The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19

doi:10.1016/j.cmet.2021.01.002

. 2021 Feb 2;33(2):258-269.e3.

doi: 10.1016/j.cmet.2021.01.002. Epub 2021 Jan 5.

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19

Jingjing Cai¹, Haomiao Li², Changjiang Zhang³, Ze Chen², Hui Liu⁴, Fang Lei⁵, Juan-Juan Qin⁵, Ye-Mao Liu², Feng Zhou⁶, Xiaohui Song², Jianghua Zhou², Yan-Ci Zhao², Bin Wu², Meiling He⁷, Huilin Yang⁷, Lihua Zhu², Peng Zhang⁸, Yan-Xiao Ji⁶, Guang-Nian Zhao⁶, Zhigang Lu⁹, Liming Liu¹⁰, Weiming Mao¹¹, Xiaofeng Liao¹², Haofeng Lu¹³, Daihong Wang¹⁴, Xigang Xia¹⁵, Xiaodong Huang¹⁶, Xiang Wei¹⁷, Jiahong Xia¹⁸, Bing-Hong Zhang¹⁹, Yufeng Yuan²⁰, Zhi-Gang She⁵, Qingbo Xu²¹, Xinliang Ma²², Yibin Wang²³, Juan Yang²⁴, Xin Zhang²⁵, Xiao-Jing Zhang²⁶, Hongliang Li²⁷

Affiliations

¹ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410000, China.
² Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
³ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, China.
⁴ School of Basic Medical Science, Wuhan University, Wuhan, China; Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China.
⁵ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
⁶ Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁷ School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
⁸ School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁹ Department of Neurology, The First People's Hospital of Jingmen affiliated to Hubei Minzu University, Jingmen 448000, China.
¹⁰ Department of General Surgery, Ezhou Central Hospital, Ezhou 436000, China.
¹¹ Department of General Surgery, Huanggang Central Hospital, Huanggang 438000, China.
¹² Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
¹³ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Changjiang University, Jingzhou, China.
¹⁴ Department of Hepatobiliary and Pancreatic Surgery, Xianning Central Hospital, Hubei Province, Xianning, China.
¹⁵ Department of Hepatobiliary Surgery, Jingzhou Central Hospital, Jingzhou, China.
¹⁶ Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China.
¹⁷ Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁸ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁹ Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, China.
²⁰ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
²¹ Centre for Clinic Pharmacology, The William Harvey Research Institute, Queen Mary University of London, London, UK.
²² Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19004, USA.
²³ Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: yibinwang@mednet.ucla.edu.
²⁴ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China. Electronic address: yangjuancat@whu.edu.cn.
²⁵ School of Basic Medical Science, Wuhan University, Wuhan, China; Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China. Electronic address: zhangxin57@whu.edu.cn.
²⁶ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China. Electronic address: zhangxjing@whu.edu.cn.
²⁷ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: lihl@whu.edu.cn.

PMID: 33421384
PMCID: PMC7832609
DOI: 10.1016/j.cmet.2021.01.002

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19

Jingjing Cai et al. Cell Metab. 2021.

. 2021 Feb 2;33(2):258-269.e3.

doi: 10.1016/j.cmet.2021.01.002. Epub 2021 Jan 5.

Authors

Affiliations

¹ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410000, China.
² Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
³ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, China.
⁴ School of Basic Medical Science, Wuhan University, Wuhan, China; Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China.
⁵ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
⁶ Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁷ School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China.
⁸ School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁹ Department of Neurology, The First People's Hospital of Jingmen affiliated to Hubei Minzu University, Jingmen 448000, China.
¹⁰ Department of General Surgery, Ezhou Central Hospital, Ezhou 436000, China.
¹¹ Department of General Surgery, Huanggang Central Hospital, Huanggang 438000, China.
¹² Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
¹³ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Changjiang University, Jingzhou, China.
¹⁴ Department of Hepatobiliary and Pancreatic Surgery, Xianning Central Hospital, Hubei Province, Xianning, China.
¹⁵ Department of Hepatobiliary Surgery, Jingzhou Central Hospital, Jingzhou, China.
¹⁶ Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China.
¹⁷ Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁸ Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁹ Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, China.
²⁰ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
²¹ Centre for Clinic Pharmacology, The William Harvey Research Institute, Queen Mary University of London, London, UK.
²² Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19004, USA.
²³ Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: yibinwang@mednet.ucla.edu.
²⁴ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China. Electronic address: yangjuancat@whu.edu.cn.
²⁵ School of Basic Medical Science, Wuhan University, Wuhan, China; Department of Gastroenterology, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China. Electronic address: zhangxin57@whu.edu.cn.
²⁶ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China. Electronic address: zhangxjing@whu.edu.cn.
²⁷ Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China; School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: lihl@whu.edu.cn.

PMID: 33421384
PMCID: PMC7832609
DOI: 10.1016/j.cmet.2021.01.002

Abstract

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.

Keywords: COVID-19; corticosteroids; inflammatory status; mortality; neutrophil-to-lymphocyte ratio.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1**
The Flow Chart of Patient Inclusion and Analysis Procedures in the Study (A) A total of 15,649 individuals admitted to hospitals from December 30, 2019, to April 17, 2020, were enrolled in the study. There were 2,787 individuals not eligible for the study that were excluded. A total of 12,682 individuals were randomly and equally divided into training and validation cohorts. Screening of blood cell factors related to high risk of COVID-19 mortality was performed in the training cohort. The neutrophil-to-lymphocyte ratio (NLR) was the integrated indicator closely associated with the risk of death, and the optimal cut-off at 6.11 was developed by the highest Youden index. The capability of NLR and its cut-off at 6.11 to discriminate the high risk of death were verified in the validation cohort. (B) The association between corticosteroid treatment and 60-day all-cause mortality was analyzed in individuals with NLR-defined high (>6.11) or low (≤6.11) risk of death in training and validation groups. In addition, the association between corticosteroid treatment and mortality was analyzed in individuals with T2D.

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References

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[1] Angus D.C., Derde L., Al-Beidh F., Annane D., Arabi Y., Beane A., van Bentum-Puijk W., Berry L., Bhimani Z., Bonten M., et al. Writing Committee for the REMAP-CAP Investigators Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 2020;324:1317–1329. - PMC - PubMed

[2] Angus D.C., Derde L., Al-Beidh F., Annane D., Arabi Y., Beane A., van Bentum-Puijk W., Berry L., Bhimani Z., Bonten M., et al. Writing Committee for the REMAP-CAP Investigators Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 2020;324:1317–1329. - PMC - PubMed

[3] Annane D., Bellissant E., Bollaert P.E., Briegel J., Confalonieri M., De Gaudio R., Keh D., Kupfer Y., Oppert M., Meduri G.U. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362–2375. - PubMed

[4] Annane D., Bellissant E., Bollaert P.E., Briegel J., Confalonieri M., De Gaudio R., Keh D., Kupfer Y., Oppert M., Meduri G.U. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362–2375. - PubMed

[5] Barnes P.J. Kinases as novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Pharmacol. Rev. 2016;68:788–815. - PubMed

[6] Barnes P.J. Kinases as novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Pharmacol. Rev. 2016;68:788–815. - PubMed

[7] Cain D.W., Cidlowski J.A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 2017;17:233–247. - PMC - PubMed

[8] Cain D.W., Cidlowski J.A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 2017;17:233–247. - PMC - PubMed

[9] Capelastegui A., España P.P., Quintana J.M., Areitio I., Gorordo I., Egurrola M., Bilbao A. Validation of a predictive rule for the management of community-acquired pneumonia. Eur. Respir. J. 2006;27:151–157. - PubMed

[10] Capelastegui A., España P.P., Quintana J.M., Areitio I., Gorordo I., Egurrola M., Bilbao A. Validation of a predictive rule for the management of community-acquired pneumonia. Eur. Respir. J. 2006;27:151–157. - PubMed

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The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19

Affiliations

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19

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