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Background: Better understanding of host inflammatory changes that precede development of severe COVID-19 could improve delivery of available antiviral and immunomodulatory therapies, and provide insights for the development of new therapies. Method(s): In plasma from individuals with COVID-19, sampled <=10 days from symptom onset from the All-Ireland Infectious Diseases Cohort study, we measured 61 biomarkers, including markers of innate immune and T cell activation, coagulation, tissue repair, lung injury, and immune regulation. We used principal component analysis (PCA) and k-means clustering to derive biomarker clusters, and univariate and multivariate ordinal logistic regression to explore association between cluster membership and maximal disease severity, adjusting for risk factors for severe COVID-19, including age, sex, ethnicity, BMI, hypertension and diabetes. Result(s): From March 2020-April 2021, we included 312 individuals, (median (IQR) age 62 (48-77) years, 7 (4-9) days from symptom onset, 54% male) in the analysis. PCA and clustering derived 4 clusters. Compared to cluster 1, clusters 2-4 were significantly older and of higher BMI but there were no significant differences in sex or ethnicity. Cluster 1 had low levels of inflammation, cluster 2 had higher levels of markers of tissue repair and endothelial activation (EGF, VEGF, PDGF, TGFalpha, serpin E1 and p-selectin). Cluster 3 and 4 were both characterised by higher overall inflammation, but compared to cluster 4, cluster 3 had downregulation of growth factors, markers of endothelial activation, and immune regulation (IL10, PDL1), but higher alveolar epithelial injury markers (RAGE, ST2). In univariate analysis, compared to cluster 1, cluster 3 had the highest odds of severe disease (OR (95% CI) 9.02 (4.62-18.31), followed by cluster 4: 5.59 (2.75-11.72) then cluster 2: 4.5 (2.38-8.81), all p < 0.05). Cluster 3 remained most strongly associated with severe disease in fully adjusted analyses;cluster 3: OR(95% CI) 5.99 (2.69-13.35), cluster 2: 3.14 (1.54-6.42), cluster 4: 3.13 (1.36-7.19), all p< 0.05). Conclusion(s): Distinct early inflammatory profiles predicted maximal disease severity independent of known risk factors for severe COVID-19. A cluster characterised by downregulation of growth factor and endothelial markers and early evidence of alveolar injury was associated with highest risk of developing severe COVID19. Whether this reflects a dysregulated inflammatory response that could improve targeted treatment requires further study. Heatmap of biomarker derived clusters and forest plot of association between clusters and disease severity. A: Heatmap demonstrating differences in biomarkers between clusters B: Forest plot demonstrating odds ratio of specific clusters for progressing to moderate or severe disease (reference Cluster 1), calculated using ordinal logistic regression. Odds ratio (95% CI) presented as unadjusted and fully adjusted (for age, sex, ethnicity, BMI, hypertension, diabetes, immunosuppression, smoking and baseline anticoagulant use). Maximal disease severity graded per the WHO severity scale.
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S44 Table 1Summary of significant medical events, thoracic computed tomography (CT) and pulmonary function tests (PFTs) in ORBCEL-C and placebo groups at 1 year follow upORBCEL-C Placebo Number of patients followed up 20 21 Significant medical events Number of patients with SMEs 6/20 9/21 Total SME events 7 11 Classification Respiratory,thoracic and mediastinal disorders 4 6 Neoplasm - benign, malignant, unspecified 1 0 Infections and infestations 1 1 Cardiac disorders 1 0 Metabolism and nutrition disorders 0 1 Injury, poisoning and procedural complications 0 1 Renal and urinary disorders 0 1 Gastrointestinal disorders 0 1 Thoracic CT Number of CTs available 5 8 Time to CT (Median, IQR) 181 (157–198) 203 (95–233) Evidence of ILD on CT 4 6 PFTs Number of PFTs available 10 8 Time to PFTs (Median, IQR) 184.5 (117.5–292.75) 203.5 (118.25–242.5) FEV1 (Mean, SD) 84.9 (13.6) 80.5 (13.3) FEV1 <80% predicted (n,%) 4/10 (44%) 4/8 (50%) FVC (Mean, SD) 78.4 (13.2) 79.3 (16.5) FVC <80% predicted (n,%) 5/10 (55%) 5/8 (62.5%) FEV1/FVC ratio (Mean, SD, n) 0.88 (0.12) N=8 0.76 (0.05) N=5 FEV1/FVC <0.7 (n,%) 0 (0%) 0 (0%) TLCO (Mean, SD, n) 78.9 (14.8) N=9 61.9 (13.4) N=7 TLCO <80% (n,%) 6/9 (66.7%) 7/7 (100%) ConclusionsOne year follow up supports the safety of ORBCEL-C MSCs in patients with moderate to severe ARDS due to COVID-19. A similar incidence of pulmonary dysfunction is reported in both groups at long term follow up.Please refer to page A?? for declarations of interest related to this .
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Introduction: After more than 50 years of research we are yet to develop an effective treatment for the Acute Respiratory Distress Syndrome (ARDS). This stands in contrast to the advances made in supportive care, a prime example of which is the maturation of Extracorporeal Membrane Oxygenation (ECMO). While technologies such as ECMO 'buy time' for recovery, the identification of a therapy remains crucial to improving outcomes. Recently, mesenchymal stem cells (MSCs) have shown promise as a novel treatment.1 Importantly, cell therapy may represent a means to overcome the hurdles associated with successful pharmacological intervention in ARDS. Little is known about the interaction between cell therapy and ECMO. This is a deficiency, given that those receiving ECMO for ARDS are among the most severely ill and therefore most likely to benefit. This programme of work was designed to close that gap. Objectives: Using a translational pipeline, our objective was to assess the safety and efficacy of MSCs during ECMO for ARDS. Methods: We employed several diverse methods to address our objectives, including an ex-vivo ECMO simulation, complex sheep models of ARDS and ARDS and venovenous ECMO, systematic review methodology, and unsupervised machine learning techniques. Results: In our ex-vivo model, we were the first to demonstrate potential harms associated with MSC therapy during ECMO.2 When 40 × 10∧6 clinical-grade human MSCs (Cynata Therapeutics Ltd., Australia) were added to fresh whole human blood and subjected to extracorporeal circulation using commercial components, oxygenator and pump performance was severely impaired within 4 hours. These experiments also demonstrated benefits associated with MSCs, including trends toward lower inflammatory cytokine concentrations and less neutrophil activation.3 To validate our findings, we sought to test hMSCs in a clinicallyrelevant sheep model. At the outset we undertook a systematic review of existing pre-clinical models of ARDS and ECMO.4 This has since produced an international collaborative effort to characterise pre-clinical models of ECMO across a range of indications. We subsequently described a 'double-hit' model of ARDS which combines oleic acid and intra-tracheal E. coli lipopolysaccharide. Using cluster analysis, we showed that this model shares qualitative similarities with the 'hypo-inflammatory' phenotype identified in clinical cohorts [Millar JE et al. Physiological Reports 2021. In Press]. Finally, in a 24-hour model, combining our novel injury method, VV-ECMO, and best practice ventilatory and supportive care, we performed a controlled trial of intra-tracheal hMSC therapy5 [Editorial: Del Sorbo L, Fan E. AJRCCM 2020]. This study showed that hMSCs reduce histological evidence of lung injury and ameliorate shock. However, hMSC-mediated impairment of oxygenator function was evident again. Conclusion: This work addresses a gap in our understanding of cell therapy in critical illness. The findings are of direct clinical relevance, highlighting the potential harms of cell therapy during extracorporeal circulation. With a recent explosion in the number of registered clinical trials of MSCs for severe COVID-19 in mind, the use of MSCs during ECMO cannot be recommended.
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Introduction: Currently patients with COVID-19 related acute respiratory failure (ARF) may receive respiratory support with conventional oxygen therapy, high-flow nasal oxygen (HFNO) or continuous positive airway pressure (CPAP). A proportion of patients will subsequently require invasive ventilation. However, there is insufficient evidence on the relative effectiveness of different modes of noninvasive respiratory support (NIRS). In the absence of robust evidence to guide clinical decisions, there is likely significant variation in their use in UK practice. The RECOVERY-RS trial sought to address this knowledge gap, aiming to identify the most effective method of non-invasive respiratory support in COVID-19. This survey, conducted whilst RECOVERY-RS was in progress, sought to characterise the current use of NIRS in COVID-19 patients across the UK. Methods: An anonymous, online survey (10 questions) was distributed via national networks and professional societies. Healthcare professionals involved in managing COVID-19 patients were invited to participate with responses collected over two months from September to October 2020. Results: Of 145 respondents, the majority were critical care (60%) or respiratory (27%) clinicians. Prior to the COVID-19 pandemic, most reported having commonly used HFNO (89%) or CPAP (70%) for infection-related ARF. A small minority (3% HFNO vs 9% CPAP) reported no previous experience of their use. In COVID-19 patients suitable for intubation and ventilation, 92% of respondents had used CPAP and 61% HFNO to bridge to or prevent intubation. Conversely, 5% reported they would never use CPAP and 8% would never use HFNO as a bridge to intubation. 68% of clinicians chose CPAP as their personal preferred method of NIRS vs 26% HFNO when treating COVID-19 patients. In patients not suitable for invasive ventilation, CPAP was also more frequently used than HFNO (92% vs 61%). 37% worked in trusts enrolled in the RECOVERY-RS trial and the majority (59%) felt that RECOVERY-RS was an important study, addressing a key unanswered research question. Conclusion: This survey identified that a variety of methods of NIRS are being used for COVID-19 patients in the UK. CPAP predominates as both a ceiling of care treatment and as a bridge to intubation. This appears to represent a change in practice compared to the management of infection-related ARF prior to the COVID-19 pandemic, despite a lack of evidence at that time to suggest superior efficacy of CPAP. The heterogeneous survey results support the need for evidence of the most effective NIRS in COVID-19 in order to deliver optimal and standardised treatment.
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Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and management therefore remains largely supportive. Mesenchymal stromal/stem cells (MSCs) are receiving considerable attention as a cytotherapeutic for viral pneumonia. Several properties of MSCs position them as a promising therapeutic strategy for viral pneumonia-induced lung injury as demonstrated in pre-clinical studies in relevant models. More recently, early phase clinical studies have demonstrated a reassuring safety profile of these cells. These investigations have taken on an added importance and urgency during the COVID-19 pandemic, with multiple trials in progress across the globe. In parallel with clinical translation, strategies are being investigated to enhance the therapeutic potential of these cells in vivo, with different MSC tissue sources, specific cellular products including cell-free options, and strategies to 'licence' or 'pre-activate' these cells, all being explored. This review will assess the therapeutic potential of MSC-based therapies for severe viral pneumonia. It will describe the aetiology and epidemiology of severe viral pneumonia, describe current therapeutic approaches, and examine the data suggesting therapeutic potential of MSCs for severe viral pneumonia in pre-clinical and clinical studies. The challenges and opportunities for MSC-based therapies will then be considered.
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The COVID‐19 pandemic has necessitated a paradigm shift in the way substance misuse services are delivered, with a move from face‐to‐face to remote consultations. This article discusses the challenges substance misuse healthcare providers have faced adapting to these changes and how technological innovations have helped ensure treatments are prescribed or supplied as safely as possible. [ABSTRACT FROM AUTHOR] Copyright of Prescriber is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)