Effect of Recombinant Human Granulocyte Colony–Stimulating Factor for Patients With COVID-19 and Lymphopenia | Critical Care Medicine | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Effect of Recombinant Human Granulocyte Colony–Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and LymphopeniaA Randomized Clinical Trial

Educational Objective
To understand the effect of Recombinant Human Granulocyte Colony–Stimulating factor for patients With COVID-19 and Lymphopenia
1 Credit CME
Key Points

Question  Can treating patients with coronavirus disease 2019 (COVID-19) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) increase their peripheral blood leukocyte and lymphocyte cell counts and lead to clinical improvement?

Findings  In this open-label, randomized clinical trial of 200 Chinese patients with COVID-19, lymphopenia, and no comorbidities, rhG-CSF treatment did not accelerate clinical improvement, but the number of patients progressing to critical illness or death may have been reduced, without an increased risk of serious adverse events.

Meaning  Preliminary findings from a randomized clinical trial suggest that rhG-CSF treatment should be studied in larger trials and in a broader range of patients with COVID-19.

Abstract

Importance  Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19).

Objective  To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19.

Design, Setting and Participants  Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing.

Exposures  Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2).

Main Outcomes and Measures  The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score.

Results  Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, −13%; 95%CI, −21.4% to −5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group.

Conclusion and Relevance  In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted.

Trial Registration  Chinese Clinical Trial Registry: ChiCTR2000030007

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: August 18, 2020.

Corresponding Author: Nan-shan Zhong, MD, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Rd, Guangzhou, Guangdong 510120, China (nanshan@vip.163.com).

Published Online: September 10, 2020. doi:10.1001/jamainternmed.2020.5503

Author Contributions: Drs Lin-ling Cheng and Duan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lin-ling Cheng, Guan, and Duan are co–first authors. Dr Zhong was the guarantor of the study.

Concept and design: L-l. Cheng, Duan, N-f. Zhang, A-l. Chen, S-y. Li, Zhuo, J-h. Zhang, P-y. Chen, C-y. Wang, Zhong.

Acquisition, analysis, or interpretation of data: L-l. Cheng, Guan, Duan, Lei, Hu, Deng, F-j. Cheng, Gao, J-h. Zhang, Xie, Hong Peng, Y-s. Li, Wu, Liu, Hui Peng, J. Wang, Xiao, P-y. Chen, Yang, Zhao, Zhong.

Drafting of the manuscript: L-l. Cheng, Guan, N. Zhang, Lei, A. Chen, S-y. Li, J-h. Zhang, Xie, Hong Peng, Hui Peng, J. Wang, P-y. Chen, Zhong.

Critical revision of the manuscript for important intellectual content: L-l. Cheng, Guan, Duan, Lei, Hu, Zhuo, Deng, F-j. Cheng, Gao, J. Zhang, Y-s. Li, Wu, Liu, Xiao, P-y. Chen, C-y. Wang, Yang, Zhao, Zhong.

Statistical analysis: Duan, J-h. Zhang, Wu, Liu, P-y. Chen.

Obtained funding: L-l. Cheng, J-h. Zhang.

Administrative, technical, or material support: L-l. Cheng, N-f. Zhang, Lei, Hu, A-l. Chen, S-y. Li, Zhuo, Deng, Gao, J-h. Zhang, Xie, Y. Li, Wu, J. Wang, Xiao, C-y. Wang, Yang, Zhao, Zhong.

Supervision: L-l. Cheng, N-f. Zhang, J-h. Zhang, Zhong.

Conflict of Interest Disclosures: Dr L. Cheng reported grants from Guangzhou Institute of Respiratory Health during the conduct of the study. No other disclosures were reported.

Funding/Support: The study was supported by grants related to the prevention and management of coronavirus disease 2019 and Guangzhou Institute for Respiratory Health. We thank Kyowa Hakko Kirin China Pharmaceutical Co Ltd for their provision of the recombinant human granulocyte colony-stimulating factor.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

References
1.
World Health Organization. WHO coronavirus disease (COVID-19) dashboard. Accessed August 11, 2020. https://covid19.who.int/
2.
Huang  C , Wang  Y , Li  X ,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5 PubMedGoogle ScholarCrossref
3.
Guan  WJ , Ni  ZY , Hu  Y ,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032 PubMedGoogle ScholarCrossref
4.
Chen  N , Zhou  M , Dong  X ,  et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.   Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7 PubMedGoogle ScholarCrossref
5.
Yang  X , Yu  Y , Xu  J ,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. 2020;8(5):475-481. doi:10.1016/S2213-2600(20)30079-5 PubMedGoogle ScholarCrossref
6.
Zhou  F , Yu  T , Du  R ,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3 PubMedGoogle ScholarCrossref
7.
Wang  D , Hu  B , Hu  C ,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. 2020. doi:10.1001/jama.2020.1585 PubMedGoogle Scholar
8.
Tan  L , Wang  Q , Zhang  D ,  et al.  Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study.   Signal Transduct Target Ther. 2020;5(1):33. doi:10.1038/s41392-020-0148-4 PubMedGoogle ScholarCrossref
9.
Zhao  H , Guo  M , Sun  X ,  et al.  Effects of recombinant human granulocyte colony-stimulating factor on central and peripheral T lymphocyte reconstitution after sublethal irradiation in mice.   J Radiat Res. 2013;54(1):83-91. doi:10.1093/jrr/rrs082 PubMedGoogle ScholarCrossref
10.
Ang  CC , Tay  YK .  Hematological abnormalities and the use of granulocyte-colony-stimulating factor in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.   Int J Dermatol. 2011;50(12):1570-1578. doi:10.1111/j.1365-4632.2011.05007.x PubMedGoogle ScholarCrossref
11.
Koizumi  T , Kubo  K , Koyama  S ,  et al.  Neutrophils pretreated with granulocyte colony-stimulating factor (G-CSF) are not related to the severity of endotoxin-induced lung injury.   Exp Lung Res. 1997;23(5):393-404. doi:10.3109/01902149709039234 PubMedGoogle ScholarCrossref
12.
Li  JG , Zhang  YJ , Wu  W ,  et al  Effect of recombinant human granulocyte colony-stimulating factor on leukopenia in severe acute respiratory syndrome patients.   Yi Shi Jin Xiu Za Zhi. 2004; 27:21-22. doi:10.3760/cma.j.issn.1673-4904.2004.23.008Google Scholar
13.
Kimura  S , Matsuda  J , Ikematsu  S ,  et al.  Efficacy of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with AIDS.   AIDS. 1990;4(12):1251-1255. doi:10.1097/00002030-199012000-00011 PubMedGoogle ScholarCrossref
14.
Zhao  SS , Fang  S , Zhu  CY , Wang  LL , Gao  CJ .  Effect of G-CSF in vitro stimulation on distribution of peripheral lymphocyte subsets in the healthy persons [article in Chinese].   Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018;26(1):258-262.PubMedGoogle Scholar
15.
Melve  GK , Ersvaer  E , Eide  GE , Kristoffersen  EK , Bruserud  Ø .  Peripheral blood stem cell mobilization in healthy donors by granulocyte colony-stimulating factor causes preferential mobilization of lymphocyte subsets.   Front Immunol. 2018;9:845. doi:10.3389/fimmu.2018.00845 PubMedGoogle ScholarCrossref
16.
San Miguel  JF , Hernández  MD , Gonzalez  M ,  et al.  A randomized study comparing the effect of GM-CSF and G-CSF on immune reconstitution after autologous bone marrow transplantation.   Br J Haematol. 1996;94(1):140-147. doi:10.1046/j.1365-2141.1996.d01-1756.x PubMedGoogle ScholarCrossref
17.
Rondelli  D , Raspadori  D , Anasetti  C ,  et al.  Alloantigen presenting capacity, T cell alloreactivity and NK function of G-CSF-mobilized peripheral blood cells.   Bone Marrow Transplant. 1998;22(7):631-637. doi:10.1038/sj.bmt.1701413 PubMedGoogle ScholarCrossref
18.
World Health Organization. Coronavirus disease (COVID-2019). Accessed September 1, 2020. https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus/en/
19.
International Severe Acute Respiratory and Emerging Infections Consortium. ISARIC home page. Accessed September 1, 2020. https://isaric.tghn.org/
20.
Fine  JP , Gray  RJ .  A proportional hazards model for the subdistribution of a competing risk.   J Am Stat Assoc. 1999;94:496-509. doi:10.1080/01621459.1999.10474144 Google ScholarCrossref
21.
Newcombe  RG .  Interval estimation for the difference between independent proportions: comparison of eleven methods.   Stat Med. 1998;17(8):873-890. doi:10.1002/(SICI)1097-0258(19980430)17:8<873::AID-SIM779>3.0.CO;2-I PubMedGoogle ScholarCrossref
22.
Hodges  JL  Jr , Lehmann  EL .  Estimates of location based on rank tests.   Ann Math Stat. 1963;34:598-611. doi:10.1214/aoms/1177704172 Google ScholarCrossref
23.
Piccirillo  N , Laurenti  L , Chiusolo  P ,  et al.  Reliability of leukostasis grading score to identify patients with high-risk hyperleukocytosis.   Am J Hematol. 2009;84(6):381-382. doi:10.1002/ajh.21418 PubMedGoogle ScholarCrossref
24.
Xu  Z , Shi  L , Wang  Y ,  et al.  Pathological findings of COVID-19 associated with acute respiratory distress syndrome.   Lancet Respir Med. 2020;8(4):420-422. doi:10.1016/S2213-2600(20)30076-X PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close