Abstract
The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.
Highlights
The Acute Respiratory Distress Syndrome (ARDS) was first recognized in the 1960s as a clinical syndrome of severe acute respiratory failure
Over the last several decades many novel therapeutics have been evaluated for the treatment of ARDS yet none have proven efficacious, and supportive care strategies including institution of antibiotics, low tidal volume mechanical ventilation, and fluid restriction remain the mainstays of therapy[1,3]
We evaluated reporting of standard Mesenchymal stromal cells (MSC) characterization criteria according to the International Society for Cellular Therapy guidelines[64] for the 18 of 54 publications that included the administration of human MSCs (S4 Table)[10,11,12,13,14,15,18,31,32,37,40,42,45,46,52,57,58,59]
Summary
The Acute Respiratory Distress Syndrome (ARDS) was first recognized in the 1960s as a clinical syndrome of severe acute respiratory failure. Definitions have been recently revised, the consistent hallmarks are the acuity of presentation, and the presence of severe hypoxemia and bilateral pulmonary infiltrates[1]. It is a devastating clinical condition with approximately 200 000 new cases identified per year in the United States and a case fatality rate of approximately 30–40%[1]. This systematic review was conducted to better inform a decision to translate MSC therapy for pre-clinical ALI into a human clinical trial. We aimed to systematically summarize all pre-clinical studies to examine the efficacy of this treatment as compared to a diseased control group across different animal and ALI induction models; MSC origin, source and preparation; and the clinical relevance of ALI models on the clinically relevant outcome death
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