Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Stem Cell Res Ther. 2021 Jan 29;12(1):91. doi: 10.1186/s13287-021-02165-4.
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 × 10 cells) every other day for a total of 600 × 10 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.
急性呼吸窘迫综合征（ARDS）是 2019 年冠状病毒病（COVID-19）的一种致命并发症。有一些关于同种异体人间充质干细胞（MSCs）作为 ARDS 潜在治疗方法的报告。在这项 1 期临床试验中，我们报告了源自胎盘和脐带的高剂量 MSC 多次输注在危重症 COVID-19 诱导的 ARDS 患者中的安全性、可行性和耐受性。
共有 11 名被诊断为 COVID-19 诱导的 ARDS 并入住两家医院 ICU 的患者入组本研究。这些患者病情危急，存在严重低氧血症，需要机械通气。患者每两天接受一次静脉输注（200×10 个细胞），共输注 600×10 个脐带 MSC（UC-MSCs；6 例）或胎盘 MSC（PL-MSCs；5 例）。
有 8 名男性和 3 名女性，年龄 42-66 岁。其中，6 例（55%）患者合并糖尿病、高血压、慢性淋巴细胞白血病（CLL）和心肌病（CMP）。细胞输注后 24-48 小时内未报告严重不良事件。我们观察到，在第一次输注后 48-96 小时内，7 名患者呼吸困难减轻，SpO2 升高。这 7 名患者中有 5 名在 2-7 天（平均 4 天）内从 ICU 出院，1 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 1 名患者在细胞输注第 7 天突然发生心脏骤停。所有 6 名幸存者的血清肿瘤坏死因子-α（TNF-α；P<0.01）、白细胞介素-8（IL-8；P<0.05）和 C 反应蛋白（CRP；P<0.01）水平显著降低。5 名（P=0.06）患者的 IL-6 水平下降，4 名（P=0.14）患者的干扰素-γ（IFN-γ）水平下降。在第一次 MSC 输注后 5-19 天（平均 10 天），4 名有器官衰竭或败血症迹象的患者死亡。淋巴细胞百分比低（<10%）和白细胞增多与不良预后相关（P=0.02）。所有 6 名幸存者在输注后第 60 天没有呼吸困难的症状，且身体状况良好。肺部计算机断层扫描（CT）的影像学参数显示出明显的恢复迹象。
我们建议多次输注高剂量同种异体产前 MSC 是安全的，并可迅速改善一些危重症 COVID-19 诱导的 ARDS 患者的呼吸窘迫症状，降低炎症生物标志物水平。发生脓毒症或多器官衰竭的患者可能不是干细胞治疗的合适人选。需要进行大型随机多中心临床试验来确定 MSC 在 COVID-19 诱导的 ARDS 中的确切治疗潜力。
Zotero 插件