Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

Abstract

Background: Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients.

Methods: A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases).

Findings: There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24-48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48-96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2-7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5-19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery.

Interpretation: We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Keywords: Acute respiratory distress syndrome; COVID-19; Cell therapy; Mesenchymal stromal cells; Placenta; Pneumonia; SARS-CoV-2; Umbilical cord.

Conflict of interest statement

Massoud Vosough and Hossein Baharvand are regulatory affairs manager and member of the board of directors in CellTech Pharmed Company, respectively. They have no-share in this company.

The other authors have no conflict of interest.

Figures

Fig. 1

Change in patients’ serum biomarker levels on days 0 (baseline) and 5 after the first infusion. Analysis of biomarkers on before (baseline) and 5 days after the first infusion (24 h after the last infusion) demonstrated a significant reduction in IL-8, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) in all six survivors. Serum IL-6 levels and interferon gamma (INF-ɣ) reduced in five and four of the recovered patients, respectively. IL-4 and IL-10 levels increased in four cases, but the differences were not statistically significant. *P < 0.05; ns, not significant

Fig. 2

Chest computed tomography (CT) images in three survivors. a Patient #2: First row is prior to cell infusion. Note the extensive mixed ground glass opacities, crazy paving appearance, vascular dilatation, consolidations with peripheral subpleural dominancy, and bilateral mild pleural effusion. The CT severity score for all five lobes was 24. The second row shows CT images 1 day after the third dose of cell therapy. There is a decrease in extension of consolidations associated with band-like opacities and traction bronchiectasis are evident. CT severity score for all five lobes was 18. The third row shows near complete resolution of opacities and subpleural bands without residual fibrosis 50 days after MSC therapy. The CT severity score for all five lobes was 2. The percentage of lung involvement in each image of the first, second, and third columns was assessed at pretreatment, 1 day after the third post-cell therapy, and after 50 days of treatment, respectively, as follows. First column: about 60%, 25%, and 0%; second column: about 75%, 30%, and 0%; and third column: about 90%, 50%, and 2%. b Patient #3: First row shows chest CT images before cell therapy. Note the patchy areas of ground glass opacity and consolidations in the subpleural regions of the lungs. The CT severity score for all five lobes was 16. The second row shows a significant reduction in the extension of lung involvement 12 days after the third dose of cell therapy. Most consolidations had resolved completely with only band-like opacities and mild tiny residual ground glass opacities present. The CT severity score for all five lobes was 8. The percentage of lung involvement in single images from the first, second, and third columns was assessed at pretreatment and 12 days after the third cell therapy, respectively, as follows. First column: about 15% and 5%; second column: about 35% and 15%; and third column: about 20% and 3%. c Patient #8: Axial CT scan images from the base of the lung before cell therapy. The left image shows peripheral subpleural consolidations and ground glass opacity. At the same level, the right image shows a significant decrease in consolidations 12 days after cell therapy; however, the patient developed bilateral pleural effusion due to acute renal failure during the course of the disease. The CT severity score for all five lobes at the initial lung CT scan was 24, which decreased to 13 at 12 days after cell therapy. The percentage of lung involvement in the pretreatment image was about 60%, which decreased to 20% in the post-treatment image. In all images, different patterns of lung involvement have the following annotations: crazy paving appearance (black boxes), consolidation (black stars), pure ground glass opacity (solid white arrows), vascular dilatation (solid white arrows), traction bronchiectasis (solid black arrows), subpleural band (dashed white arrows), architectural distortion (white boxes), and pleural effusion (dashed black arrows)