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1.
JMIR Form Res ; 2022 May 22.
Article in English | MEDLINE | ID: covidwho-1862485

ABSTRACT

BACKGROUND: The COVID-19 pandemic stimulated the availability and use of population and individual health data to optimise tracking and analysis of the spread of the virus. Many health care services have had to rapidly digitalise in order to maintain the continuity of care provision. Data collection and dissemination have provided critical support to defence against the spread of the virus since the beginning of the pandemic; however, little is known about public perceptions of and attitudes towards the use, privacy, and security of data. OBJECTIVE: The goal of this study is to better understand people's willingness to share data in the context of COVID-19. METHODS: A web-based survey was conducted, looking at individuals' use of and attitudes toward health data for those 18 years and older, and in particular, with a reported diagnosis of a chronic health condition placing them most 'at risk' of severe COVID-19. RESULTS: In total, 4,764 individuals responded to this web-based survey. 4,674 (98.1%) reported a medical diagnosis of at least 1 health condition (average 4 per person), with type 2 diabetes (2,974, 62.7%), hypertension (2,147, 45.2%) and type 1 diabetes (1,299, 27.4%) being most prominent in our sample. In general, more people are comfortable with sharing anonymised data than personally identifiable data. People reported feeling comfortable sharing data that were able to benefit others; 66% (3,121 respondents) would share personal identifiable data if its primary purpose was deemed beneficial for the health of others. Almost two-thirds (3,026; 63.9%) would consent to sharing personal, sensitive health data with government or health authority organisations. Conversely, over a quarter of respondents (1,297, 27.8%) stated they did not trust any organisation to protect their data and 54% (2,528) reported concerns about the implications of sharing personal information. Almost two-thirds (3,054, 65%) of respondents were concerned around the provisions of appropriate legislation that seeks to prevent data misuse and hold organisations accountable in the case of data misuse. CONCLUSIONS: Although our survey focused mainly on the views of those living with chronic health conditions, the results indicate that data sensitivity is highly contextual. More people are more comfortable with sharing anonymised data than personally identifiable data. Willingness to share data also depended on the receiving body, highlighting trust as a key theme, in particular who may have access to shared personal health data and how they may be used in the future. The nascency of legal guidance in this area suggests a need for humanitarian guidelines for data responsibility during disaster relief operations such as pandemics, and for involving the public in their development.

2.
BMJ Open ; 11(10): e055435, 2021 10 22.
Article in English | MEDLINE | ID: covidwho-1480255

ABSTRACT

OBJECTIVES: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009-2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples. OUTCOME MEASURES: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality. RESULTS: Vitamin D insufficiency (total 25(OH)D 25-50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators. CONCLUSIONS: Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza, Human , Vitamin D Deficiency , Critical Illness , Cross-Sectional Studies , Humans , Influenza, Human/complications , Influenza, Human/epidemiology , Pandemics , SARS-CoV-2 , Survivors , Vitamin D , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology
3.
JMIR Form Res ; 5(10): e31273, 2021 Oct 06.
Article in English | MEDLINE | ID: covidwho-1456217

ABSTRACT

BACKGROUND: The COVID-19 pandemic is taking a toll on people's mental health, particularly as people are advised to adhere to social distancing, self-isolation measures, and government-imposed national lockdowns. Digital health technologies have an important role to play in keeping people connected and in supporting their mental health and well-being. Even before the COVID-19 pandemic, mental health and social services were already strained. OBJECTIVE: Our objective was to evaluate the 12-week outcomes of the digitally delivered Gro Health intervention, a holistic digital behavior change app designed for self-management of mental well-being, sleep, activity, and nutrition. METHODS: The study used a quasi-experimental research design consisting of an open-label, single-arm, pre-post intervention engagement using a convenience sample. Adults who had joined the Gro Health app (intervention) and had a complete baseline dataset (ie, 7-item Generalized Anxiety Disorder scale, Perceived Stress Scale, and 9-item Patient Health Questionnaire) were followed up at 12 weeks (n=273), including 33 (12.1%) app users who reported a positive COVID-19 diagnosis during the study period. User engagement with the Gro Health platform was tracked by measuring total minutes of app engagement. Paired t tests were used to compare pre-post intervention scores. Linear regression analysis was performed to assess the relationship between minutes of active engagement with the Gro Health app and changes in scores across the different mental health measures. RESULTS: Of the 347 study participants, 273 (78.67%) completed both the baseline and follow-up surveys. Changes in scores for anxiety, perceived stress, and depression were predicted by app engagement, with the strongest effect observed for changes in perceived stress score (F1,271=251.397; R2=0.479; P<.001). CONCLUSIONS: A digital behavior change platform that provides remote mental well-being support can be effective in managing depression, anxiety, and perceived stress during times of crisis such as the current COVID-19 pandemic. The outcomes of this study may also support the implementation of remote digital health apps supporting behavior change and providing support for low levels of mental health within the community.

4.
JMIR Form Res ; 5(9): e29110, 2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1443967

ABSTRACT

BACKGROUND: Obesity underlies much chronic disease. Digitalization of obesity management provides an opportunity to innovate our traditional model of health care delivery within this setting, and to transform its scalability potentially to the population level. OBJECTIVE: The objective was to assess the feasibility and effectiveness of the Low Carb Program app for weight loss, applied within our hospital-based (tier 3) obesity service. Due to the disrupting effects of the COVID-19 pandemic on our obesity service, we compared the clinical outcomes from the Low Carb Program app applied in the context of remote patient appointments over the telephone with the prepandemic traditional standard of care. METHODS: We invited patients who attended our hospital-based obesity service to engage with the Low Carb Program smartphone app. We combined this approach with remote delivery (over the telephone) of obesity management from medical and psychology members of our obesity team during the COVID-19 pandemic. Outcome variables included changes in body weight and changes in HbA1c as a marker of glycemic control. We compared data from the Low Carb Program group with a retrospective control group (n=126) that had received traditional face-to-face obesity management from our team without concomitant use of the Low Carb Program app in the pre-COVID-19 era. T test comparisons were employed, with P<.05 considered significant. RESULTS: The mean weight of participants (n=105) was 130.2 kg, with 59% (n=62) females and a mean age of 48.8 years. Most participants (90/105, 86%) completed the Low Carb Program app registration process and engaged with the Low Carb Program app program; at follow-up, most participants (88/105, 84%) had actively engaged with the Low Carb Program app within the prior 30 days. The majority of participants (58/105, 55%) self-reported outcomes within the app. Mean duration of clinical follow-up for recruited participants who received the app was 7.4 months. Paired data were available for 48 participants for body weight and 41 participants for HbA1c. Paired sample t test analysis revealed a statistically significant mean loss of body weight of 2.7 kg (P=.001) and improvement in HbA1c of 3.3 mmol/mol (P=.01). The mean weight of control group patients (n=126) was 137.1 kg, with 74% (93/126) females and a mean age of 44.4 years. The mean follow-up for this group was 6 months. Data comparisons between the app user group and the pre-COVID-19 retrospective control group revealed equivalence for loss of body weight and change in HbA1c between the two groups. CONCLUSIONS: We provide evidence to support the feasibility of implementing the Low Carb Program app combined with remote management; this is the first proof of concept for digitalized management within a hospital-based (tier 3) obesity service. We demonstrate the potential clinical efficacy of the approach in terms of improvements in body weight and glycemic control.

5.
JMIR Form Res ; 5(10): e31273, 2021 Oct 06.
Article in English | MEDLINE | ID: covidwho-1378177

ABSTRACT

BACKGROUND: The COVID-19 pandemic is taking a toll on people's mental health, particularly as people are advised to adhere to social distancing, self-isolation measures, and government-imposed national lockdowns. Digital health technologies have an important role to play in keeping people connected and in supporting their mental health and well-being. Even before the COVID-19 pandemic, mental health and social services were already strained. OBJECTIVE: Our objective was to evaluate the 12-week outcomes of the digitally delivered Gro Health intervention, a holistic digital behavior change app designed for self-management of mental well-being, sleep, activity, and nutrition. METHODS: The study used a quasi-experimental research design consisting of an open-label, single-arm, pre-post intervention engagement using a convenience sample. Adults who had joined the Gro Health app (intervention) and had a complete baseline dataset (ie, 7-item Generalized Anxiety Disorder scale, Perceived Stress Scale, and 9-item Patient Health Questionnaire) were followed up at 12 weeks (n=273), including 33 (12.1%) app users who reported a positive COVID-19 diagnosis during the study period. User engagement with the Gro Health platform was tracked by measuring total minutes of app engagement. Paired t tests were used to compare pre-post intervention scores. Linear regression analysis was performed to assess the relationship between minutes of active engagement with the Gro Health app and changes in scores across the different mental health measures. RESULTS: Of the 347 study participants, 273 (78.67%) completed both the baseline and follow-up surveys. Changes in scores for anxiety, perceived stress, and depression were predicted by app engagement, with the strongest effect observed for changes in perceived stress score (F1,271=251.397; R2=0.479; P<.001). CONCLUSIONS: A digital behavior change platform that provides remote mental well-being support can be effective in managing depression, anxiety, and perceived stress during times of crisis such as the current COVID-19 pandemic. The outcomes of this study may also support the implementation of remote digital health apps supporting behavior change and providing support for low levels of mental health within the community.

6.
Clin Trials ; 18(5): 615-621, 2021 10.
Article in English | MEDLINE | ID: covidwho-1280563

ABSTRACT

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19 , Clinical Trials as Topic/standards , Pandemics , COVID-19/prevention & control , Clinical Trials as Topic/organization & administration , Humans , Pandemics/prevention & control , State Medicine , United Kingdom/epidemiology
7.
Thorax ; 77(2): 129-135, 2022 02.
Article in English | MEDLINE | ID: covidwho-1247403

ABSTRACT

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , COVID-19 Testing , Humans , Pandemics , Research , Respiration, Artificial , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , United Kingdom/epidemiology
8.
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
9.
Intensive Care Med ; 46(12): 2157-2167, 2020 12.
Article in English | MEDLINE | ID: covidwho-911887

ABSTRACT

Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards - treatments that have a solid evidence base and are well established as targets for usual care - and also evolving standards - treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.


Subject(s)
Respiratory Distress Syndrome/therapy , Standard of Care/trends , COVID-19/complications , COVID-19/physiopathology , Fluid Therapy/methods , Fluid Therapy/trends , Humans , Prone Position/physiology , Respiratory Distress Syndrome/physiopathology
10.
ProQuest Central; 2020.
Preprint in English | ProQuest Central | ID: ppcovidwho-2094

ABSTRACT

Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus (S. aureus). We sought to investigate whether humans using ACEwere at increased risk of S. aureus infection, comparing them to users of Angiotensin IReceptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEor AR(as an active comparator drug). We regarded prescription of ACEor ARas time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEto periods with ARprescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEversus AR(Gram-negative sepsis, hifracture and herpes zoster) and one that we did (dry cough). Results: We identified 445,341 new users of ACE(mean age 64.0±14.0, male 51.7%) and 41,824 new users of AR(mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEvs. ARB) was 1.18 (95% C1.10–1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes;rates of Gram-negative sepsis, hifracture and dry cough were also increased during periods of time treated with ACEcompared to ARwhile herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARusers appear an ideal control for analyses of ACEeffects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection.

11.
Trials ; 21(1): 691, 2020 Jul 31.
Article in English | MEDLINE | ID: covidwho-699024

ABSTRACT

OBJECTIVES: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95 , registered 28th April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , Antiviral Agents/adverse effects , Benzamides/therapeutic use , COVID-19 , Hospitalization , Humans , Pandemics , Pyrazines/therapeutic use , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Standard of Care
12.
Lancet Respir Med ; 8(8): 822-830, 2020 08.
Article in English | MEDLINE | ID: covidwho-599200

ABSTRACT

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/prevention & control , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Disease Progression , Humans , Immunomodulation , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Respiratory Distress Syndrome/virology , SARS-CoV-2
13.
Wellcome Open Res ; 5: 77, 2020.
Article in English | MEDLINE | ID: covidwho-596584

ABSTRACT

Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus ( S. aureus). We sought to investigate whether humans using ACEI were at increased risk of S. aureus infection, comparing them to users of Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEI to periods with ARB prescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis, hip fracture and herpes zoster) and one that we did (dry cough). Results: We identified 445,341 new users of ACEI (mean age 64.0±14.0, male 51.7%) and 41,824 new users of ARB (mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEI vs. ARB) was 1.18 (95% CI 1.10-1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARB users appear an ideal control for analyses of ACEI effects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection.

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