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      Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

      a , b , c , 1 , * , b , d , e , 1 , a , b , c , 1 , f , g , h , i , j , f , g , h , k , l , b , m , b , g , s , d , n , n , o , b , q , b , c , r , n , p , b , g , s , t , b , d , e , u , 1 , b , c , m , 1 , *

      EClinicalMedicine

      The Authors. Published by Elsevier Ltd.

      COVID-19, SARS-CoV-2, Pneumonia, Mechanical ventilation, Mesenchymal stromal cells, Cellular therapy, Case series

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          Abstract

          Background

          Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients.

          Methods

          Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 10 6 (IQR 0.50 × 10 6) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters.

          Findings

          First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement.

          Interpretation

          Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects.

          Funding

          None.

          Related collections

          Most cited references 16

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          Updated Approaches against SARS-CoV-2

          Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials.
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            Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use.

            COVID-19 has affected the United States leading to a national emergency with health care and economic impact, propelling the country into a recession with disrupted lifestyles not seen in recent history. COVID-19 is a serious illness leading to multiple deaths in various countries including the United States. Several million Americans satisfy the Center for Disease Control and Prevention (CDC) criteria for being high risk. Unfortunately, the available supply of medical beds and equipment for mechanical ventilation are much less than is projected to be needed. The World Health Organization (WHO) and multiple agencies led by the CDC in the United States have attempted to organize intensive outbreak investigation programs utilizing appropriate preventive measures, evaluation, and treatment. The clinical spectrum of COVID-19 varies from asymptomatic forms to conditions encompassing multiorgan and systemic manifestations in terms of septic shock, and multiple organ dysfunction (MOD) syndromes. The presently approved treatments are supportive but not curative for the disease. There are multiple treatments being studied. These include vaccines, medications Remdesivir and hydroxychloroquine and potentially combination therapy. Finally, expanded umbilical cord mesenchymal stem cells or (UC-MSCs) may have a role and are being studied. The cure of COVID-19 is essentially dependent on the patients' own immune system. When the immune system is over activated in an attempt to kill the virus, this can lead to the production of a large number of inflammatory factors, resulting in severe cytokine storm. The cytokine storm may induce organ damage followed by the edema, dysfunction of air exchange, acute respiratory distress syndrome (ARDS), acute cardiac injury, and secondary infection, which may lead to death. Thus, at this point, the avoidance of the cytokine storm may be the key for the treatment of HCOV-19 infected patients.In China, where there was limited availability of effective modalities to manage COVID-19 several patients were treated with expanded UC-MSCs. Additionally, the Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care have reported guidelines to treat coronavirus patients with stem cells in the hope of decreasing the number of patients going to the ICU, and, also relatively quickly getting them out of ICU. In this manuscript, we describe the urgent need for various solutions, pathogenesis of coronavirus and the clinical evidence for treatment of COVID-19 with stem cells. The limited but emerging evidence regarding UC MSC in managing COVID-19 suggests that it might be considered for compassionate use in critically ill patients to reduce morbidity and mortality in the United States. The administration and Coronavirus Task Force might wish to approach the potential of expanded UC-MSCs as an evolutionary therapeutic strategy in managing COVID-19 illness with a 3-pronged approach: If proven safe and effective on a specific and limited basis…1. Minimize regulatory burden by all agencies so that critically ill COVID-19 patients will have access regardless of their financial circumstance.2. Institute appropriate safeguards to avoid negative consequences from unscrupulous actors.3. With proper informed consent from patients or proxy when necessary, and subject to accumulation of data in that cohort, allow the procedure to be initiated in critically ill patients who are not responding to conventional therapies.KEY WORDS: Coronavirus, COVID-19, cytokine storm, multiorgan failure, expanded umbilical cord mesenchymal stem cells.
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              Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?

              Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the "cryo stun effect" is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.
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                Author and article information

                Contributors
                Journal
                EClinicalMedicine
                EClinicalMedicine
                EClinicalMedicine
                The Authors. Published by Elsevier Ltd.
                2589-5370
                10 July 2020
                10 July 2020
                Affiliations
                [a ]Cell Therapy Area, Hematology Department, IBSAL-Hospital Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain
                [b ]RETIC TerCel, ISCIII, Madrid, Spain
                [c ]Grupo Español de Trasplante y Terapia Celular (GETH), Spain
                [d ]New Therapies Unit, Health Research Institute Fundación Jiménez Díaz, Madrid, Spain
                [e ]Surgery Department. School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
                [f ]Department of Anesthesia and Intensive Care, Clínica Universidad de Navarra, Pamplona, Spain
                [g ]Instituto de Investigación Sanitaria (IiSGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain
                [h ]Intensive Care Unit, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
                [i ]CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain
                [j ]Intensive Care Unit, IBSAL- Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain
                [k ]Department of Anesthesia, IBSAL- Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain
                [l ]Infectious Diseases Division, Microbiology Department, Clínica Universidad de Navarra, Spain
                [m ]Cell Therapy Area and Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain
                [n ]Hospital General Universitario de Alicante (Universidad Miguel Hernandez-ISABIAL), Alicante, Spain
                [o ]Hospital General Universitario de Alicante (Departamento de Biotecnología, Universidad de Alicante-ISABIAL), Alicante, Spain
                [p ]Institute of Bioengineering, Universidad Miguel Hernández, Alicante, Spain
                [q ]Department of Cell Biology, Universidad Complutense, Madrid, Spain
                [r ]Servicio de Hematología, Hospital Clinico Universitario Virgen de la Arrixaca, IMIB, Universidad de Murcia, Murcia, Spain
                [s ]CIBER Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
                [t ]Department of Medicine, Universidad Complutense, Madrid, Spain
                [u ]Department of Surgery, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
                Author notes
                [* ]Corresponding authors at: Cell Therapy Area and Hematology Department, IBSAL-Hospital Universitario de Salamanca. Paseo de San Vicente 58-182, 37007, Salamanca, Spain (F. Sánchez-Guijo) and Clínica Universidad de Navarra, Av. Pío XII, 36, 31008, Pamplona, Spain (F. Prósper). ferminsg@ 123456usal.es fprosper@ 123456unav.es
                [1]

                These authors contributed equally to the manuscript.

                Article
                S2589-5370(20)30198-X 100454
                10.1016/j.eclinm.2020.100454
                7348610
                © 2020 The Authors. Published by Elsevier Ltd.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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