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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?
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.
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.
Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19).
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.
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.
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.
Chinese Clinical Trial Registry: ChiCTR2000030007
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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 (email@example.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.
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