Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells

Lei Shu1, Changming Niu2, Ruyou Li3, Tingrong Huang4, Yan Wang5, Mao Huang6, Ningfei Ji6, Zheng You4, Xiaolin Chen1, Lei Shi1, Mingjing Wu1, Kaili Deng1, Jing Wei1, Xueli Wang1, Yang Cao1, Jiaxin Yan1, Ganzhu Feng7
1Department of Respiratory Medicine, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
2Department of Critical Care Medicine, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
3Department of Respiratory Medicine, Huangshi Central Hospital, Hangshi, 435000, Hubei, China
4Department of Nephrology, Huangshi Hospital of Traditional Chinese Medicine, Hangshi, 435000, Hubei, China
5Jiangsu Cell Tech Medical Research Institute, Nanjing, 211166, Jiangsu, China
6Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
7Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Nanjing Medical University, Address: No. 121 Jiangjiayuan Rd, Gulou District, Nanjing, 210011, Jiangsu, China

Tóm tắt

Abstract Background

COVID-19 is a highly infectious respiratory disease. No therapeutics have yet been proven effective for treating severe COVID-19.

Objectives

To determine whether human umbilical cord mesenchymal stem cell infusion may be effective and safe for the treatment of severe COVID-19.

Methods

Patients with severe COVID-19 were randomly divided into 2 groups: the standard treatment group and the standard treatment plus hUC-MSC infusion group. The incidence of progression from severe to critical illness, 28-day mortality, clinical symptom improvement, time to clinical symptom improvement, hematologic indicators including C-reactive protein, lymphocyte number, and interleukin 6, and imaging changes were observed and compared between the two groups.

Measurements and main results

The incidence of progression from severe to critical illness and the 28-day mortality rate were 0 in the hUC-MSC treatment group, while 4 patients in the control group deteriorated to critical condition and received invasive ventilation; 3 of them died, and the 28-day mortality rate was 10.34%. In the hUC-MSC treatment group, the time to clinical improvement was shorter than that in the control group. Clinical symptoms of weakness and fatigue, shortness of breath, and low oxygen saturation obviously improved beginning on the third day of stem cell infusion and reached a significant difference on day 7. CRP and IL-6 levels were significantly lower from day 3 of infusion, the time for the lymphocyte count to return to the normal range was significantly faster, and lung inflammation absorption was significantly shorter on CT imaging in the hUC-MSC group than in the control group.

Conclusions

Intravenous transplantation of hUC-MSCs is a safe and effective method that can be considered a salvage and priority treatment option for severe COVID-19.

Trial registration

Chinese Clinical Trial Registration; ChiCTR2000031494; Registered on 2 April 2020; http://www.medresman.org

Từ khóa


Tài liệu tham khảo

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–20.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.

Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, 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;63:457–60.

WHO, Coronavirus disease (COVID-19) Situation Dashboard. (2020). https://experience.arcgis.com/experience/685d0ace521648f8a5beeeee1b9125cd. Accessed.

Cao J, Tu WJ, Cheng W, Yu L, Liu YK, Hu X, et al. Clinical features and short-term outcomes of 102 patients with corona virus disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71:748–55.

WHO, WHO characterizes COVID-19 as a pandemic. (2020). https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen. Accessed 2020-03-12.

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.e8.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–74.

Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41.

Geng L, Tang X, Wang S, Sun Y, Wang D, Tsao BP, et al. Reduced let-7f in bone marrow-derived mesenchymal stem cells triggers Treg/Th17 imbalance in patients with systemic lupus erythematosus. Front Immunol. 2020;11:233.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. 2020 2020-02-07.

McIntyre LA, Stewart DJ, Mei S, Courtman D, Watpool I, Granton J, et al. Cellular immunotherapy for septic shock. A phase I clinical trial. Am J Respir Crit Care Med. 2018;197:337–47.

Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15:39.

Li T, Xia M, Gao Y, Chen Y, Xu Y. Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther. 2015;15:1293–306.

Chen P, Zhang KH, Na T, Wang L, Yin WD, Yuan BZ, et al. The hUC-MSCs cell line CCRC-1 represents a novel, safe and high-yielding HDCs for the production of human viral vaccines. Sci Rep. 2017;7:12484.

Jagiello J, Sekula-Stryjewska M, Noga S, Adamczyk E, Dzwigonska M, Kurcz M, et al. Impact of graphene-based surfaces on the basic biological properties of human umbilical cord mesenchymal stem cells: implications for ex vivo cell expansion aimed at tissue repair. Int J Mol Sci. 2019;20:4561.

Loy H, Kuok D, Hui K, Choi M, Yuen W, Nicholls JM, et al. Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A(H5N1) virus-associated acute lung injury. J Infect Dis. 2019;219:186–96.

Leng Z, ZRHW. Transplantation of ACE2 mesenchymal stem cells improves the outcomes of patients with COVID-19 pneumonia. Aging Dis. 2020;216:228.

WHO, Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: interim guidance. https://www.who.int/internalpublications-detail/clinical-management-of-severe-acuterespiratoryinfection-when-novel-coronavirus-(ncov)-infection-is-suspected (2020). Accessed Jan 11, 2020.

New coronavirus pneumonia diagnosis and treatment program (6th ed.) (in Chinese). http://www.nhc.gov.cn/xcs/zhengcwj/202002/3b09b894ac9b4204a79db5b8912d4. 440.shtml (2020). Accessed 15 Mar 2020.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

Wu M, Zhang R, Zou Q, Chen Y, Zhou M, Li X, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8:5014.

Schoen K, Horvat N, Guerreiro N, de Castro I, de Giassi KS. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect Dis. 2019;19:964.

Li K, Wu J, Wu F, Guo D, Chen L, Fang Z, et al. The clinical and chest CT features associated with severe and critical COVID-19 pneumonia. Investig Radiol. 2020;55:327–31.

Chang YC, Yu CJ, Chang SC, Galvin JR, Liu HM, Hsiao CH, et al. Pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section CT. Radiology. 2005;236:1067–75.

Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, et al. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J Infect Dis. 2020;21:1688–98.

National Early Warning Score (NEWS) 2: standardising the assessment of acuteillness severity in the NHS. London: Royal College of Physicians. (2017) (https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2). Accessed.

Lai CC, Wang CY, Wang YH, Hsueh SC, Ko WC, Hsueh PR. Global epidemiology of coronavirus disease 2019: disease incidence, daily cumulative index, mortality, and their association with country healthcare resources and economic status. Int J Antimicrob Agents. 2020;55:105946.

Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020;395:1014–5.

Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, et al. Mesenchymal stem cell-based therapy of inflammatory lung diseases: current understanding and future perspectives. Stem Cells Int. 2019;2019:4236973.

Yan X, Fu X, Jia Y, Ma X, Tao J, Yang T, et al. Nrf2/Keap1/ARE signaling mediated an antioxidative protection of human placental mesenchymal stem cells of fetal origin in alveolar epithelial cells. Oxidative Med Cell Longev. 2019;2019:2654910.

Sinclair KA, Yerkovich ST, Chen T, McQualter JL, Hopkins PM, Wells CA, et al. Mesenchymal stromal cells are readily recoverable from lung tissue, but not the alveolar space, in healthy humans. Stem Cells. 2016;34:2548–58.

Naji A, Favier B, Deschaseaux F, Rouas-Freiss N, Eitoku M, Suganuma N. Mesenchymal stem/stromal cell function in modulating cell death. Stem Cell Res Ther. 2019;10:56.

Sauler M, Bazan IS, Lee PJ. Cell death in the lung: the apoptosis-necroptosis axis. Annu Rev Physiol. 2019;81:375–402.

Naji A, Suganuma N, Espagnolle N, Yagyu KI, Baba N, Sensebe L, et al. Rationale for determining the functional potency of mesenchymal stem cells in preventing regulated cell death for therapeutic use. Stem Cells Transl Med. 2017;6:713–9.

Cai J, Wu Z, Xu X, Liao L, Chen J, Huang L, et al. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care. 2016;39:149–57.

Liu X, Zheng P, Wang X, Dai G, Cheng H, Zhang Z, et al. A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cell Res Ther. 2014;5:57.

Carlsson PO, Schwarcz E, Korsgren O, Le Blanc K. Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes. 2015;64:587–92.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;5:1054–62.

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. Jama Intern Med. 2020;395:1054–62.

Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020:e3319. https://doi.org/10.1002/dmrr.3319.

Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, 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;8:475–81.