Efficacy and Safety of Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome-a Systematic Review and Meta-analysis

Overview

Journal J Thorac Dis

Publisher AME Publishing Company

Specialty Pulmonary Medicine

Date 2024 Oct 24

PMID 39444918

Authors

Lingyan Fang

Fangyuan Hu

Han Li

Wei Chang

Ling Liu

Affiliations

Soon will be listed here.

Abstract

Background: Mesenchymal stem cells (MSC) therapy for acute respiratory distress syndrome (ARDS) represents a burgeoning treatment approach, supported by numerous preclinical studies confirming its efficacy. Our study aims to provide a comprehensive evaluation of both the safety and effectiveness of MSC.

Methods: We conducted searches across three databases (PubMed, Embase, Cochrane) for randomized controlled studies up to June 23, 2024. A meta-analysis was performed on variables including adverse events, mortality, changes in the PaO/FiO ratio, intensive care unit (ICU), length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines. Relative risk (RR) values were employed for dichotomous variables, while mean difference (MD) and standard mean difference (SMD) were used for continuous variables. Risk bias was assessed using risk of bias 2 (ROB2).

Results: The meta-analysis encompassed 17 experiments involving 796 patients, with 410 undergoing MSC treatment and 386 in the control group. Primary outcomes indicated that MSC treatment did not escalate adverse events [RR =1.04; 95% confidence interval (CI): 0.90, 1.19; P=0.59; I=0%]. On the contrary, it significantly diminishes the mortality (RR =0.79; 95% CI: 0.64, 0.97; P=0.02; I=0%). Regarding secondary outcomes, MSCs led to a significant improvement in the PaO/FiO ratio for ARDS patients (SMD =0.53; 95% CI: 0.15, 0.92; P=0.007; I=0%). However, there were no significant differences in ICU length of stay (MD =-1.77; 95% CI: -6.97, 3.43; P=0.50; I=63%) and ventilation-free days (MD =-1.29; 95% CI: -4.09, 1.51; P=0.37; I=0%). MSCs significantly lowered C-reactive protein (CRP) (SMD =-0.65; 95% CI: -1.18, -0.13; P=0.01; I=56%) and interleukin-6 (IL-6) levels compared to the control group (SMD =-0.76; 95% CI: -1.34, -0.17; P=0.01; I=74%). However, changes in interleukin-10 (AIL-10) (SMD =-0.46; 95% CI: -1.51, 0.58; P=0.38; I=77%), and changes in tumor necrosis factor-alpha (ATNF-α) (SMD =-1.5; 95% CI: -3.39, 0.40; P=0.12; I=92%) levels showed no significant changes.

Conclusions: MSC therapy demonstrates reliable safety, with a significant impact on reducing mortality and improving certain clinical symptoms. Moreover, in certain aspects, it may alleviate the inflammatory response in ARDS. Nonetheless, these findings necessitate validation through additional high-quality randomized controlled trials.

References

Barcia R, Santos J, Filipe M, Teixeira M, Martins J, Almeida J . What Makes Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells Superior Immunomodulators When Compared to Bone Marrow Derived Mesenchymal Stromal Cells?. Stem Cells Int. 2015; 2015:583984. PMC: 4443932. DOI: 10.1155/2015/583984. View

Bowdish M, Barkauskas C, Overbey J, Gottlieb R, Osman K, Duggal A . A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19. Am J Respir Crit Care Med. 2022; 207(3):261-270. PMC: 9896641. DOI: 10.1164/rccm.202201-0157OC. View

Meduri G, Headley S, Kohler G, Stentz F, Tolley E, Umberger R . Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 1995; 107(4):1062-73. DOI: 10.1378/chest.107.4.1062. View

Zhou Y, Yamamoto Y, Xiao Z, Ochiya T . The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated via Paracrine Activity. J Clin Med. 2019; 8(7). PMC: 6678920. DOI: 10.3390/jcm8071025. View

Wilson J, Liu K, Zhuo H, Caballero L, McMillan M, Fang X . Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2014; 3(1):24-32. PMC: 4297579. DOI: 10.1016/S2213-2600(14)70291-7. View

Sweeney R, McAuley D . Acute respiratory distress syndrome. Lancet. 2016; 388(10058):2416-2430. PMC: 7138018. DOI: 10.1016/S0140-6736(16)00578-X. View

Perlee D, de Vos A, Scicluna B, Mancheno P, de la Rosa O, Dalemans W . Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae. Stem Cells Transl Med. 2019; 8(8):785-796. PMC: 6646807. DOI: 10.1002/sctm.18-0260. View

Zarrabi M, Shahrbaf M, Nouri M, Shekari F, Hosseini S, Hashemian S . Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial. Stem Cell Res Ther. 2023; 14(1):169. PMC: 10294333. DOI: 10.1186/s13287-023-03402-8. View

Ranieri V, Rubenfeld G, Thompson B, Ferguson N, Caldwell E, Fan E . Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012; 307(23):2526-33. DOI: 10.1001/jama.2012.5669. View

10.

Chen M, Lai K, Chien K, Teng S, Lin Y, Chao W . pcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury. Front Immunol. 2022; 13:871828. PMC: 9109702. DOI: 10.3389/fimmu.2022.871828. View

11.

Golchin A, Seyedjafari E, Ardeshirylajimi A . Mesenchymal Stem Cell Therapy for COVID-19: Present or Future. Stem Cell Rev Rep. 2020; 16(3):427-433. PMC: 7152513. DOI: 10.1007/s12015-020-09973-w. View

12.

Devaney J, Horie S, Masterson C, Elliman S, Barry F, OBrien T . Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat. Thorax. 2015; 70(7):625-35. DOI: 10.1136/thoraxjnl-2015-206813. View

13.

Li X, Bai J, Ji X, Li R, Xuan Y, Wang Y . Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014; 34(3):695-704. PMC: 4121354. DOI: 10.3892/ijmm.2014.1821. View

14.

Atluri S, Manchikanti L, Hirsch J . Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. Pain Physician. 2020; 23(2):E71-E83. View

15.

Martinez-Munoz M, Payares-Herrera C, Lipperheide I, Malo de Molina R, Salcedo I, Alonso R . Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial. Bone Marrow Transplant. 2024; 59(6):777-784. DOI: 10.1038/s41409-024-02230-5. View

16.

McIntyre L, Moher D, Fergusson D, Sullivan K, Mei S, Lalu M . Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review. PLoS One. 2016; 11(1):e0147170. PMC: 4731557. DOI: 10.1371/journal.pone.0147170. View

17.

Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R . Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021; 6(1):58. PMC: 7873662. DOI: 10.1038/s41392-021-00488-5. View

18.

Lanzoni G, Linetsky E, Correa D, Cayetano S, Alvarez R, Kouroupis D . Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021; 10(5):660-673. PMC: 8046040. DOI: 10.1002/sctm.20-0472. View

19.

Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, Makarem J, Nasiri R, Salahshour F . Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II. Stem Cell Res Ther. 2022; 13(1):96. PMC: 8899458. DOI: 10.1186/s13287-022-02771-w. View

20.

Aghayan H, Salimian F, Abedini A, Ghazi S, Yunesian M, Alavi-Moghadam S . Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment. Stem Cell Res Ther. 2022; 13(1):365. PMC: 9330663. DOI: 10.1186/s13287-022-02953-6. View