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Trials ; 22(1): 595, 2021 Sep 06.
Article in English | MEDLINE | ID: covidwho-1398873


BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

COVID-19 , Diabetes Mellitus, Type 2 , Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cells , Noma , Adipose Tissue , Animals , Clinical Trials, Phase II as Topic , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/therapy , Double-Blind Method , Humans , Ischemia/diagnosis , Ischemia/therapy , Multicenter Studies as Topic , Quality of Life , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
Blood ; 136(Supplement 1):31-32, 2020.
Article in English | PMC | ID: covidwho-1339067


Background: Clinical and analytical data on patients suffering from coronavirus disease-2019 (COVID-19) indicate that endothelial damage plays a key role in the pathophysiology of the disease and is responsible for the pulmonary complications and the thrombotic microangiopathy affecting multiple organs, which contribute directly to mortality (Ackerman et al. N Engl J Med 2020). Detection of biomarkers of endothelial injury in circulating blood may provide critical diagnostic and prognostic information on the disease course (Goshua et al. Lancet Haematology 2020). Endothelial injury is also a cornerstone of pathobiology in other septic and potentially life-threatening inflammatory syndromes.Objectives: To identify circulating markers of endothelial damage in COVID-19 patients, and compare their levels with those observed in other septic syndromes.Methods: Plasma samples from non-critically ill patients with confirmed COVID-19 pneumonia (positive nasopharyngeal swab and confirmatory radiological chest imaging) requiring admission (n=42) were collected during the first 36h of hospitalization. Endothelial damage was evaluated by measuring in plasma: i) markers of endothelial function and activation (sVCAM-1, VWF, ADAMTS-13 activity, Protein C and α2-antiplasmin as a marker of fibrinolysis);ii) heparan sulfate (HS) levels, as indicators of endothelial glycocalyx degradation and loss of endothelial barrier function;and iii) C5b9 deposits on endothelial cells in culture, and soluble C5b9 (sC5b9) levels, to measure complement activation. Circulating dsDNA was analyzed as an indicator of the presence of neutrophil extracellular traps (NETs). ELISA tests were used for sVCAM-1, Protein C, HS, and sC5b9 levels. ADAMTS-13 activity was evaluated by FRETS. VWF, Protein C, and α2-antiplasmin were measured at the Atellica COAG 360 (Siemens Healthineers). C5b9 deposits were assessed by immunofluorescence and dsDNA levels by Quant-iT PicoGreen assay kit. Results were compared with those obtained in healthy donors (controls, n=45), and patients with non-infectious systemic inflammatory response syndrome (NI-SIRS, n=8) and septic shock (SS, n=8).Results: Levels of sVCAM-1 were significantly higher in COVID-19 patients vs. controls, NI-SIRS and SS (159±12 vs. 79±4, 57±8 and 80±10 ng/mL, respectively, p<0.005) (Mean±SDM). VWF was elevated in COVID-19 patients vs. controls (240±26 vs. 96±5%, p<0.001), with similar values in NI-SIRS (271±40%), and significantly reduced vs. SS (476±43%, p<0.001). HS levels in COVID-19 patients were twice those detected in controls (1669±174 vs. 839±36 ng/mL, p=0.001), but they did not differ from those in NI-SIRS (1372±368 ng/mL), and were significantly lower than in SS (3677±880 ng/mL, p<0.001 vs COVID-19). Regarding complement activation, deposits of C5b9 on endothelial cells were significantly increased vs. controls (2-fold, p<0.01), with no notable differences vs. NI-SIRS (3±1-fold) and significantly lower than in SS (8±2-fold, p<0.001). Remarkably, sC5b9 levels were much more elevated in COVID-19 patients (1064±120 vs. 204±11 ng/mL, p<0.001), and no significant differences were observed vs. NI-SIRS (902±160 ng/mL) or SS (958±180 ng/mL). Also of note, presence of NETs was significantly elevated in the plasma of COVID-19 patients vs. controls (16±1.3 vs. 2±0.3 ng/ml, p<0.001), but similar to NI-SIRS (19±5 ng/mL) and clearly inferior to SS (33±6 ng/mL, p<0.001) (Figure). Importantly and in contrast, ADAMTS-13 activity, Protein C, and α2-antiplasmin values were within the normal range in COVID-19 patients.Conclusions: Our data clearly demonstrate the presence of endothelial stress products in the circulating blood of non-critically ill COVID-19 patients. These biomarkers of endothelial injury are suggestive indicators of different aspects of the disease: specifically, release of acute phase reactants, degradation of the endothelial cell glycocalyx, and activation of the complement system. Furthermore, this profile of biomarkers in COVID-19 appears spec fic, with a differential behavior in comparison with septic shock, in which endothelial damage is also known to be critical. Additional studies are needed to validate these biomarkers as diagnostic and prognostic tools of the endothelial complications in COVID-19 patients, both in early disease and later, as well as supporting specific forms of therapeutic intervention.Figure

Blood ; 136(Supplement 1):5-6, 2020.
Article in English | PMC | ID: covidwho-1339066


INTRODUCTIONCoronavirus disease 2019 (COVID-19) caused by SARS-CoV2 virus is thought to be more severe in patients with prior hematological diseases. There is evidence suggesting that hematological patients are particularly vulnerable and have a higher risk of developing severe events, with higher mortality rate than general population. However, the available data are limited, and prognostic factors at admission still remain unclear. With this background, our aims were to analyze the impact of hematological diseases and their therapy on the COVID-19 severity and to identify clinical and biological risk factors to predict the outcome in these patients.METHODSWe carried out a multicenter retrospective observational study with data collection from 19 Spanish centers. A total of 491 patients with hematological diseases who developed COVID-19 (HEMATOCOVID patients) from March 8th to June 9th were included in the study. Clinical and biological data were collected at the time of emergency room assistance or hospital admission. For statistical analysis, chi-square test and Mann-Whitney U-test were used to identify differences between groups. The effects of multiple predictor variables on COVID-19 outcomes were assessed by logistic binary regression.RESULTSThe geographic distribution of the studied HEMATOCOVID patients was similar to the national geographic spread of the COVID-19 (Figure 1). Most patients (94,3%) were confirmed cases of COVID-19 with a positive result on SARS-CoV2 RT-PCR on a nasopharyngeal swab or serologic testing, and 15% were nosocomial infections. The mean age was 71 years with 57% males, and 70% had at least one associated comorbidity. The most frequent hematological diseases among COVID-19 patients were Lymphoid Malignancies (53,8%), and 51,7% of patients were on active treatment. Most common symptoms were fever (59%), cough (54%) and dyspnea (46%), with associated pneumonia in 70% of cases. Hospital admission was required in 89% of patients and 6,3% were admitted to intensive care units.Mortality rate was about 36%. Non-survival patients were older and had a higher Charlson comorbidity index and ECOG performance status. Furthermore, patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), and those with an active or progressive hematological disease at the diagnosis of COVID-19 had higher mortality. Patients who had undergone hematopoietic stem cell transplantation (autologous, allogeneic, and both) had better outcomes. Other factors such as low lymphocyte and platelets counts, or high lactate dehydrogenase (LDH), C-reactive protein (CRP) and procalcitonin values were also associated with poorer outcomes (Table 1). In addition, COVID-19 therapy had no impact on survival, except for corticosteroids, that correlated with a negative impact (p <0,001) probably because they were not administrated to patients with less severe COVID-19. Multivariate regression analysis showed the following risk factors for death: age >70 years, ECOG ≥2, absolute lymphocyte count ≤0.6·109/L, platelet count ≤40·109/L, high LDH (higher than upper normal limit) and CRP >11 mg/dL (Table 2).CONCLUSIONSSARS-CoV2 infection causes more severe disease and higher mortality rates in hematological patients, especially those with AML/MDS or active/progression status disease. In addition, advanced age, co-morbidities, poor performance status, low lymphocyte and platelet counts and high LDH and CRP at admission are associated with poorer survival. This worse disease evolution could be explained by the immunosuppression state induced by underlying disease and treatments received. These particular features should be taken into account for a population that is highly exposed to SARS-CoV2 contagion due to high number of hospital visits for treatment.