Efficacy and safety of mesenchymal stem cell therapy for acute respiratory distress syndrome—a systematic review and meta-analysis

Introduction

Acute respiratory distress syndrome (ARDS) is a prevalent clinical syndrome characterized by diffuse pulmonary inflammation and edema, leading to acute respiratory failure. A primary cause of ARDS is the systemic inflammatory response triggered by endotoxins or injurious factors (1-3). This response increases endothelial and epithelial permeability, resulting in alveolar edema and worsening respiratory failure, ultimately leading to ARDS (4). The LUNG-SAFE study indicates that ARDS patients constitute 10.4% of intensive care unit (ICU) admissions in 50 countries, with a high mortality rate ranging from 34.9% to 46.1% (5). Current conventional treatments for ARDS primarily focus on respiratory support, including lung-protective ventilation strategies, prone positioning, extracorporeal membrane oxygenation (ECMO), and others (6). Therefore, there is an urgent need for research into new therapeutic approaches targeting the pathogenesis of ARDS.

As a result of the coronavirus disease 2019 (COVID-19) outbreak, the uncontrolled inflammatory response in ARDS is being increasingly scrutinized. Regulating the pro-inflammatory and anti-inflammatory balance in ARDS has become crucial. Mesenchymal stem cells (MSCs) are proposed as a potential therapeutic modality for ARDS due to their ability to modulate this balance.

MSCs possess characteristics of plastic adhesion and multipotent differentiation potential, making them advanced cell therapy products. MSCs can be isolated from various sources, including bone marrow, adipose tissue, perinatal tissues, dermal tissues, dental tissues, and peripheral blood (7). The potential of MSCs as a treatment for ARDS has been demonstrated in numerous animal experiments.

Firstly, MSCs can modulate the balance of the inflammatory environment by directly secreting soluble factors that regulate immune cells, suppressing pro-inflammatory cytokines, and upregulating anti-inflammatory cytokines (8,9). Secondly, in a mouse lipopolysaccharide (LPS) model, MSCs can reduce tissue damage in the ARDS model, mitigating alveolar hemorrhage, edema, membrane formation, and collagen deposition while restoring the function of endothelial and epithelial cells (10,11). Lastly, MSCs can secrete antimicrobial peptides (AMPs) with direct antibacterial effects to enhance bacterial clearance (9,10,12).

Despite some clinical trials assessing the safety and efficacy of MSC therapy for ARDS, uncertainties persist due to generally small sample sizes and many are associated with COVID-19 (13-29). Therefore, we conducted a comprehensive meta-analysis of clinical trials involving MSC treatment for ARDS patients up to June 23, 2024. We evaluated adverse events, mortality, PaO₂/FiO₂ ratio, ICU length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines to thoroughly assess the safety and effectiveness of MSC therapy for ARDS. We present this article in accordance with PRISMA reporting checklist (30) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-281/rc).

Methods

Protocol and registration

The study protocol was registered at the International Prospective Register of Systematic Reviews (CRD42023427079).

Eligibility criteria

Our inclusion criteria were as follows: (I) study type: all published randomized controlled trials (RCTs) that evaluated the safety and/or efficacy of MSCs. (II) Study subjects: individuals aged 18 years and above, conclusively diagnosed with ARDS based on the Berlin definition. (III) Intervention measures: the intervention involved the application of MSCs. (IV) Outcome measures: the included outcome measures comprised adverse events, mortality, ICU length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines.

The exclusion criteria were as follows: (I) conference records and abstracts; (II) case series studies; (III) animal experiments; (IV) clinical protocols; (V) data that could not be extracted.

Data collection

Between January 23, 2024 and June 23, 2024, we systematically searched for relevant studies in three databases: PubMed, Embase, and Cochrane, encompassing publications up to June 23, 2024.

Search strategy

The search keywords included ‘ARDS’, ‘ALI’, ‘Acute Respiratory Distress Syndrome’, ’shock Lung’, ‘acute lung injury’, ‘Respiratory Distress Syndromes’, ‘MSCs’, ‘Mesenchymal Stem Cell’, ‘Mesenchymal Stromal Cell’, and ‘Mesenchymal Progenitor Cell’. The detailed search strategies for the three English databases can be found in the Appendix 1.

Study selection

Two researchers independently conducted title and abstract screening in the databases to identify literature for full-text assessment. If the information in the titles and abstracts met the inclusion criteria, both researchers retrieved the full text for independent screening. In cases of disagreement, consensus was reached through discussion, or a third party was consulted for resolution.

Data extraction

Two independent data extractors collected pertinent information according to our predefined data extraction table. In instances of discordance, the two extractors engaged in discussion to achieve consensus. The extracted data encompassed: (I) first author, publication year; (II) study type; (III) number of included patients; (IV) details regarding MSC and control group sources, doses, administration routes, and timing; (V) adverse events, mortality, ICU length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines.

Analysis of results

The primary outcomes of the study focused on adverse events and all-cause mortality. Secondary outcomes included the changes in the PaO₂/FiO₂ ratio, ICU length of stay, ventilation-free days, as well as changes of levels of pro-inflammatory and anti-inflammatory cytokines.

Risk of bias assessment

For RCTs, we employed the Cochrane Risk of Bias tool for evaluation. This tool assesses six key aspects: (I) sequence generation, (II) allocation concealment, (III) blinding of participants and outcome assessors, (IV) incomplete outcome data, (V) selective outcome reporting, and (VI) other sources of bias. We utilized the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to ascertain the certainty of the impact of MSCs on adverse event rates and mortality.

Statistical analysis

We conducted a meta-analysis of the safety and efficacy of MSCs in treating ARDS using RevMan 5.4 and Stata 15.0 software. For dichotomous variables, we calculated the relative risk (RR) for each relevant outcome between the experimental and control groups. For continuous variables, we computed the mean difference (MD) or standardized mean difference (SMD) between the experimental and control groups. Heterogeneity among studies was assessed using the I² test. The random-effects model was utilized in all our analyses. Funnel plots and the trim-and-fill method were employed for publication bias analysis. Sensitivity analysis was performed to assess the stability of the results. Additionally, subgroup analysis was conducted based on different sources of MSCs. All statistical tests were two-tailed, and a P value less than 0.05 was considered statistically significant.

Results

Literature screening process

Following the designated search strategy, we identified 2,372 records in the databases. After eliminating 612 duplicates, 1,760 remaining records underwent title and abstract screening. During this initial screening, 1,705 records were preliminarily excluded. Subsequently, full-text screening was conducted, resulting in the exclusion of thirty-eight articles for the following reasons: (I) 2 articles were reviews; (II) 4 articles had subjects that did not meet the inclusion criteria; (III) 1 article had inappropriate intervention measures; (IV) 9 articles reported outcomes that did not meet the requirements; (V) 22 articles had flawed experimental designs. Ultimately, 17 articles met the criteria and were included in the meta-analysis (Figure 1).

Figure 1 Flowchart of the preferred reporting item search strategy for systematic evaluation and meta-analysis and inclusion of studies.

Characteristics of included studies

Tables 1,2 provide a comprehensive overview of the primary features of the 17 included studies and the demographic details of the patients. A total of 796 patients were enrolled in these studies, with 410 in the MSC group and 386 in the control group; of these, males comprised 62.75%. Regarding the severity of ARDS, two studies delineated the distribution among mild, moderate, and severe ARDS patients, while five studies included individuals with PaO₂/FiO₂ <200 mmHg. Concerning the etiology of ARDS, 15 studies reported COVID-19 as the inducing factor, while the remaining two did not specify the cause. Characteristics of MSCs in all studies matched the International Society for Cell & Gene Therapy (ISCT) criteria. The MSC products employed for treatment originated from diverse sources, including adipose tissue, bone marrow, umbilical cord, and placenta. Dosages ranged from 1×10⁶/kg to 10×10⁶/kg, with intravenous injection as the common administration route. Meanwhile, concomitant treatments of the included studies were reported in the Table S1.

Primary results

The primary outcome for assessing the safety of MSC therapy is the number of adverse events. Among the 17 included studies, 12 reported adverse event numbers. Of these, 5 studies documented adverse events related to MSC infusion, all of which were mild and self-limiting (16,18,22,24,29). Additionally, 9 studies reported severe adverse events, but these were deemed unrelated to MSC infusion (13,15,16,18,20,22,24,26,29). The consolidated findings revealed no significant difference in adverse event numbers between the MSC and control groups, suggesting that MSC infusion does not lead to an increase in adverse events [RR =1.04; 95% confidence interval (CI): 0.90, 1.19; P=0.59; I²=0%] (Figure 2). The evidence quality was considered good, with no evident heterogeneity observed and no notable publication bias detected (Figure S1).

Figure 2 Forest plot of adverse event counts. M-H, Mantel-Haenszel test; CI, confidence interval.

For all-cause mortality, data from all 16 studies were available. Combining the results across all studies, it indicates that MSCs can significantly reduce mortality (RR =0.79; 95% CI: 0.64, 0.97; P=0.02; I²=0%) (Figure 3). The evidence exhibits low heterogeneity, and no evident publication bias was observed (Figure S2). Sensitivity analysis indicated a robust stability of the results (Figures S3,S4).

Figure 3 Forest plot of all-cause mortality. M-H, Mantel-Haenszel test; CI, confidence interval.

Secondary outcomes

Change in the PaO₂/FiO₂ ratio

Five studies examined changes in the PaO₂/FiO₂ ratio, and our analysis identified significant heterogeneity in one of these studies (19,21,23,24,29). Upon exclusion of this outlier, it was revealed that MSC treatment had an obvious positive effect on improving the PaO₂/FiO₂ ratio (SMD =0.53; 95% CI: 0.15, 0.92; P=0.007; I²=0%) (Figure 4, Figure S5). This suggests that MSCs may enhance clinical outcomes to some extent. Additionally, no significant publication bias was detected, and the quality of the data remained stable (Figures S6,S7).

Figure 4 Forest plot of changes in PaO₂/FiO₂ ratio. IV, inverse variance; SD, standard deviation; CI, confidence interval.

ICU length of stay

Five studies provided data on the ICU length of stay (15,16,18,21,24). The results of the analysis indicate that, in comparison to the control group, the MSC group shows a trend towards a shorter ICU stay, although it lacked statistical significance (MD =−1.77; 95% CI: −6.97, 3.43; P=0.50; I²=63%) (Figure S8). This observation may be influenced by the small sample size in the included experiments and baseline imbalances. The data did not reveal any significant bias (Figure S9).

Ventilation-free days

The duration without mechanical ventilation supporting to some extent reflected the extent of respiratory function recovery in ARDS patients. Six studies analyzed the days without mechanical ventilation support (15,18,22-24,29). Unfortunately, similar to the ICU length of stay, MSC treatment had the potential to increase ventilation-free days, but the change was not statistically significant (MD =−1.29; 95% CI: −4.09, 1.51; P=0.37; I²=0%) (Figure S10). The data quality was high, and there is low heterogeneity (Figure S11).

Analysis of pro-inflammatory and anti-inflammatory cytokines

All 17 studies reported data on pro-inflammatory and anti-inflammatory cytokines. Among them, seven studies provided values for C-reactive protein (CRP) (13,17,19,22,25,27,28). The analysis of ∆CRP (the difference in CRP levels between baseline and the endpoint) revealed a significant difference in CRP levels between the MSC and control groups whether or not heterogeneity is excluded (SMD =−0.65; 95% CI: −1.18, −0.13; P=0.01; I²=56%) (Figure 5A, Figure S12). Eight studies reported changes in interleukin-6 (IL-6) levels (13,19,20,22,25,27-29), and pooled analysis of ∆IL-6 showed a significant reduction in IL-6 levels in the MSC group (SMD =−0.76; 95% CI: −1.34, −0.17; P=0.01; I²=74%) (Figure 5B). Other pro-inflammatory factors such as tumor necrosis factor alpha (TNF-α) (SMD =−1.5; 95% CI: −3.39, 0.40; P=0.12; I²=92%) showed no significant differences between the MSC and control groups (Figure S13).

Figure 5 Forest plot of ∆CRP and ∆IL-6. (A) The forest plot of ∆CRP. (B) The forest plot of ∆IL-6. IV, inverse variance; SD, standard deviation; CI, confidence interval; CRP, C-reactive protein; IL, interleukin.

Concerning anti-inflammatory factors, we performed a statistical analysis of ∆IL-10 levels. After excluding an article with significant heterogeneity, the results revealed no statistically significant difference in IL-10 levels between the MSC group and the control group (SMD =−0.46; 95% CI: −1.51, 0.58; P=0.38; I²=77%) (Figure S14).

The results presented above exhibit significant heterogeneity. Galbraith plot for heterogeneity in ∆IL-6 (Figure S15) revealed that 3 articles exhibited high heterogeneity in ∆IL-6, collectively representing 37.5% of the total studies included in the meta-analysis. Simple exclusion of these studies was deemed inappropriate. Subsequently, we conducted a trim-and-fill analysis, which did not alter the results. Moreover, sensitivity analyses for it affirmed the stability and reliability of the findings (Figures S16,S17). Correlation analysis of CRP level also showed similar results (Figures S18,S19). The limited number of studies and inconsistency in endpoint times may contribute to the observed heterogeneity.

Subgroup analysis results

We performed subgroup analyses for all-cause mortality rates and the number of adverse events based on the different sources of MSCs. The studies included 3 using MSCs from bone marrow (15,21,22), 1 from placental origin (14), 1 from adipose tissue (29), 10 from umbilical cord (13,16,18-20,23-27), 1 from human menstrual blood (17), and 1 from perinatal tissue (without clarification if it was from placenta or umbilical cord) (28).

Mortality was statistically significant for UC-MSCs but not for bone marrow origin MSCs, likely due to the small number of studies (Figure S20). No significant difference was observed between subgroups in the number of adverse events (Figure S21).

Risk of bias assessment

We employed the ROB2 tool to evaluate the risk of bias in RCTs. Most domains received a low-risk rating, with some uncertainties primarily arising from unspecified randomization methods (Figure S22).

Discussion

Our study reveals that, firstly, in terms of safety, MSCs exhibit similarity to the standard treatment group, suggesting that the use of MSCs does not elevate the risk of adverse reactions. Secondly, significant reductions in mortality can be seen during MSC treatments. Lastly, MSC therapy not only effectively regulates the uncontrolled inflammatory response but also improves patients’ clinical symptoms to a certain extent.

Among the 17 included studies, the analysis of adverse reactions indicates the reliability of MSC treatment’s safety. Adverse reactions induced by MSCs were mostly non-severe, such as diarrhea and rash, with the majority of patients recovering within 1–2 days, as reported in most studies. Such results are consistent with the findings of Wilson et al. (31).

According to previous studies, the over-activated immune state in ARDS patients, characterized by a severe imbalance between anti-inflammatory and pro-inflammatory factors, is a significant cause of their mortality (3). In contrast, MSCs have been shown to inhibit pro-inflammatory factors and increase the capacity of anti-inflammatory factors (32,33). Based on this mechanism, MSC treatment has the potential to reduce mortality in ARDS patients. A meta-analysis of animal experiments on MSC treatment of ARDS by McIntyre et al. found that MSC substantially reduced mortality in animal models of ARDS (34). This finding is consistent with the results of our meta-analysis of clinical studies. Furthermore, Chen’s cohort study also supports our conclusion (35). Our study, which used mortality as the primary measure of the effectiveness of MSC treatment, found that MSC significantly reduced mortality in ARDS patients. Only the studies by Matthay and Rebelatto showed opposite results (22,25), which were related to the imbalance of clinical baseline characteristics between the experimental and control groups.

Alveolar injury caused by a storm of inflammatory factors is a significant determinant of respiratory function and prognosis in patients with ARDS. Improvement in clinical symptoms in ARDS depends on the recovery of alveolar epithelial function. Animal experiments have demonstrated that MSC reduces inflammatory lung injury and promotes the recovery of alveolar epithelial function (36). In the case report series by Atluri et al., MSC effectively relieved patients’ clinical symptoms and improved their oxygenation index, consistent with our findings (37). However, these results still need to be supported by more large-scale clinical trials.

In our statistical analysis of anti-inflammatory and pro-inflammatory cytokines, MSCs were found to significantly reduce CRP and IL-6 levels, especially the IL-6 levels, aligning with the findings of Jackson et al. Their study demonstrated that in an ARDS model, MSC administration led to a substantial reduction in IL-6 levels (38-43). IL-6 plays a pivotal role in the inflammatory response to ARDS. A marked increase in IL-6 can trigger various immune cells to migrate from the circulation to specific organs, resulting in immune hyperactivity and invasion of lung tissue (44). Evidence suggests that ARDS patient survival rates are lower when the baseline level of IL-6 is higher, and the substantial reduction in IL-6 levels induced by MSCs partially reflects the potency of the anti-inflammatory impact of MSCs (45). While a trend of reduction in pro-inflammatory factors such as TNF-α was observed, significance was not evident.

In terms of anti-inflammatory factors, Rebelatto’s study shows that the ∆IL-10 levels can also be substantially reduced (25). However, in our study, we found that the MSC group did not show a significant increase in the levels of IL-10. Therefore, more experiments are needed to prove that MSC can promote the production of anti-inflammatory factors.

We observed significant heterogeneity in the statistical results of these biomarkers. After analyzing the sources of heterogeneity, we found that half of the studies contributed to the observed heterogeneity, suggesting the need for more large-scale RCTs to systematically investigate changes in the levels of inflammatory factors and standardize endpoint time points to reduce heterogeneity. However, through the application of trim-and-fill analysis and sensitivity analysis, we bolstered the stability of the results, indicating that the findings are robust and reliable. Thus, to some extent, it can be inferred that MSCs may mitigate inflammatory responses and modulate the inflammatory storm in ARDS.

Although MSC therapy is a promising treatment, it is crucial to use it wisely. We analyzed different sources of MSC as one of the factors that may affect its effectiveness (46-48). In our subgroup analysis of different MSC sources, we found that only the umbilical cord source demonstrated a statistically significant reduction in mortality. This may also be related to the lack of experimental data for the bone marrow source. Additionally, varying MSC doses and the microenvironment of ARDS patients may influence the efficacy of MSC, which warrants further investigation in future studies.

There are some limitations in this study. Firstly, the absence of large-scale RCTs and the relatively small sample size may introduce selection bias. Secondly, the measurement of mortality and laboratory indicators at non-uniform time points introduces variability. Thirdly, there is an imbalance in the male-to-female ratio, with a higher proportion of males. Lastly, the majority of experiments focused on ARDS caused by COVID-19, and there is a lack of data from studies on ARDS unrelated to COVID-19.

Conclusions

In summary, the safety of MSC therapy is deemed reliable. MSCs have the ability to reduce mortality and improve clinical symptoms to some extent. Furthermore, MSCs may offer certain benefits in alleviating the inflammatory response in ARDS. However, these findings necessitate further validation through high-quality RCTs.

Acknowledgments

Funding: This study was supported by National Key R&D Program of China (No. 2022YFC2504405), the Clinical Science and Technology Specific Projects of Jiangsu Province (BE2020786), the National Natural Science Foundation of China (Nos. 81870066 and 82270083), the Second Level Talents of the “333 High Level Talents Training Project” in the sixth phase in Jiangsu (LGY2022025), and Jiangsu Provincial Medical Key Laboratory (ZDXYS202205).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-281/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-281/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-281/coif). All authors report that this study was supported by National Key R&D Program of China (No. 2022YFC2504405), the Clinical Science and Technology Specific Projects of Jiangsu Province (BE2020786), the National Natural Science Foundation of China (Nos. 81870066 and 82270083), the Second Level Talents of the “333 High Level Talents Training Project” in the sixth phase in Jiangsu (LGY2022025), and Jiangsu Provincial Medical Key Laboratory (ZDXYS202205). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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