Critically-ill COVID-19 Patients Research Articles

The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Background COVID-19 counts 46 million people infected and killed more than 1.2 million. Hypoxaemia is one of the main clinical manifestations, especially in severe cases. HIF1α is a master transcription factor involved in the cellular response to oxygen levels. The immunopathogenesis of this severe form of COVID-19 is poorly understood. Methods We performed scRNAseq from leukocytes from five critically ill COVID-19 patients and characterized the expression of hypoxia-inducible factor1α and its transcriptionally regulated genes. Also performed metanalysis from the publicly available RNAseq data from COVID-19 bronchoalveolar cells. Results Critically-ill COVID-19 patients show a shift towards an immature myeloid profile in peripheral blood cells, including band neutrophils, immature monocytes, metamyelocytes, monocyte-macrophages, monocytoid precursors, and promyelocytes-myelocytes, together with mature monocytes and segmented neutrophils. May be the result of a physiological response known as emergency myelopoiesis. These cellular subsets and bronchoalveolar cells express HIF1α and their transcriptional targets related to inflammation (CXCL8, CXCR1, CXCR2, and CXCR4); virus sensing, (TLR2 and TLR4); and metabolism (SLC2A3, PFKFB3, PGK1, GAPDH and SOD2). Conclusions The up-regulation and participation of HIF1α in events such as inflammation, immunometabolism, and TLR make it a potential molecular marker for COVID-19 severity and, interestingly, could represent a potential target for molecular therapy. Key messages Critically ill COVID-19 patients show emergency myelopoiesis. HIF1α and its transcriptionally regulated genes are expressed in immature myeloid cells which could serve as molecular targets. HIF1α and its transcriptionally regulated genes is also expressed in lung cells from critically ill COVID-19 patients which may partially explain the hypoxia related events.

Nurse adaptability: Implementing clinical trials in the midst of a pandemic

Working in Manhattan, the center of the nations’ outbreak of the novel coronavirus-19 virus truly demonstrated how adaptable nurses are. During this time, multiple clinical research trials began at our academic medical center, NYU Langone Health, as researchers attempted to learn what medical interventions worked best to treat critically-ill COVID-19 patients. In designing and implementing these trials, the researchers had little familiarity with the workings of inpatient hospital units. They did not understand how nursing staff provided care to patients on these units. Likewise, many bedside nurses had never assisted researchers in conducting clinical research on their patients. Therefore, a nursing operations team (NOT) was needed to assist both the research teams and the inpatient nurses. NOT met with the researchers to review proposed clinical research trials and determine how nursing staff would be utilized to complete the required research tasks such as specimen and data collection, study intervention administration, and patient monitoring. Toward that end, NOT developed education and training materials on all of the research trials that were implemented at NYU Langone Health for our bedside nurses. This education included tip sheets, safety huddle rounds with the involved units, and “just in time” education to any nurse whose patient was urgently enrolled in a trial. In this way, NOT helped bedside nurses quickly adapt to their role in assisting the research team conduct their studies on our COVID positive inpatients.

Predictors of Venous Thromboembolism in Severe COVID-19 Patients: A Retrospective Multi-Center Cohort Study

Background: Diagnosis of venous thromboembolism (VTE) in severe COVID-19 patients is challenging. D-dimer was reported to be the strongest independent factor that can predict VTE.Methods: This multicenter retrospective study describes the factors that might predict VTE diagnosis in 219 critically-ill COVID-19 patients. The primary outcome of interest was D-dimer cutoff values to predict VTE diagnosis in anticoagulation vs. no-anticoagulation cohorts.Findings: Of all included patients, 57 (26%) patients were diagnosed with VTE. At baseline, patients in the VTE cohort were more likely to be male and to age between 50-70 years. The optimum cutoff value for D-dimer to predict VTE in all patients was 2000 ng/ml (sensitivity of 86·0% and NPV of 91·3%). Patients who didn’t receive thrombo-prophylaxis, D-dimer value of less than 500 ng/ml can be used to rule-out DVT (sensitivity of 100·0%, NPV of 100·0%, and negative LR of 0). Patients who received thrombo-prophylaxis, D-dimer value of less than 1000 ng/ml can be used to rule-out DVT (sensitivity of 94·4%, NPV of 93·9%, and negative LR of 0·2). A total of 36 (16%) deaths occurred during the follow-up period. Elevated D-dimer (>2000 mg/ml, OR 1·7 [0·8-3·8]) was not associated with an increased risk of death. The use of intensified prophylactic anticoagulation was not significantly associated with a better survival outcome (OR 0·801, CI:0·67-1·748).Interpretation: In patients with severe COVID-19, D-dimer levels can be used to predict and rule-out VTE. The use of intensified prophylactic anticoagulation was not associated with better survival outcomes; this finding requires validation by randomized clinical trials.Funding Statement: This study was not funded by any source.Declaration of Interests: The authors declare that they have no conflict of interest.Ethics Approval Statement: This study was approved by the institutional review board of Cleveland Clinic.

Multi-Organ System Outcomes and Predictors of Mortality in Critically Ill Patients with COVID-19

Background: We sought to describe the epidemiology, presentation, multi-system outcomes, and predictors of mortality of the critically-ill COVID-19 patients

Viral sepsis is a complication in patients with Novel Corona Virus Disease (COVID-19)

BackgroundUntil June 23th 2020, 9,195,635 laboratory-confirmed cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been reported worldwide, including 473,127 deaths. Bacterial infection is the main cause of sepsis, however, sepsis caused by virus is often ignored. Increased awareness, early recognition of viral sepsis, rapid administration of appropriate antiviral drugs, and urgent treatment can significantly reduce deaths of viral sepsis. ObjectivesGiven the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. MethodsHere we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. ResultsWe analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. ConclusionsTherefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS.Given the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. Here we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. We analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. Therefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS.

Monocyte-Driven Atypical Cytokine Storm and Aberrant Neutrophil Activation as Key Mediators of COVID19 Disease Severity

The host immune response in symptomatic COVID-19 patients seems ineffective in clearing SARS-CoV-2, yet excessive in causing local tissue damage and hypercytokinemia. To elucidate the immunopathology underlying COVID-19 severity, cytokine profiling was performed in mild-moderate and critically-ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, but was increased in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels followed by deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that both a quantitative and qualitative reduction in T-lymphocytes correlate with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presentation and co-stimulatory molecules was reduced in critical disease, while also neutrophils contributed to disease severity and local tissue damage by amplifying hypercytokinemia and neutrophil extracellular trap formation. We suggest a monocyte-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.Funding: This work was funded by KU Leuven (internal fund and grant C14/17/084 and C16/17/010), VIB (Grand Challenge project), UZ Leuven (KOOR project), FWO grant I007418N, the Rega Foundation (research expert fellowship to G.M.) and ‘het Leuvens Kankerinstituut’. E.D. is a postdoctoral research fellow of the Research Foundation – Flanders (FWO), Belgium (grant number 12X9420N). J.G. holds a postdoctoral research fellowship granted by the clinical research and education council of the University Hospitals Leuven. Y.S. received funding from the Flemish Government (AI Research Program). L.V. is supported by an FWO PhD fellowship (grant number 11E9819N). P.V.M. is supported by an FWO PhD fellowship (grant number 1S66020N). S.V.G. is an ISAC Marylou Ingram Scholar and supported by an FWO postdoctoral research grant (Research Foundation – Flanders). E.W. is supported by Stichting tegen Kanker (Mandate for basic & clinical oncology research). J.W. is supported by an FWO Fundamental Clinical Mandate (1833317N). Conflict of Interest: The authors declare no competing interests.Ethical Approval: All study procedures were approved by the Ethics Committee of the University Hospitals Leuven. Informed consent was obtained from all individuals or their legal guardians.

Clinical ethics recommendations for the allocation of intensive care treatments, in exceptional, resource-limited circumstances.

On February 21st, 2020 the first case of severe acute respiratory syndrome due to the coronavirus 2 (SARS-CoV-2) causing the CoViD-19 disease, was identified in Italy. In the following days, despite the restrictive public health measures aimed to avoid the infection's spread, the number of cases increased. As of March 8th, 2020, Italy is the 2nd most affected country in the world. As of March 6th, 2020, the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) published operational recommendations and ethical considerations to support the clinicians involved in the care of critically-ill CoViD-19 patients, in regard a probable scenario where an imbalance between supply and demand of ICU beds, is put in place by a steadily rising number of these patients.