

[24] Murray J F, Matthay M A, Luce J M, et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis, 1988, 138: 720-723 CrossRef PubMed Google Scholar

[25] Ko J H, Park G E, Lee J Y, et al. Predictive factors for pneumonia development and progression to respiratory failure in mers-cov infected patients. J Infection, 2016, 73: 468-475 CrossRef PubMed Google Scholar

[26] Liu C L, Lu Y T, Peng M J, et al. Clinical and laboratory features of severe acute respiratory syndrome Vis-À-Vis onset of fever. Chest, 2004, 126: 509-517 CrossRef PubMed Google Scholar

[27] Leem A Y, Park B, Kim Y S, et al. Incidence and risk of chronic obstructive pulmonary disease in a korean community-based cohort. COPD, 2018, 13: 509-517 CrossRef PubMed Google Scholar

[28] Guo J, Huang F, Liu J, et al. The serum profile of hypercytokinemia factors identified in h7n9-infected patients can predict fatal outcomes. Sci Rep, 2015, 5: 10942 CrossRef PubMed Google Scholar

[29] Mortensen E M, Nakashima B, Cornell J, et al. Population-based study of statins, angiotensin ii receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis, 2012, 55: 1466-1473 CrossRef PubMed Google Scholar

[30] Yan Y W, Liu Q, Li N, et al. Angiotensin ii receptor blocker as a novel therapy in acute lung injury induced by avian influenza a h5n1 virus infection in mouse. Sci China Life Sci, 2015, 58: 208-211 CrossRef PubMed Google Scholar

  • Figure 1

    A timeline of events in human cases with 2019-nCoV. Patients are ordered in chronological order based on the date of admission to our hospital. Various milestones in the disease course are indicated with different graphics. Patients within a family were marked in red and blue, respectively

  • Figure 2

    Computed tomographic (CT) scans and Chest radiographs of case 2. CT scans (A) and chest radiographs (B) of case 2 taken at indicated date were shown (color online)

  • Figure 3

    The Ct value of virus are highly correlated with clinical and laboratory manifestations in 2019-nCoV-infected patients. The Ct value of virus is highly correlated with PaO2/FiO2 ratio, Murray score (A) and CRP, ALB, LYM(%), LYM, NEU (B) in 2019-nCoV-infected patients. The Ct value were detected available in 10 patients with 2019-nCoV infection. PaO2/FiO2 ratio, Murray score, ALB, LYM(%), LYM, NEU, CRP and LDH were detected from 12 2019-nCoV-infected patients. Spearman rank correlation analysis (r) and P value are provided in each graph

  • Figure 4

    Murray score are highly correlated with laboratory manifestations in 2019-nCoV-infected patients. The Murray score is highly correlated with ALB, LYM, LDH, LYM(%), NEU(%), and CRP. Murray score, ALB, LYM, LDH, LYM(%), NEU(%), and CRP were detected from 12 2019-nCoV-infected patients. Spearman rank correlation analysis (r) and P value are provided in each graph

  • Figure 5

    Receiver operating characteristic (ROC) curve of clinical and biochemical indicators of 2019-nCoV-infected patients. ROC curve of the age, Murray score, Ct value of 2019-nCoV, PaO2/FiO2 ratio (A) and ROC curve of the ALB, LYM, CRP, LYM(%), LDH and NEU(%) (B) were calculated between 4 mild 2019-nCov-infected patients and 8 severe 2019-nCov-infected patients. Detailed information is shown in Table 1 and Table 2 (color online)

  • Figure 6

    Plasmas angiotensin II levels are increased in 2019-nCoV-infected patients and correlated with viral Ct value and PaO2/FiO2 ratio. Box plot of angiotensin II levels in plasma of healthy controls (n=8) and 2019-nCov-infected patients (n=12) (A). ***, P<0.001 (Mann-Whiney U test). The correlation analysis between plasmas angiotensin II levels and viral Ct value (B), or PaO2/FiO2 ratio (C) of patients with 2019-nCoV infection. The viral titers were detected available in 10 patients with 2019-nCoV infection. PaO2/FiO2 ratio were detected from 12 2019-nCoV-infected patients. Spearman rank correlation analysis (r) and P value are provided in each graph (color online)

  • Table 1   Epidemiological and clinical features of human subjects hospitalized with 2019-nCoV infection

    特征

    病例 1

    病例 2

    病例 3

    病例 4

    病例 5

    病例 6

    病例 7

    病例 8

    病例 9

    病例 10

    病例 11

    病例 12

    年龄

    65

    66

    62

    63

    63

    36

    10

    35

    51

    65

    72

    56

    性别

    女性

    男性

    男性

    男性

    女性

    男性

    男性

    男性

    男性

    女性

    男性

    女性

    发病至入院日期(天)

    9

    8

    4

    5

    8

    5

    5

    7

    13

    16

    16

    7

    初始症状

     

    发热

    咳嗽

    头痛

    肌痛

    畏寒

    恶心或呕吐

    腹泻

    基础疾病

     

    慢性心脏疾病

    慢性肺脏疾病

    慢性肾脏疾病

    慢性肝脏疾病

    糖尿病

    高血压

    肿瘤

    细菌合并感染

    并发症

     

    肺炎

    急性呼吸窘迫综合征

    重症急性呼吸窘迫综合征a)

    呼吸衰竭

    肝功能不全

    肾功能不全

    心力衰竭

    休克

    治疗

     

    抗病毒治疗

    奥司他韦利巴韦林干扰素

    奥司他韦利巴韦林干扰素

    奥司他韦利巴韦林干扰素

    奥司他韦利巴韦林干扰素

    利巴韦林 干扰素

    利巴韦林干扰素

    利巴韦林干扰素

    利巴韦林干扰素

    利巴韦林干扰素

    利巴韦林干扰素

    利巴韦林干扰素

    利巴韦林 干扰素

    皮质类激素

    机械通气

    有创机械通气

    免疫球蛋白

    重症急性呼窘迫综合征: 动脉血氧分压(PaO2)/ 吸氧浓度 (FiO2)<100 mmHg

  • Table 2   Clinical Characteristics and laboratory results of subjects hospitalized with 2019-nCoV infection

    正常范围

    病例1

    病例2

    病例3

    病例4

    病例5

    病例6

    病例7

    病例8

    病例9

    病例10

    病例11

    病例12

    动脉血氧分压/吸氧浓度

    400~500

    131

    96

    159

    65

    256

    438

    469

    561

    420

    126

    249

    386

    白细胞(×109/升)

    3.5~9.5

    4.31

    5.24

    3.85

    6.79

    6.71

    13.55

    6.72

    4.62

    4.94

    5.89

    4.99

    3.98

    淋巴细胞百分比(%)

    20~50

    20.4

    23.1

    21.6

    3.8

    11.5

    17.5

    56.4

    34.4

    29.4

    7.1

    19.8

    20.9

    淋巴细胞计数(×109/升)

    1.10~3.20

    0.88

    1.21

    0.83

    0.26

    0.77

    2.37

    3.79

    1.59

    1.45

    0.42

    NA 

    0.83

    中性粒细胞百分比(%)

    40~75

    72.6

    67.4

    58.7

    93

    80.9

    77.4

    33.7

    56.8

    64.3

    90.9

    74.8

    75.3

    中性粒细胞计数(×109/升)

    1.8~6.3

    3.13

    3.53

    2.26

    6.31

    5.43

    10.49

    2.26

    2.62

    3.18

    5.35

    3.73

    3

    血小板(×109/升)

    100~300

    161

    118

    121

    119

    215

    250

    196

    236

    184

    118

    99

    152

    天冬氨酸氨基转移酶

    (单位/升)

    0~45

    26.7

    33.6

    26

    107

    26.2

    29.3

    34.7

    28.9

    37.7

    52

    42.1

    36.1

    丙氨酸氨基转移酶(单位/升)

    0~45

    26.6

    26.5

    26

    62

    45.3

    30

    32.8

    22.4

    39.5

    15.7

    29

    23.6

    总胆红素(微摩尔/升)

    3.0~22

    10.8

    9.5

    9.1

    6.2

    11.6

    12

    8.5

    7.8

    7.8

    8.4

    9.6

    5.9

    白蛋白(克/升)

    40.0~55.0

    36.8

    39.5

    41.6

    35.1

    38.3

    48.9

    46.4

    43.4

    46.2

    34.6

    42.6

    38.4

    肌酐(微摩尔/升)

    58~110

    46.5

    81.9

    104

    220

    44.1

    79.7

    53

    95.4

    82.5

    54.1

    122

    43.6

    尿素氮(毫摩尔/升)

    3.2~7.1

    2.87

    5.37

    5.51

    9.81

    4.8

    6.65

    7.65

    4.21

    3.71

    4.48

    6.89

    3.12

    肌酸激酶(单位/升)

    50~310

    46

    118

    97

    876

    NA

    111

    70

    NA

    NA

    NA

    NA

    NA

    肌红蛋白(纳克/毫升)

    0~110

    25.2

    38.66

    50.1

    390.97

    32.7

    35

    18.7

    20.5

    27

    40.1

    111.9

    23.7

    肌钙蛋白(微克/毫升)

    0~0.1

    0.012

    0.012

    0.012

    11.37

    0.012

    0.012

    0.012

    0.012

    0.012

    0.014

    0.012

    0.012

    血浆脑钠肽(皮摩尔/升)

    0~23.1

    4.32

    5.7

    3.78

    161.99

    NA

    NA

    NA

    NA

    NA

    NA

    NA

    NA

    肌酸激酶同工酶(纳克/毫升)

    0~2.37

    0.24

    0.48

    <0.22

    20.53

    <0.22

    0.25

    0.26

    <0.22

    <0.22

    0.23

    0.97

    <0.22

    乳酸脱氢酶(单位/升)

    114.0~240.0

    662

    593

    169

    720

    696

    491

    475

    558

    476

    1266

    510

    648

    C反应蛋白(毫克/升)

    <10 

    52.6

    38.6

    52.95

    89.94

    53.6

    5.8

    <5

    35.6

    13

    33.2

    85

    28.4

    降钙素原(纳克/毫升)

    0~0.5

    0.048

    0.04

    0.095

    9.18

    0.031

    <0.020

    <0.020

    0.029

    <0.020

    0.077

    0.218

    0.033

    CD4(计数/微升)

    34~52

    47.3

    45.8

    41.2

    18.7

    30.9

    NA

    NA

    NA

    50.2

    34.9

    50.7

    43

    CD8(计数/微升)

    21~39

    16.7

    16.5

    11.6

    10.9

    23

    NA

    NA

    NA

    24.9

    14.3

    17

    17.4

    CD4/CD8

    0.9~3.6

    2.83

    2.78

    3.56

    1.72

    1.34

    NA

    NA

    NA

    2.02

    2.45

    2.98

    2.47

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