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Aging and disease    2021, Vol. 12 Issue (2) : 360-370     DOI: 10.14336/AD.2020.1218
Orginal Article |
Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19
Iglesias Martin1,9,*, Butrón Patricia1, Torre-Villalvazo Iván2, Torre-Anaya Erik A2, Sierra-Madero Juan3, Rodriguez-Andoney José J4, Tovar-Palacio Armando R2, Zentella-Dehesa Alejandro5, Domínguez-Cherit Guillermo4,9, Rodriguez-Reyna Tatiana S6, Granados-Arriola Julio7, Espisosa-Cruz Verónica8, Téllez-Pallares Fernando P10, Lozada-Estrada Alexia10, Zepeda Carrillo Carol A10, Vázquez-Mézquita Aldo J11, Nario-Chaidez Hector F12
1Plastic and Reconstructive Surgery Service at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
2Nutrition Physiology Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
3Infectology Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
4Intensive Care Unit Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
5Biochemistry Laboratory at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
6Rheumatology Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
7Inmunogenetic and Transplant Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
8Radiology and Imaging Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
9Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, México.
10Fellow-Clerk of Plastic Surgery at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México.
11Radiology and Molecular Imaging Department at the American British Cowdray Medical Center.
12Head of Mesenchymal Stem cell Therapy Department of CBCells Biotechnology.
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Abstract  

Mesenchymal stem cells (MSC) have received particular attention due to their ability to inhibit inflammation caused by cytokine storm induced by COVID-19. In this way some patients have been treated successfully. The aim of this study was to evaluate the safety and describe the clinical changes after IV administration of allogeneic human umbilical cord MSC (ahUCMSC), in patients with bilateral pneumonia caused by COVID-19, complicated with severe ARDS, as compassionate treatment. This was a pilot, open-label, prospective, longitudinal study. Five patients that did not improve in their clinical conditions after 48 hours of receiving the standard medical management used by the Medical Center and with persistent PaO2/FiO2 less than 100 mmHg were enrolled. ahUCMSC were infused IV, at dose of 1x106 per Kg of body weight over 15 minutes. Patients were monitored after the infusion to detect adverse event. Pa02/FiO2, vital signs, D-dimer, C reactive protein and total lymphocytes were monitored for 21 days after the infusion or until the patient was discharged from the hospital. Descriptive statistics were used with means or medians and standard deviation or interquartile range according to the type of variable. The Wilcoxon’s rank-sum was used for stationary samples. Adverse events occurred in three patients and were easily and quickly controlled. Immediately after the infusion of ahUCMSC, constant rise of PaO2/FiO2 was observed in all patients during the first 7 days, with statistical significance. Three patients survived and were extubated on the ninth day post-infusion. Two patients died at 13 and 15 days after infusion. The infusion of ahUCMSC in patients with severe ARDS caused by COVID-19, was safe, and demonstrated its anti-inflammatory capacity in the lungs, by improving the respiratory function expressed by PaO2 / FiO2, which allowed the survival of 3 patients, with extubation at 9 days.

Keywords mesenchymal stem cell      stromal cell      COVID-19      ARDS      cell transplantation     
Corresponding Authors: Iglesias Martin   
Just Accepted Date: 21 December 2020   Issue Date: 24 March 2021
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Iglesias Martin
Butrón Patricia
Torre-Villalvazo Iván
Torre-Anaya Erik A
Sierra-Madero Juan
Rodriguez-Andoney José J
Tovar-Palacio Armando R
Zentella-Dehesa Alejandro
Domínguez-Cherit Guillermo
Rodriguez-Reyna Tatiana S
Granados-Arriola Julio
Espisosa-Cruz Verónica
Téllez-Pallares Fernando P
Lozada-Estrada Alexia
Zepeda Carrillo Carol A
Vázquez-Mézquita Aldo J
Nario-Chaidez Hector F
Cite this article:   
Iglesias Martin,Butrón Patricia,Torre-Villalvazo Iván, et al. Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19[J]. Aging and disease, 2021, 12(2): 360-370.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2020.1218     OR
Figure 1.  The total respiratory evolution of the patients according to the values of PaO2/FiO2.
Patient dataPatient 1Patient 2Patient 3Patient 4Patient 5
Age (years)3458666243
Sexmalefemalemalemalemale
Weight (Kg)116786080117
Height (cm)162149165170170
BMI44.235.32227.640.4
ComorbidityMorbid ObesityDM II, AH, Morbid Obesity, PAD, hT, DyslipidemiaDM II, Pulmonary FibrosisOverweightMorbid obesity
SOFA67466
PaO2/FiO2 Pre infusion76*84*62**86*59*
ARDSCritically SevereCritically SevereCritically SevereCritically SevereCritically Severe
PCR SARS COV2(+)(+)(+)(+)(+)
Table 1  Demographic Data and Medical Status
Figure 2.  The respiratory evolution of the patients during the first seven days after the infusion of ahUCMSC according PaO2/FiO2.
Figure 3.  Biochemical evolution of the patients after ahUCMSC infusion.
Patient 1Patient 2Patient 3Patient 4Patient 5
Days pre infusion disease/Intubated27(17)12(6)2210(4)16(1)
Adverse EventsnonenoneMuscle contractions in extremitiesMuscle contractions in extremities and chest, PO2 decreased 78%, AH1, respiratory effortHypotension
TreatmentnonenonenonePropofol, Increasing FiO2vasopresin
Duration (min)0015560
Total days in ICU/after MSC*27(10)18(12)019(15)14(13)
Complications due to COVIDParalytic Ileus
Mixed Delirium
Bacterial Pneumonia
Cardiomyopathy
Hypoactive DeliriumCardiomyopathy, Liver Failure
Bacterial Pneumonia Active bleeding, LLEAT2
AKI3 KDIGO III Active bleeding
StatusAliveAliveAliveDeadDead
Table 2  Infusion, Adverse Events and Final Outcomes.
Time after ahUCMSC infusion (hours)PaO2/FiO2 Median (IQR)P value (0.05)**
Basal76 (62-84)-
24144 (133-150)0.047
48142 (133-167)0.008
72138 (133-134)0.008
96152 (150-157)0.009
120154 (146-160)0.009
144154 (140-172)0.009
168140 (113-171)0.019
Table 3  Oxigenation after ahUMSC * infusion.
Figure 4.  The images of the first row correspond to patient 1 (a, b, c, d), while images of the second row correspond to patient 4 (e, f, g, and h). CT scans in coronal plane are shown before (a, e) and after treatment (c, g) with their respective three-dimensional segmentation (b, and f before treatment; c and g after treatment). Notice in the affected lung parenchyma in the CT scans as ground-glass opacities and consolidations. In the three-dimensional lung segmentation, blue corresponds to undamaged parenchyma, the yellow color corresponds to ground-glass opacities, while the red color corresponds to consolidation. Notice the reduction of ground-glass opacities and consolidations in the lungs of both patients after treatment.
PatientInfusion StageTotal lung volume (cc)Undamaged lung parenchyma (cc/%)Damaged lung parenchyma (cc/%)
1Pre1914202 (10.6)1712 (89.4)
Post122621517 (67.1)745 (32.9)
2Pre17771280 (72.0)497 (28.0)
Post124622182 (88.6)280 (11.4)
3Pre33982059 (60.6)1339 (39.4)
Post225501846 (72.4)704 (27.6)
4Pre39141582 (40.4)2332 (59.6)
Post332391019 (31.5)2220 (68.5)
*5Pre2016371 (18.4)1645 (81.6)
Table 4  Total volume pulmonar undamage and damage by Covid-19.
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