Acute respiratory distress syndrome (ARDS) carries a poor prognosis. Historically, few pharmacological agents have demonstrated a beneficial impact on mortality, quality of life, or modifying the disease process.
Bellingan et al. published a phase 1/2 multicentre, randomised, blinded trial in which 300 million or 900 million adult multipotent progenitor bone marrow-derived allogenic stromal cells were administered to three cohorts of adults with moderate-severe ARDS (defined as Pa02/Fi02 <27 kPa). The hypothesis tested was that multipotent adult progenitor cells are safe to use in adult ARDS and promote a shift in the host immune response from a pro-inflammatory to an anti-inflammatory state, with consequent mediation of ARDS pathophysiology and improved clinical outcomes.
Cohorts 1 and 2 measured only safety data in a small number of patients, whereas cohort 3 (900 million cells per infusion) randomised 30 patients (intervention n=20, control = 10) to each infusion. The control group received a concealed placebo solution of identical volume and composition without cells.
The primary outcome of this study was the safety and tolerability of the multipotent adult progenitor cells in this patient group.
- No toxic reactions to transfusion or specific adverse events, including hypoxaemic, haemodynamic or cardiac events, were recorded in the 4 hours following administration. In addition, no Serious Unexpected Adverse Reactions (SUSARs) were observed in the 24 hours following infusion.
- No difference in severe Treatment-Emergent Adverse Effects (TEAEs) were reported between the two groups. Only one possibly related non-serious TEAE was reported, pyrexia, which resolved without intervention in a patient treated with 900 million cells. An independent board attributed one death in Cohort 2 to be unrelated to cell therapy in a critically ill patient.
As for the secondary outcomes related to the clinical efficacy of the stem cell infusions in ARDS:
- 28-day mortality was lower in the cell treatment group (25%, 5 of 20) than in the placebo group (40%, 4 of 10) and remained lower at day 365 also (40% intervention, 50% placebo).
- In the analysis of a “severe hypoxia” sub-group (Pa02/Fi02 < 20 kPa), 28-day mortality was 25% (2 of 8) in the cell group versus 50% (4 of 8) in the placebo.
- On day 28, the treatment group had higher median ventilator-free days (18.5 vs 6.5) and higher median ICU-free days (12.5 vs 4.5) than the placebo group. In the specified severe hypoxia subgroup, ventilator-free days were 18.5 in the cell group vs 3.5 in the placebo group and median ICU free days were 12.5 and only 1, respectively.
- Improvements in the Pa02/Fi02 ratio were observed in both groups; the increases were greater in the placebo group at day 3 (12=/- 14.6 kPa) than the cell treatment group 3.2 +/- 1.9 kPa) – although it is notable that the mean Pa02/Fi02 at baseline was different between the two groups 23.1 versus 17.1.
Regarding the exploratory outcomes, several pro-inflammatory markers, including IFN-gamma, IL-1 beta, IL-1R2, IL-6, IL-12, TNF-alpha, were decreased in the cell treatment group though they were not part of the statistical analysis.
STUDY STRENGTHS & LIMITATIONS
- Consistently high median viability of pluripotent stem cells (92%) in this trial compared to prior studies (36-85%) – previous studies noted higher viability associated with clinical efficacy.
- Standardised cell preparation and more timely delivery than prior studies.
- Comprehensive and long duration of follow-up for safety and efficacy. Vital signs, laboratory parameters, mortality and QoL were measured at escalating time intervals to 365 days post-infusion. In addition, ventilator settings, changes in respiratory mechanics and ventilator- and/or ICU-free days were measured to 28 days.
- Patients only required to fulfil a moderate ARDS definition (P/F < 27Kpa) within 6 hours of the infusion and required only a P/F ratio of < 40 and baseline cardiorespiratory stability for 2 hours prior to infusion – may limit generalisability to severe or unstable ARDS patients.
- Essentially, all patients had pneumonia as the precipitant of their ARDS – limiting generalisability of the hypothesised immunomodulatory mechanism to stem cell use in this category of patients.
- The study is not sufficiently powered for efficacy outcomes.
- Significant baseline differences between the intervention and placebo groups – the cell recipients were younger (mean age 51 vs 59, with a more favourable Pa02/Fi02 ratio (mean 23.1 vs 17.1) and a lower modified SOFA score than the placebo group. However, the intervention group did have a greater proportion of patients with a significant vasopressor requirement than the placebo group (45% vs 30%).
This trial reinforces the safety and tolerability of intravenous adult multipotent progenitor cells in patients with ARDS. Caveated by some key baseline physiological differences between the groups, it has generated some encouraging preliminary data on efficacy which supports progression to larger trials powered to detect therapeutic benefit.
This article review was prepared and submitted by Dr Liam McCarthy (Junior Clinical Fellow) and Dr Andrew Martin (Consultant in Anaesthetics and Intensive Care) – Manchester Royal Infirmary, Manchester, UK, on behalf of the ESICM Journal Review Club.
Bellingan, G. et al. Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial. Intensive Care Med 48, 36–44 (2022). https://doi.org/10.1007/s00134-021-06570-4. PMID: 34811567.