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. 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). 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. 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.

中文翻译：

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围产期组织来源的间充质干细胞治疗重症COVID-19诱导的ARDS患者的病例系列

急性呼吸窘迫综合征（ARDS）是2019年冠状病毒病（COVID-19）的致命并发症。关于异体人类间充质干细胞（MSCs）作为ARDS的潜在治疗方法的报道很少。在此1期临床试验中，我们介绍了重症COVID-19诱发的ARDS患者多次输注源自胎盘和脐带的高剂量MSC的安全性，可行性和耐受性。共有11名被诊断为COVID-19诱导的ARDS的患者入选了该研究的两家医院的重症监护病房（ICU）。患者患有严重的低氧血症危重病，需要机械通气。患者每隔一天接受三次静脉输液（200×106细胞），总共600×106人脐带间充质干细胞（UC-MSCs）。6例）或胎盘MSC（PL-MSC; 5例）。年龄在42至66岁之间的男性为8位，女性为3位。其中，六（55％）位患者合并有糖尿病，高血压，慢性淋巴细胞性白血病（CLL）和心肌病（CMP）。输注细胞后24–48 h没有报告严重的不良事件。我们观察到7例患者首次输注后48-96小时内呼吸困难减轻，SpO2升高。在这7例患者中，有5例在2-7天内（平均4天内）从ICU出院，一名有急性肾和肝功能衰竭迹象的患者在第18天从ICU出院，最后一名患者突然出现心脏在细胞输注的第7天停止。血清肿瘤坏死因子-α（TNF-α; P <0.01），IL-8（P <0.05），在所有六个幸存者中均检测到了CRP和C反应蛋白（CRP）（P <0.01）。五名患者（P = 0.06）的IL-6水平下降，四名患者（P = 0.14）的干扰素γ（IFN-γ）水平下降。初次MSC输注后5到19天（平均10天），有4位有多器官衰竭或败血症迹象的患者死亡。低百分比的淋巴细胞（<10％）和白细胞增多与不良预后相关（P = 0.02）。输注后第60天，所有6名幸存者均健康，无呼吸困难的症状。肺部计算机断层扫描（CT）扫描的放射学参数显示出明显的恢复迹象。我们建议，在某些重症COVID-19诱发的ARDS病例中，大剂量异体产前MSC的多次输注是安全的，可以迅速改善呼吸窘迫并减少炎症生物标志物。发生败血症或多器官功能衰竭的患者可能不是干细胞治疗的理想人选。需要进行大规模的随机多中心临床试验才能确定MSC在COVID-19诱导的ARDS中的确切治疗潜力。