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

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 × 106 (IQR 0.50 × 106) 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.We would like to acknowledge the Instituto de Salud Carlos III (ISCIII) through the project “RD16/0011: Red de Terapia Celular”, from the sub-program RETICS, integrated in the “Plan Estatal de I+D+I 2013-2016” and co-financed by the European Regional Development Fund “A way to make Europe”, groups RD16/0011/0001, -/0002, -/005, -/0013, -/0015, -/0029), the Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain and AvanCell-CM (Red de Investigación de Terapia Celular de la Comunidad de Madrid, Spain), for supporting some personnel and networking activities

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Análise dos aspectos bioéticos nos programas de doação em assistolia controlada

Solid organs trasplant constitutes a treatment for many diseases in terminal phase. Patients subjected to this type of intervention enhance survival and quality of life in general and it is considered a beneficial progress in medicine for society. In the last decades and due to the stagnation of donations and the progressive increase of waiting lists, some actions have been developed with the goal to widen the potential number of donors, reconsidering again those coming from cardiovascular arrest (asystole donors). The aim of this article consists in reflecting on the legitimacy of combining in the same process two complex ethical decisions: the withdrawal of life support techniques (WLST) and the limitation of therapeutic effort (LTE), and the possibility of considering these patients as organ donors. With this purpose, we will analyze the ethical problems involved in each step in decision making and on the actions taken by controlled asystole programs, according to the criteria of type III donors of Masstricht conference, 1995, as base to establish an ethical judgment for the process.El trasplante de órganos sólidos constituye el tratamiento de un gran número de enfermedades en fase terminal, mejora globalmente la supervivencia y la calidad de vida de los pacientes sometidos a este tipo de intervención y es considerado como un beneficioso progreso de la medicina para el conjunto de la sociedad. En las últimas décadas, y debido al estancamiento en la cantidad de donaciones y al aumento progresivo de las listas de espera, se han desarrollado diferentes acciones con el objetivo de ampliar el número potencial de donantes, reconsiderando nuevamente aquellos procedentes de parada cardiocirculatoria (donantes en asistolia). El objetivo de este trabajo consiste en reflexionar sobre la legitimidad de compaginar en un mismo proceso dos complejas decisiones éticas: la retirada de las técnicas de soporte vital (RTSV) y limitación del esfuerzo terapéutico (LET), y la posibilidad de considerar a estos pacientes como donantes de órganos. Con este propósito, analizaremos los problemas éticos que se plantean a cada paso en la toma de decisión y en las actuaciones en los programas en asistolia controlada, según el criterio de donantes tipo III adoptado en la conferencia de Maastricht de 1995, como fundamento para establecer un juicio ético de todo el proceso.O transplante de órgãos sólidos constitui o tratamento de um grande número de enfermidades em fase terminal, melhora globalmente a sobrevivência e a qualidade de vida dos pacientes submetidos a este tipo de intervenção e é considerado como um beneficente progresso da medicina para o conjunto da sociedade. Nas últimas décadas, e devido ao estancamento na quantidade de doações e ao aumento progressivo das listas de espera, desenvolveram-se diferentes ações com o objetivo de ampliar o número potencial de doadores, reconsiderando novamente aqueles procedentes de parada cardiocirculatória (doadores em assistolia). O objetivo deste trabalho consiste em refletir sobre a legitimidade de compaginar num mesmo processo duas complexas decisões éticas: a retirada das técnicas de suporte vital (RTSV) e limitação do esforço terapêutico (LET), e a possibilidade de considerar estes pacientes como doadores de órgãos. Com este propósito, analisaremos os problemas éticos que se apresentam a cada passo na tomada de decisão e nas atuações nos programas em assistolia controlada, segundo o critério de doadores tipo III adotado na conferência de Maastricht de 1995, como fundamento para estabelecer um juízo ético de todo o processo

Análise dos aspectos bioéticos nos programas de doação em assistolia controlada

Solid organs trasplant constitutes a treatment for many diseases in terminal phase. Patients subjected to this type of intervention enhance survival and quality of life in general and it is considered a beneficial progress in medicine for society. In the last decades and due to the stagnation of donations and the progressive increase of waiting lists, some actions have been developed with the goal to widen the potential number of donors, reconsidering again those coming from cardiovascular arrest (asystole donors). The aim of this article consists in reflecting on the legitimacy of combining in the same process two complex ethical decisions: the withdrawal of life support techniques (WLST) and the limitation of therapeutic effort (LTE), and the possibility of considering these patients as organ donors. With this purpose, we will analyze the ethical problems involved in each step in decision making and on the actions taken by controlled asystole programs, according to the criteria of type III donors of Masstricht conference, 1995, as base to establish an ethical judgment for the process.El trasplante de órganos sólidos constituye el tratamiento de un gran número de enfermedades en fase terminal, mejora globalmente la supervivencia y la calidad de vida de los pacientes sometidos a este tipo de intervención y es considerado como un beneficioso progreso de la medicina para el conjunto de la sociedad. En las últimas décadas, y debido al estancamiento en la cantidad de donaciones y al aumento progresivo de las listas de espera, se han desarrollado diferentes acciones con el objetivo de ampliar el número potencial de donantes, reconsiderando nuevamente aquellos procedentes de parada cardiocirculatoria (donantes en asistolia). El objetivo de este trabajo consiste en reflexionar sobre la legitimidad de compaginar en un mismo proceso dos complejas decisiones éticas: la retirada de las técnicas de soporte vital (RTSV) y limitación del esfuerzo terapéutico (LET), y la posibilidad de considerar a estos pacientes como donantes de órganos. Con este propósito, analizaremos los problemas éticos que se plantean a cada paso en la toma de decisión y en las actuaciones en los programas en asistolia controlada, según el criterio de donantes tipo III adoptado en la conferencia de Maastricht de 1995, como fundamento para establecer un juicio ético de todo el proceso.O transplante de órgãos sólidos constitui o tratamento de um grande número de enfermidades em fase terminal, melhora globalmente a sobrevivência e a qualidade de vida dos pacientes submetidos a este tipo de intervenção e é considerado como um beneficente progresso da medicina para o conjunto da sociedade. Nas últimas décadas, e devido ao estancamento na quantidade de doações e ao aumento progressivo das listas de espera, desenvolveram-se diferentes ações com o objetivo de ampliar o número potencial de doadores, reconsiderando novamente aqueles procedentes de parada cardiocirculatória (doadores em assistolia). O objetivo deste trabalho consiste em refletir sobre a legitimidade de compaginar num mesmo processo duas complexas decisões éticas: a retirada das técnicas de suporte vital (RTSV) e limitação do esforço terapêutico (LET), e a possibilidade de considerar estes pacientes como doadores de órgãos. Com este propósito, analisaremos os problemas éticos que se apresentam a cada passo na tomada de decisão e nas atuações nos programas em assistolia controlada, segundo o critério de doadores tipo III adotado na conferência de Maastricht de 1995, como fundamento para estabelecer um juízo ético de todo o processo