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Frontiers of Medicine

Front. Med.    2020, Vol. 14 Issue (5) : 664-673     https://doi.org/10.1007/s11684-020-0810-9
LETTER TO FRONTIERS OF MEDICINE
Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19
Lingling Tang1, Yingan Jiang2, Mengfei Zhu1, Lijun Chen3, Xiaoyang Zhou2, Chenliang Zhou2, Peng Ye2, Xiaobei Chen2, Baohong Wang3, Zhenyu Xu4, Qiang Zhang4, Xiaowei Xu3, Hainv Gao1, Xiaojun Wu2, Dong Li2, Wanli Jiang2, Jingjing Qu3, Charlie Xiang3(), Lanjuan Li1,3()
1. The Shulan (Hangzhou) Hospital, Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310022, China
2. Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
4. Innovative Precision Medicine (IPM) Group, Hangzhou 311215, China
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Abstract

The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was identified in December 2019. The symptoms include fever, cough, dyspnea, early symptom of sputum, and acute respiratory distress syndrome (ARDS). Mesenchymal stem cell (MSC) therapy is the immediate treatment used for patients with severe cases of COVID-19. Herein, we describe two confirmed cases of COVID-19 in Wuhan to explore the role of MSC in the treatment of COVID-19. MSC transplantation increases the immune indicators (including CD4 and lymphocytes) and decreases the inflammation indicators (interleukin-6 and C-reactive protein). High-flow nasal cannula can be used as an initial support strategy for patients with ARDS. With MSC transplantation, the fraction of inspired O2 (FiO2) of the two patients gradually decreased while the oxygen saturation (SaO2) and partial pressure of oxygen (PO2) improved. Additionally, the patients’ chest computed tomography showed that bilateral lung exudate lesions were adsorbed after MSC infusion. Results indicated that MSC transplantation provides clinical data on the treatment of COVID-19 and may serve as an alternative method for treating COVID-19, particularly in patients with ARDS.

Keywords coronavirus disease 2019 (COVID-19)      mesenchymal stem cell      acute respiratory distress syndrome      stem cell therapeutics     
Corresponding Author(s): Charlie Xiang,Lanjuan Li   
Just Accepted Date: 28 June 2020   Online First Date: 06 August 2020    Issue Date: 12 October 2020
 Cite this article:   
Lingling Tang,Yingan Jiang,Mengfei Zhu, et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19[J]. Front. Med., 2020, 14(5): 664-673.
 URL:  
http://journal.hep.com.cn/fmd/EN/10.1007/s11684-020-0810-9
http://journal.hep.com.cn/fmd/EN/Y2020/V14/I5/664
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Lingling Tang
Yingan Jiang
Mengfei Zhu
Lijun Chen
Xiaoyang Zhou
Chenliang Zhou
Peng Ye
Xiaobei Chen
Baohong Wang
Zhenyu Xu
Qiang Zhang
Xiaowei Xu
Hainv Gao
Xiaojun Wu
Dong Li
Wanli Jiang
Jingjing Qu
Charlie Xiang
Lanjuan Li
Fig.1  Detailed CONSORT diagram for the treatment of two patients in our study. The two patients for clinical trial were diagnosed with severe COVID-19. Their informed consent for MSC therapy was obtained accordingly. The first patient received MSC transplant on February 5, February 6, and February 8, 2020. The second patient received MSC transplant on February 8, February 9, and February 11, 2020. They were then subjected to routine blood examination and tests for liver function, immune indicators, inflammation indicators, oxygenation indicators, and chest CT scan within 2 weeks post-MSC infusion. The two patients were then discharged from the hospital and regularly examined.
Variables Reference range Jan 31 Feb 4 Feb 5 MSC treatment Feb 6 MSC treatment Feb 7 Feb 8 MSC treatment Feb 9 Feb 10 Feb 11 Feb 14 Feb 17
Temperature (°C) 36.1–37 38.7 37.8 37 37 38 37.2 37.2 36.7 36.8 37.1 37.1
Routine blood examination
LC (×109/L) 3.5–9.5 13.6 3.2 5 5.3 5.3 4.4 3.1 2.7 3.2 3.5 2.3
Lymphocytes (%) 20–50 4.1 16.9 25.4 13.2 11 13.8 15.4 23.4 21.2 28.9 41.6
Neutrophils (%) 40–75 95 80.3 71.8 84.1 86.7 83 79.2 68.2 69.5 63.2 47.6
Platelets (×109/L) 125–325 319 350 305 323 243 237 278 321 334 347 320
Hb (g/L) 115–150 72 85 87 84 79 77 76 77 81 87 89
Liver function
ALB (g/L) 40–55 38 35.1 34.9 33.5 32.6 32 31.2 31.3 32.3 33.6 34.7
ALT (U/L) 7–40 18 23 27 25 21 18 19 18 20 25 26
AST (U/L) 13–35 20 22 26 26 19 17 18 16 23 25 22
Immune indicator
CD4 (%) 33–58 47.7 N/A 55.2 51.5 N/A N/A 54.9 58 N/A N/A N/A
CD8 (%) 13–39 18.1 N/A 16.3 18.5 N/A N/A 16.5 17.1 N/A N/A N/A
IgG (g/L) 7–16 N/A N/A 20 21.5 N/A N/A 21.9 22 N/A N/A N/A
IgM (g/L) 0.4–2.3 N/A N/A 2.4 2.3 N/A N/A 1.8 1.8 N/A N/A N/A
IgA (g/L) 0.7–4 N/A N/A 2.5 2.2 N/A N/A 2 1.9 N/A N/A N/A
Inflammation indicator
CRP (mg/L) 0–10 N/A 42.5 20.3 42.3 103.4 103.4 32.9 37.6 20.7 10.9 5
IL-6 (pg/mL) <10 N/A 27.1 15.7 N/A N/A 18 21.5 9.8 5.6 5 2.2
Oxygenation indicator
FiO2 (%) <60 100 100 N/A 55 50 50 60 55 N/A N/A N/A
SaO2 (%) 95–98 98 92 N/A 96 93 98 99 97 N/A N/A N/A
PO2 (mmHg) 80–100 99 66 N/A 85 67 97 131 86 N/A N/A N/A
Tab.1  Routine laboratory test values, pre- and post-admission of MSC in the 1st patient
Fig.2  Chest computerized tomography (CT) images of the first patient. The chest X-ray on February 1 and 4 indicated large, patchy, and high-density lesions in the bilateral lungs, and the costal diaphragm angle was not clear. The X-ray on February 6 and 10 showed the absorption of the exudate lesions in the bilateral lungs.
Variables Reference range Feb 7 Feb 8 MSC treatment Feb 9 MSC treatment Feb 10 Feb 11 MSC treatment Feb 12 Feb 13 Feb 15 Feb 17 Feb 19 Feb 22
Temperature (°C) 36.1–37 36.5 36.1 36.1 36.3 36.3 N/A 36.6 36.2 N/A 36.5 36.5
Routine blood examination
LC (×109/L) 3.5–9.5 2.6 5.8 6.6 6.5 5.7 5.4 4.8 4.8 3 4.2 4
Lymphocytes (%) 20–50 10.5 10.4 10.8 11.8 9.3 15.4 24.6 23.3 31.2 28.7 35.5
Neutrophils (%) 40–75 81.3 73.4 82.8 82.7 83.8 75.2 74.8 62.6 53.9 60.8 53.5
Platelets (×109/L) 125–325 273 295 267 247 215 213 181 149 132 99 138
Hb (g/L) 115–150 132 125 126 127 132 133 128 133 123 122 114
Liver function
ALB (g/L) 40–55 34.6 29.4 32.5 34.1 31.8 31.5 32.7 31.2 33 29.9 30.7
ALT (U/L) 7–40 106 80 60 45 39 45 71 109 88 126 102
AST (U/L) 13–35 73 40 25 23 20 29 48 72 46 65 43
Immune indicator
CD4 (%) 33–58 N/A N/A 27.2 N/A N/A 27.3 N/A 37.9 N/A 44.3 46.4
CD8 (%) 13–39 N/A N/A 19.7 N/A N/A 18.4 N/A 16.6 N/A 17.9 16
IgG (g/L) 7–16 18.8 N/A 21.5 N/A N/A 29.9 N/A 33.4 N/A 34.6 39.8
IgM (g/L) 0.4–2.3 0.61 N/A 0.62 N/A N/A 0.75 N/A 0.89 N/A 0.91 0.94
IgA (g/L) 0.7–4.0 2.29 N/A 2.16 N/A N/A 1.9 N/A 1.85 N/A 1.66 1.64
Inflammation indicator
CRP (mg/L) 0–10 15.5 64.3 28.5 19.7 9.1 6.2 4.1 3.9 6.8 4.6 3.8
IL-6 (pg/mL) <10 5.1 N/A 1.5 1.5 16.5 3.3 4 14.7 5.9 6.1 10.5
Oxygenation indicator
FiO2 (%) <60 80 N/A 76 N/A 44 44 41 30 N/A 34 30
SaO2 (%) 95–98 98 N/A 96 N/A 97 99 99 99 N/A 96 99
PO2 (mmHg) 80–100 99 N/A 81 N/A 101 114 122 169 N/A 195 150
Tab.2  Routine laboratory test values, pre- and post-admission of MSC in the 2nd patient
Fig.3  Chest CT images of second patient. The chest X-ray on February 7 and 10 indicated patchy and high-density shadows in the lower lung fields and the left middle lung. Repeat chest X-ray on February 15 and 22 showed that high-density exudate was absorbed in the lower lung fields and the left middle lung.
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