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1.
Trials ; 23(1): 47, 2022 Jan 17.
Article in English | MEDLINE | ID: covidwho-1636360

ABSTRACT

BACKGROUND: The acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient's physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. METHODS: We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. DISCUSSION: Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs' pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic) could change the outcome of mechanically ventilated patients during the course of this and future pandemics. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04115709. Registered on 4 October 2019, version 4.0.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Humans , Lung , Multicenter Studies as Topic , Pandemics , Randomized Controlled Trials as Topic , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/therapy , SARS-CoV-2
2.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295700

ABSTRACT

Background The Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. Methods We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. Discussion Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic), could change the outcome of mechanically ventilated patients during the course of this and future pandemics. Trial registration ClinicalTrials.gov identifier ( NCT number): NCT04115709 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ).

3.
Expert Rev Respir Med ; 15(3): 301-324, 2021 03.
Article in English | MEDLINE | ID: covidwho-978559

ABSTRACT

Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Pandemics , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Sepsis/therapy , COVID-19/epidemiology , Comorbidity , Humans , Respiratory Distress Syndrome/epidemiology , Sepsis/epidemiology
4.
Nature ; 591(7848): 92-98, 2021 03.
Article in English | MEDLINE | ID: covidwho-971937

ABSTRACT

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.


Subject(s)
COVID-19/genetics , COVID-19/physiopathology , Critical Illness , 2',5'-Oligoadenylate Synthetase/genetics , COVID-19/pathology , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 21/genetics , Critical Care , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Drug Repositioning , Female , Genome-Wide Association Study , Humans , Inflammation/genetics , Inflammation/pathology , Inflammation/physiopathology , Lung/pathology , Lung/physiopathology , Lung/virology , Male , Multigene Family/genetics , Receptor, Interferon alpha-beta/genetics , Receptors, CCR2/genetics , TYK2 Kinase/genetics , United Kingdom
5.
Comput Biol Med ; 126: 104030, 2020 11.
Article in English | MEDLINE | ID: covidwho-891965

ABSTRACT

Mechanical ventilation is a lifesaving tool and provides organ support for patients with respiratory failure. However, injurious ventilation due to inappropriate delivery of high tidal volume can initiate or potentiate lung injury. This could lead to acute respiratory distress syndrome, longer duration of mechanical ventilation, ventilator associated conditions and finally increased mortality. In this study, we explore the viability and compare machine learning methods to generate personalized predictive alerts indicating violation of the safe tidal volume per ideal body weight (IBW) threshold that is accepted as the upper limit for lung protective ventilation (LPV), prior to application to patients. We process streams of patient respiratory data recorded per minute from ventilators in an intensive care unit and apply several state-of-the-art time series prediction methods to forecast the behavior of the tidal volume metric per patient, 1 hour ahead. Our results show that boosted regression delivers better predictive accuracy than other methods that we investigated and requires relatively short execution times. Long short-term memory neural networks can deliver similar levels of accuracy but only after much longer periods of data acquisition, further extended by several hours computing time to train the algorithm. Utilizing Artificial Intelligence, we have developed a personalized clinical decision support tool that can predict tidal volume behavior within 10% accuracy and compare alerts recorded from a real world system to highlight that our models would have predicted violations 1 hour ahead and can therefore conclude that the algorithms can provide clinical decision support.


Subject(s)
Artificial Intelligence , Respiration, Artificial , Humans , Intensive Care Units , Lung , Neural Networks, Computer , Tidal Volume
6.
Thorax ; 75(11): 1009-1016, 2020 11.
Article in English | MEDLINE | ID: covidwho-729414

ABSTRACT

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/therapy , Lung Diseases/therapy , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Respiration Disorders/therapy , Algorithms , COVID-19 , Coronavirus Infections/diagnosis , Humans , Lung Diseases/diagnosis , Lung Diseases/virology , Pandemics , Pneumonia, Viral/diagnosis , Respiration Disorders/diagnosis , Respiration Disorders/virology , SARS-CoV-2
7.
Intensive Care Med ; 46(12): 2265-2283, 2020 12.
Article in English | MEDLINE | ID: covidwho-639094

ABSTRACT

ARDS, first described in 1967, is the commonest form of acute severe hypoxemic respiratory failure. Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of lung injury and repair, and advances in supportive care, particularly ventilatory management, there remains no effective pharmacological therapy for this syndrome. Hospital mortality at 40% remains unacceptably high underlining the need to continue to develop and test therapies for this devastating clinical condition. The purpose of the review is to critically appraise the current status of promising emerging pharmacological therapies for patients with ARDS and potential impact of these and other emerging therapies for COVID-19-induced ARDS. We focus on drugs that: (1) modulate the immune response, both via pleiotropic mechanisms and via specific pathway blockade effects, (2) modify epithelial and channel function, (3) target endothelial and vascular dysfunction, (4) have anticoagulant effects, and (5) enhance ARDS resolution. We also critically assess drugs that demonstrate potential in emerging reports from clinical studies in patients with COVID-19-induced ARDS. Several therapies show promise in earlier and later phase clinical testing, while a growing pipeline of therapies is in preclinical testing. The history of unsuccessful clinical trials of promising therapies underlines the challenges to successful translation. Given this, attention has been focused on the potential to identify biologically homogenous subtypes within ARDS, to enable us to target more specific therapies 'precision medicines.' It is hoped that the substantial number of studies globally investigating potential therapies for COVID-19 will lead to the rapid identification of effective therapies to reduce the mortality and morbidity of this devastating form of ARDS.


Subject(s)
COVID-19/drug therapy , Drug Therapy/trends , Respiratory Distress Syndrome/drug therapy , Antioxidants/therapeutic use , Ascorbic Acid/therapeutic use , Citrulline/therapeutic use , Glycoproteins/therapeutic use , Humans , Mesenchymal Stem Cells , Pandemics , Peptides, Cyclic/therapeutic use , Pyridones/therapeutic use , Pyrimidines/therapeutic use , Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors , Receptors, Tumor Necrosis Factor, Type I/therapeutic use , Steroids/therapeutic use , Trypsin Inhibitors/therapeutic use
8.
Int J Infect Dis ; 96: 431-439, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-276112

ABSTRACT

As of May 17th 2020, the novel coronavirus disease 2019 (COVID-19) pandemic has caused 307,395 deaths worldwide, out of 3,917,366 cases reported to the World Health Organization. No specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and/or vaccines are found. In search of effective treatments, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical trials on a range of antiviral drug regimens and repurposed drugs in various combinations. A paradigm shift is underway from the current focus of drug development targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2 and high COVID-19 mortality rates. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for treatment of COVID-19. MSCs should also be trialed for treatment of other circulating WHO priority Blueprint pathogens such as MERS-CoV which causes upto 34% mortality rates. It's about time funding agencies invested more into development MSCs per se, and also for a range of other HDTs, in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 death rates and preventing long-term functional disability in those who survive disease.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Mesenchymal Stem Cell Transplantation , Pneumonia, Viral/therapy , COVID-19 , Clinical Trials as Topic , Consensus , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Humans , Morbidity , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , SARS-CoV-2
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