1. 2020;23;S391-S420Safety and Effectiveness of Intravascular Mesenchymal Stem Cells to Treat Organ Failure and Possible Application in COVID-19 Complications
   Narrative Review
   Vivek Manocha, MD, Sudhir Diwan, MD, Zaid Syed, ., Sachi Bhati, ., Navneet Boddu, MD, Sairam Atluri, MD, and Laxmaiah Manchikanti, MD.

BACKGROUND: Although only a small percentage of patients with COVID-19 deteriorate to a critical condition, because of the associated high mortality rate and the sheer number of cases, it imposes a tremendous burden on the society and unprecedented strains the health care resources. Albeit lung is the primary organ involved resulting in acute respiratory distress syndrome (ARDS), many patients additionally present with secondary multiorgan failure. Unfortunately, there is no definitive or curative treatment for this condition, and the management has been predominantly confined to supportive care, which necessitates an urgent need for novel therapies. Mesenchymal stem cell (MSC) therapy has a vast array of preclinical data and early, preliminary clinical data that suggests its potential to regenerate and restore the function of damaged tissues and organs. To date, there has been no review of all the clinical trials that have assessed the safety and efficacy of MSC therapy in organ failure commonly seen in seriously complicated COVID-19 patients.

OBJECTIVES: To evaluate the effectiveness of MSC therapy in managing multiorgan failure, utilizing currently available literature.

STUDY DESIGN: A review of human randomized controlled trials (RCTs) and observational studies assessing the role of MSC therapy in managing multiorgan failure.

METHODS: PubMed, Cochrane Library, US National Guideline Clearinghouse, Google Scholar, and prior systematic reviews and reference lists were utilized in the literature search from 1990 through May 2020. Studies that included embryonic stem cells, induced pluripotent stem cells, differentiated MSCs into specific lineage cells, and hematopoietic stem cells were excluded. Trials with intraorgan infiltration of MSC were also excluded.

OUTCOME MEASURES: The primary outcome evaluated the improvement in clinical assessment scores and indices of organ function. The secondary outcome assessed the safety of MSC therapy in the clinical trials.

RESULTS: Based on search criteria, 12 studies were found for lung, 52 for heart, 23 for liver, 16 for stroke, and 9 for kidney. Among the 6 studies that specifically assessed the effectiveness of MSC therapy in ARDS, 4 showed positive outcomes. Forty-one of the 52 trials that examined ischemic and nonischemic heart failure reported beneficial effects. Twenty of 23 trials for liver failure from different etiologies revealed favorable outcomes. Nine out of the 15 studies evaluating stroke had satisfactory effects. However, only 3 out of the 9 studies for kidney failure showed positive results. Nonexpanded bone marrow mononuclear cells were used in most of the negative studies. The incidence of disease worsening or major complications was extremely rare from MSC therapy.

LIMITATIONS: Among the studies evaluated, although there were many RCTs, there were also numerous case series. Additionally, most recruited a small number of patients.

CONCLUSIONS: MSC therapy seems to be promising to treat multiorgan failure from COVID-19. More studies are urgently needed to assess both safety and efficacy.

KEY WORDS: Mesenchymal stem cell, multiorgan failure, randomized controlled trial