New therapeutic options are needed to treat life-threatening manifestations of respiratory virus infections such as coronavirus disease-19 (COVID-19) and influenza that do not resolve despite appropriate respiratory support and management with the currently recommended antivirals, immunomodulators, and antiinflammatory agents.

The therapeutic potential of mesenchymal stem/stromal cells (MSCs) and MSC-derived products is under evaluation in a huge number of clinical trials, on the basis of the favorable results of preclinical studies.

Although it is unclear how this investigational therapy could be integrated into the approved clinical management protocol for serious respiratory virus infections in the future, its use as an adjunctive therapy would fulfill the currently unmet need.

This paper therefore focuses on the critical assessment of published clinical studies that have specifically tested MSCs and MSC-derived products as add-on therapy to reduce mortality and the requirement for invasive mechanical ventilation in hospitalized patients with severe and critical COVID-19 and influenza.

Results are promising but inconclusive and solutions are proposed for improving the clinical development plan for the currently most needed add-on-therapy indication, with adequate consideration of regulatory and pharmacoeconomic issues.