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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314876

ABSTRACT

Background: Acute Respiratory Distress Syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal Stem Cells (MSC) are potent immunomodulatory cells. The aim of this study was to determine safety and explore efficacy of Umbilical Cord (UC)-MSC infusions in COVID-19 ARDS.Methods: A double-blind, phase 1/2a, randomized, controlled trial was performed in subjects with ARDS secondary to COVID-19, at a single institution in Miami, Florida, USA. Randomization and stratification by ARDS severity was used to foster balance among groups. Participants received two intravenous infusions of 100x106 UC-MSC, or vehicle, at day 0 and 3. The primary endpoint was safety, defined by occurrence of pre-specified infusion associated adverse events, along with adverse events during 28 day follow-up. All subjects were analyzed under an intention to treat design. Exploratory efficacy endpoints included survival at 28 days and time to recovery.Findings: 24 subjects (12 per group) were recruited between April 25 and July 21 2020. At 28 days post last infusion, patient survival was 91% and 42% in the UC-MSC and Control groups, respectively (p=0.015). No serious adverse events (SAEs) were observed related to UC-MSC infusions. There was no observed difference in number of subjects experiencing infusion-associated adverse events. Treatment unrelated SAEs were reported in 2 and 8 patients in the UC-MSC and Control groups, respectively (p=0.04). UC-MSC treatment was associated with increased SAE-free survival (p=0.008) and decreased time to recovery (p=0.03) compared to controls.Interpretation: UC-MSC infusions in COVID-19 subjects with ARDS were safe and associated with fewer SAEs, compared to control. Further, exploratory efficacy analyses provide preliminary evidence of reduction in mortality and time to recovery. Notwithstanding sample size limitations of this trial, the observed findings strongly support further investigation in a larger trial designed to estimate and test for efficacy.Trial Registration: (ClinicalTrials.gov NCT04355728).Funding Statement: The trial was funded by the Barilla Group and Family, The Cure Alliance, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, the North America’s Building Trades Unions, and the Diabetes Research Institute Foundation. This publication was supported by the Clinical Translational Research Site Grants Number UL1TR000460 and UL1TR002736 from the National Center for Advancing Translational Sciences (NCATS).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: Ethics Committee Approval by the regulatory and institutional review boards were obtained by the Western Institutional Review Board (WIRB) and UM Human Subject Research Office/Institutional Review Board, in accordance with local institutional requirements.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-306481

ABSTRACT

The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), or Covid-19, burst into a pandemic in the beginning of 2020. An unprecedented worldwide effort involving academic institutions, regulatory agencies and industry is facing the challenges imposed by the rapidly spreading disease. Emergency use authorization for vaccines were granted in the beginning of December 2020 in Europe and nine days later in the United States. The urge for vaccination started a race, forcing governs and health care agencies to take decisions on the fly regarding the vaccination strategy and logistics. So far, the vaccination strategies and non-pharmaceutical interventions, such as social distancing and the use of face masks, are the only efficient actions to stop the pandemic. In this context, it is of fundamental importance to understand the dynamical behavior of the Covid-19 spread along with possible vaccination strategies. In this work a Susceptible - Infected - Removed - Sick with vaccination (SIRSi-Vaccine) model is proposed. In addtion, the SIRSi-Vaccine model also accounts for unreported, or asymptomatic, cases and the possibility of temporary immunity, either after infection or vaccination. Disease free and endemic equilibrium points existence conditions are determined in the (! ? ?) vaccine-effort and social distancing parameter space. The model is adjusted to the data from São Paulo, Santos and Campinas, three major cities in the State of São Paulo, Brazil.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-306480

ABSTRACT

The outbreak of Covid-19 led the world to an unprecedent health and economical crisis. In an attempt to responde to this emergency researchers worldwide are intensively studying the Covid-19 pandemic dynamics. In this work, a SIRSi compartmental model is proposed, which is a modification of the known classical SIR model. The proposed SIRSi model considers differences in the immunization within a population, and the possibility of unreported or asymptomatic cases. The model is adjusted to three major cities of São Paulo State, in Brazil, namely, São Paulo, Santos and Campinas, providing estimates on the duration and peaks of the outbreak.

4.
Stem Cells Transl Med ; 10(5): 660-673, 2021 05.
Article in English | MEDLINE | ID: covidwho-1008163

ABSTRACT

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods , Cytokines/blood , Double-Blind Method , Female , Humans , Male , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells , Middle Aged , SARS-CoV-2/drug effects , Severity of Illness Index , Treatment Outcome , Umbilical Cord/cytology
5.
Chaos Solitons Fractals ; 142: 110388, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-893669

ABSTRACT

The coronavirus disease 2019 (Covid-19) outbreak led the world to an unprecedented health and economic crisis. In an attempt to respond to this emergency, researchers worldwide are intensively studying the dynamics of the Covid-19 pandemic. In this study, a Susceptible - Infected - Removed - Sick (SIRSi) compartmental model is proposed, which is a modification of the classical Susceptible - Infected - Removed (SIR) model. The proposed model considers the possibility of unreported or asymptomatic cases, and differences in the immunity within a population, i.e., the possibility that the acquired immunity may be temporary, which occurs when adopting one of the parameters ( γ ) other than zero. Local asymptotic stability and endemic equilibrium conditions are proved for the proposed model. The model is adjusted to the data from three major cities of the state of São Paulo in Brazil, namely, São Paulo, Santos, and Campinas, providing estimations of duration and peaks related to the disease propagation. This study reveals that temporary immunity favors a second wave of infection and it depends on the time interval for a recovered person to be susceptible again. It also indicates the possibility that a greater number of patients would get infected with decreased time for reinfection.

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