Key Takeaways & Executive Findings
- •• MSC therapy demonstrates long-term safety in severe COVID-19 patients over a 3-year follow-up, with no significant increase in new-onset complications or tumor marker levels. • Patients receiving MSCs showed a higher rate of normal CT findings (46.94% vs 34.48%) and improved general health scores on SF-36 (67.0 vs 50.0), suggesting potential benefits for lung recovery and quality of life. • No significant differences were observed in total lung severity scores, 6-minute walking distance, pulmonary function tests, or Long COVID symptoms between MSC and placebo groups. • The study supports the potential of MSC therapy as a safe adjunct treatment for severe COVID-19, with possible advantages in lung recovery and quality of life for Long COVID patients.
Abstract
Background The long-term effects and outcomes of human mesenchymal stem cell (MSC) therapy in patients with severe coronavirus disease 2019 (COVID-19) remain poorly understood. This study aimed to evaluate the extended safety and efficacy of MSC treatment in severe patients with COVID-19 who participated in our earlier randomized, double-blind, placebo-controlled clinical trial, with follow-up conducted over 3 years. Methods One hundred patients with severe COVID-19 were randomized to receive either an MSC infusion (n=65, 4×10^7 cells/dose, on days 0, 3, and 6) or a placebo, with both groups receiving the standard of care. At 36 months post-MSC therapy, patients were followed up to long-term safety and efficacy, particularly the effects of MSC therapy on persistent COVID-19 symptoms. Evaluated outcomes included lung imaging results, 6-min walking distance (6-MWD), pulmonary function test results, quality of life scores based on the Short Form-36 (SF-36) health survey, Long COVID symptoms, new-onset comorbidities, tumor marker levels, and rates of COVID-19 reinfection. Results Three years post-treatment, 46.94% (23/49) of patients in the MSC group and 34.48% (10/29) in the placebo group showed normal findings on computed tomography (CT) images (odds ratio [OR]=1.68, 95% confidence interval [CI]: 0.65–4.34). The general health (GH) score from the SF-36 was higher in the MSC group (67.0) compared to the placebo group (50.0), with a difference of 12.86 (95% CI: 1.44–24.28). Both groups showed similar results for total lung severity scores (TSS), 6-MWD, pulmonary function tests, and Long COVID symptoms. No significant differences between groups were observed in new-onset complications (including tumorigenesis) or tumor marker levels. After adjusting for China’s dynamic zero-COVID-19 strategy, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection rates were 53.06% (26/49) in the MSC group and 67.86% (19/28) in the placebo group (OR=0.54, 95% CI: 0.20–1.41). Conclusions These findings support the long-term safety of MSC therapy in patients with severe COVID-19 over 3 years. MSC treatment may offer potential benefits for lung recovery and improved quality of life in patients experiencing Long COVID symptoms. Trial registration: ClinicalTrials.gov, NCT04288102. Registered 28 February 2020, https://clinicaltrials.gov/study/NCT04288102.
1. Introduction
Since December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has continued to impact populations worldwide [1, 2]. As of October 13, 2024, the World Health Organization (WHO) statistics report >776 million confirmed cases and 7.07 million deaths globally [3]. With faster-spreading variants and increased immune escape, SARS-CoV-2 infections continue to rise [4]. Despite the widespread use of antiviral treatments and vaccines, challenges remain due to viral mutations, antiviral resistance [4, 5], persistence of SARS-CoV-2 in tissues, and reinfections [6, 7]. Patients with severe or critical COVID-19 continue to experience high mortality rates and poor prognoses [8, 9].
Additionally, a significant proportion of patients with COVID-19 experience long-term symptoms across multiple organs and systems even after testing negative for the virus, a condition commonly known as “Long COVID.” Symptoms include persistent fatigue, intermittent headaches, shortness of breath, cognitive impairments, loss of smell and taste, and sleep disturbances [10–13]. Thus, there is a need to explore new treatment modalities for these persistent effects.
Mesenchymal stem cells (MSCs), known for their self-renewal, multidirectional differentiation, and immunomodulatory properties, have emerged as a promising therapeutic approach for COVID-19 and its long-term sequelae. This study presents the 3-year follow-up results of a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of MSC therapy in severe COVID-19 patients.
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Meng-Qi Yuan, Le Song, Ze-Rui Wang, Zi-Ying Zhang, Ming Shi, Junli He, Qiong Mo, Ning Zheng, Wei-Qi Yao, Yu Zhang, Tengyun Dong, Yuanyuan Li, Chao Zhang, Jinwen Song, Lei Huang, Zhe Xu, Xin Yuan, Jun-Liang Fu, Cheng Zhen, Jianming Cai, Jinghui Dong, Jianzeng Zhang, Wei-Fen Xie, Yonggang Li, Bo Zhang, Lei Shi, Fu-Sheng Wang (2026). Long-term outcomes of mesenchymal stem cell therapy in severe COVID-19 patients: 3-year follow-up of a randomized, double-blind, placebo-controlled trial. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04148-1
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Frequently Asked Questions
What is the long-term safety of mesenchymal stem cell therapy in severe COVID-19 patients?
The 3-year follow-up study found no significant differences in new-onset complications or tumor marker levels between MSC-treated and placebo groups, supporting the long-term safety of MSC therapy in severe COVID-19 patients.
Does MSC therapy improve lung recovery in COVID-19 patients?
The study observed a higher percentage of normal CT findings in the MSC group (46.94%) compared to placebo (34.48%), suggesting potential benefits for lung recovery, although the difference was not statistically significant.
What are the effects of MSC therapy on quality of life in Long COVID patients?
MSC-treated patients had a significantly higher general health score on the SF-36 (67.0 vs 50.0), indicating improved quality of life compared to placebo, particularly in the context of Long COVID symptoms.
Are there any differences in COVID-19 reinfection rates after MSC therapy?
After adjusting for China's dynamic zero-COVID-19 strategy, the reinfection rate was lower in the MSC group (53.06%) compared to placebo (67.86%), but the difference was not statistically significant (OR=0.54, 95% CI: 0.20–1.41).
What is the clinical significance of this 3-year follow-up trial?
This trial provides evidence for the long-term safety of MSC therapy in severe COVID-19 and suggests potential benefits for lung recovery and quality of life, supporting its consideration as an adjunct treatment for patients with Long COVID.
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