GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background ‘Long COVID' describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. Methods Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. Findings Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47;P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events;none were serious, or led to treatment discontinuation. Interpretation Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. Funding Axcella Therapeutics.

STIMULATE-ICP-Delphi (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways Delphi): Study protocol.

INTRODUCTION: As mortality rates from COVID-19 disease fall, the high prevalence of long-term sequelae (Long COVID) is becoming increasingly widespread, challenging healthcare systems globally. Traditional pathways of care for Long Term Conditions (LTCs) have tended to be managed by disease-specific specialties, an approach that has been ineffective in delivering care for patients with multi-morbidity. The multi-system nature of Long COVID and its impact on physical and psychological health demands a more effective model of holistic, integrated care. The evolution of integrated care systems (ICSs) in the UK presents an important opportunity to explore areas of mutual benefit to LTC, multi-morbidity and Long COVID care. There may be benefits in comparing and contrasting ICPs for Long COVID with ICPs for other LTCs. METHODS AND ANALYSIS: This study aims to evaluate health services requirements for ICPs for Long COVID and their applicability to other LTCs including multi-morbidity and the overlap with medically not yet explained symptoms (MNYES). The study will follow a Delphi design and involve an expert panel of stakeholders including people with lived experience, as well as clinicians with expertise in Long COVID and other LTCs. Study processes will include expert panel and moderator panel meetings, surveys, and interviews. The Delphi process is part of the overall STIMULATE-ICP programme, aimed at improving integrated care for people with Long COVID. ETHICS AND DISSEMINATION: Ethical approval for this Delphi study has been obtained (Research Governance Board of the University of York) as have approvals for the other STIMULATE-ICP studies. Study outcomes are likely to inform policy for ICPs across LTCs. Results will be disseminated through scientific publication, conference presentation and communications with patients and stakeholders involved in care of other LTCs and Long COVID. REGISTRATION: Researchregistry: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/6246bfeeeaaed6001f08dadc/.

STIMULATE-ICP-CAREINEQUAL (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways) study protocol: Defining usual care and examining inequalities in Long Covid support.

INTRODUCTION: Individuals with Long Covid represent a new and growing patient population. In England, fewer than 90 Long Covid clinics deliver assessment and treatment informed by NICE guidelines. However, a paucity of clinical trials or longitudinal cohort studies means that the epidemiology, clinical trajectory, healthcare utilisation and effectiveness of current Long Covid care are poorly documented, and that neither evidence-based treatments nor rehabilitation strategies exist. In addition, and in part due to pre-pandemic health inequalities, access to referral and care varies, and patient experience of the Long Covid care pathways can be poor. In a mixed methods study, we therefore aim to: (1) describe the usual healthcare, outcomes and resource utilisation of individuals with Long Covid; (2) assess the extent of inequalities in access to Long Covid care, and specifically to understand Long Covid patients' experiences of stigma and discrimination. METHODS AND ANALYSIS: A mixed methods study will address our aims. Qualitative data collection from patients and health professionals will be achieved through surveys, interviews and focus group discussions, to understand their experience and document the function of clinics. A patient cohort study will provide an understanding of outcomes and costs of care. Accessible data will be further analysed to understand the nature of Long Covid, and the care received. ETHICS AND DISSEMINATION: Ethical approval was obtained from South Central-Berkshire Research Ethics Committee (reference 303958). The dissemination plan will be decided by the patient and public involvement and engagement (PPIE) group members and study Co-Is, but will target 1) policy makers, and those responsible for commissioning and delivering Long Covid services, 2) patients and the public, and 3) academics.

Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab-cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab-cilgavimab in preventing progression to severe COVID-19 or death. METHODS: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab-cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. FINDINGS: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab-cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab-cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6-71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1-8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab-cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab-cilgavimab group and six in the placebo group. INTERPRETATION: A single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab-cilgavimab might lead to more favourable outcomes. FUNDING: AstraZeneca.

Non-invasive respiratory support in the management of acute COVID-19 pneumonia: considerations for clinical practice and priorities for research.

Non-invasive respiratory support (NIRS) has increasingly been used in the management of COVID-19-associated acute respiratory failure, but questions remain about the utility, safety, and outcome benefit of NIRS strategies. We identified two randomised controlled trials and 83 observational studies, compromising 13 931 patients, that examined the effects of NIRS modalities-high-flow nasal oxygen, continuous positive airway pressure, and bilevel positive airway pressure-on patients with COVID-19. Of 5120 patients who were candidates for full treatment escalation, 1880 (37%) progressed to invasive mechanical ventilation and 3658 of 4669 (78%) survived to study end. Survival was 30% among the 1050 patients for whom NIRS was the stated ceiling of treatment. The two randomised controlled trials indicate superiority of non-invasive ventilation over high-flow nasal oxygen in reducing the need for intubation. Reported complication rates were low. Overall, the studies indicate that NIRS in patients with COVID-19 is safe, improves resource utilisation, and might be associated with better outcomes. To guide clinical decision making, prospective, randomised studies are needed to address timing of intervention, optimal use of NIRS modalities-alone or in combination-and validation of tools such as oxygenation indices, response to a trial of NIRS, and inflammatory markers as predictors of treatment success.

Exergy intensity and environmental consequences of the medical face masks curtailing the COVID-19 pandemic: Malign bodyguard?

On January 30, 2020, the World Health Organization identified SARS-CoV-2 as a public health emergency of global concern. Accordingly, the demand for personal protective equipment (PPE), including medical face masks, has sharply risen compared with 2019. The new situation has led to a sharp increase in energy demand and the environmental impacts associated with these product systems. Hence, the pandemic's effects on the environmental consequences of various PPE types, such as medical face masks, should be assessed. In light of that, the current study aimed to identify the environmental hot-spots of medical face mask production and consumption by using life cycle assessment (LCA) and tried to provide solutions to mitigate the adverse impacts. Based on the results obtained, in 2020, medical face masks production using fossil-based plastics causes the loss of 2.03 × 103 disability-adjusted life years (DALYs); 1.63 × 108 PDF*m2*yr damage to ecosystem quality; the climate-damaging release of 2.13 × 109 kg CO2eq; and 5.65 × 1010 MJ damage to resources. Besides, annual medical face mask production results in 5.88 × 104 TJ demand for exergy. On the other hand, if used makes are not appropriately handled, they can lead to 4.99 × 105 Pt/yr additional damage to the environment in 2020 as determined by the EDIP 2003. Replacement of fossil-based plastics with bio-based plastics, at rates ranging from 10 to 100%, could mitigate the product's total yearly environmental damage by 4-43%, respectively. Our study calls attention to the environmental sustainability of PPE used to prevent virus transmission in the current and future pandemics.

Intensive care physicians' perceptions of the diagnosis & management of patients with acute hypoxic respiratory failure associated with COVID-19: A UK based survey.

Background: Whilst the management of Coronavirus disease-2019 (COVID-19) has evolved in response to the emerging data, treating such patients remains a challenge, and many treatments lack robust clinical evidence. We conducted a survey to evaluate Intensive Care Unit (ICU) management of COVID-19 patients with acute hypoxic respiratory failure and compared the results with data from a similar survey focusing on Acute Respiratory Distress Syndrome (ARDS) that was conducted in 2013. Methods: The questionnaire was refined from a previous survey of ARDS-related clinical practice using an online electronic survey engine (Survey Monkey®) and all UK intensivists were encouraged to participate. The survey was conducted between 16/05/2020 and 17/06/2020. Results: There were 137 responses from 89 UK centres. Non-invasive ventilation was commonly used in the form of CPAP. The primary ventilation strategy was the ARDSnet protocol, with 63% deviating from its PEEP recommendations. Similar to our previous ARDS survey, most allowed permissive targets for hypoxia (94%), hypercapnia (55%) and pH (94%). The routine use of antibiotics was common, and corticosteroids were frequently used, usually in the context of a clinical trial (45%). Late tracheostomy (>7 days) was preferred (92%). Routine follow-up was offered by 66% with few centres providing routine dedicated rehabilitation programmes following discharge. Compared to the ARDS survey, there is an increased use of neuromuscular agents, APRV ventilation and improved provision of rehabilitation services. Conclusions: Similar to our previous ARDS survey, this survey highlights variations in the management strategies used for patients with acute hypoxic respiratory failure due to COVID-19.

Dysnatremia is a Predictor for Morbidity and Mortality in Hospitalized Patients with COVID-19.

CONTEXT: Dysnatremia is an independent predictor of mortality in patients with bacterial pneumonia. There is paucity of data about the incidence and prognostic impact of abnormal sodium concentration in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This work aimed to examine the association of serum sodium during hospitalization with key clinical outcomes, including mortality, need for advanced respiratory support and acute kidney injury (AKI), and to explore the role of serum sodium as a marker of inflammatory response in COVID-19. METHODS: This retrospective longitudinal cohort study, including all adult patients who presented with COVID-19 to 2 hospitals in London over an 8-week period, evaluated the association of dysnatremia (serum sodium < 135 or > 145 mmol/L, hyponatremia, and hypernatremia, respectively) at several time points with inpatient mortality, need for advanced ventilatory support, and AKI. RESULTS: The study included 488 patients (median age, 68 years). At presentation, 24.6% of patients were hyponatremic, mainly due to hypovolemia, and 5.3% hypernatremic. Hypernatremia 2 days after admission and exposure to hypernatremia at any time point during hospitalization were associated with a 2.34-fold (95% CI, 1.08-5.05; P = .0014) and 3.05-fold (95% CI, 1.69-5.49; P < .0001) increased risk of death, respectively, compared to normonatremia. Hyponatremia at admission was linked with a 2.18-fold increase in the likelihood of needing ventilatory support (95% CI, 1.34-3.45, P = .0011). Hyponatremia was not a risk factor for in-hospital mortality, except for the subgroup of patients with hypovolemic hyponatremia. Sodium values were not associated with the risk for AKI and length of hospital stay. CONCLUSION: Abnormal sodium levels during hospitalization are risk factors for poor prognosis, with hypernatremia and hyponatremia being associated with a greater risk of death and respiratory failure, respectively. Serum sodium values could be used for risk stratification in patients with COVID-19.

The post-ICU presentation screen (PICUPS) and rehabilitation prescription (RP) for intensive care survivors part I: Development and preliminary clinimetric evaluation.

Background: Patients who have had prolonged stays in intensive care have ongoing rehabilitation needs. This is especially true of COVID-19 ICU patients, who can suffer diverse long-term ill effects. Currently there is no systematic data collection to guide the needs for therapy input for either of these groups nor to inform planning and development of rehabilitation services. These issues could be resolved in part by the systematic use of a clinical tool to support decision-making as patients progress from the Intensive Care Unit (ICU), through acute hospital care and onwards into rehabilitation. We describe (i) the development of such a tool (the Post-ICU Presentation Screen (PICUPS)) and (ii) the subsequent preparation of a person-centred Rehabilitation Prescription (RP) to travel with the patient as they continue down the care pathway. Methods: PICUPS development was led by a core group of experienced clinicians representing the various disciplines involved in post-ICU rehabilitation. Key constructs and item-level descriptors were identified by group consensus. Piloting was performed as part of wider clinical engagement in 26 acute hospitals across England. Development and validation of such a tool requires clinimetric analysis, and this was based on classical test theory. Teams also provided feedback about the feasibility and utility of the tool. Results: Initial PICUPS design yielded a 24-item tool. In piloting, a total of 552 records were collated from 314 patients, of which 121 (38.5%) had COVID-19. No obvious floor or ceiling effects were apparent. Exploratory factor analysis provided evidence of uni-dimensionality with strong loading on the first principal component accounting for 51% of the variance and Cronbach's alpha for the full-scale score 0.95 - although a 3-factor solution accounted for a further 21%. The PICUPS was responsive to change both at full scale- and item-level. In general, positive responses were seen regarding the tool's ability to describe the patients during their clinical course, engage and flag the relevant professionals needed, and to inform what should be included in an RP. Conclusions: The PICUPS tool has robust scaling properties as a clinical measure and is potentially useful as a tool for identifying rehabilitation needs as patients step down from ICU and acute hospital care.

Healthcare Workers Bioresource: Study outline and baseline characteristics of a prospective healthcare worker cohort to study immune protection and pathogenesis in COVID-19.

Background: Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-up sampling to evaluate the quality and duration of immune memory. Methods: We conducted a prospective study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later (recruitment still ongoing, target n=1,000). Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swab (for SARS-CoV-2 RNA by RT-PCR tests) and blood samples (mononuclear cells, serum, plasma, RNA and DNA are biobanked) at 16 weekly study visits, and at 6 and 12 months. Results: Preliminary baseline results for the first 731 HCWs (400 single-centre, 331 multicentre extension) are presented. Mean age was 38±11 years; 67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities; 18% smokers; 13% obesity; 11% asthma; 7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396 (7.1%, 95% CI 4.9-10.0%) and 15 of 385 (3.9%, 2.4-6.3%) had circulating IgG antibodies. Conclusions: This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application  https://covid-consortium.com/application-for-samples/.

The Post-ICU presentation screen (PICUPS) and rehabilitation prescription (RP) for intensive care survivors part II: Clinical engagement and future directions for the national Post-Intensive care Rehabilitation Collaborative.

Background: Many Intensive Care Unit (ICU) survivors suffer from a multi- system disability, termed the post-intensive care syndrome. There is no current national coordination of either rehabilitation pathways or related data collection for them. In the last year, the need for tools to systematically identify the multidisciplinary rehabilitation needs of severely affected COVID-19 survivors has become clear. Such tools offer the opportunity to improve rehabilitation for all critical illness survivors through provision of a personalised Rehabilitation Prescription (RP). The initial development and secondary refinement of such an assessment and data tools is described in the linked paper. We report here the clinical and workforce data that was generated as a result. Methods: Prospective service evaluation of 26 acute hospitals in England using the Post-ICU Presentation Screen (PICUPS) tool and the RP. The PICUPS tool comprised items in domains of a) Medical and essential care, b) Breathing and nutrition; c) Physical movement and d) Communication, cognition and behaviour. Results: No difference was seen in total PICUPS scores between patients with or without COVID-19 (77 (IQR 60-92) vs. 84 (IQR 68-97); Mann-Whitney z = -1.46, p = 0.144. A network analysis demonstrated that requirements for physiotherapy, occupational therapy, speech and language therapy, dietetics and clinical psychology were closely related and unaffected by COVID-19 infection status. A greater proportion of COVID-19 patients were referred for inpatient rehabilitation (13% vs. 7%) and community-based rehabilitation (36% vs.15%). The RP informed by the PICUPS tool generally specified a greater need for multi-professional input when compared to rehabilitation plans instituted. Conclusions: The PICUPS tool is feasible to implement as a screening mechanism for post-intensive care syndrome. No differences are seen in the rehabilitation needs of patients with and without COVID-19 infection. The RP could be the vehicle that drives the professional interventions across the transitions from acute to community care. No single discipline dominates the rehabilitation requirements of these patients, reinforcing the need for a personalised RP for critical illness survivors.

Genetic mechanisms of critical illness in COVID-19.

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.

COVID-19: UK frontline intensivists' emerging learning.

The Intensive Care Society held a webinar on 3 April 2020 at which representatives from 11 of the most COVID-19 experienced hospital trusts in England and Wales shared learning around five specific topic areas in an open forum. This paper summarises the emerging learning and practice shared by those frontline clinicians.