Managing the long term effects of covid-19 : summary of NICE, SIGN, and RCGP rapid guideline

For a proportion of people covid-19 leads to long term effects that can have a significant impact on quality of life. According to the Office for National Statistics, around one in five people testing positive for covid-19 exhibit symptoms for a period of five weeks or more.1 This presents challenges for determining best-practice standards of care. As yet, no commonly agreed clinical definition of long term covid-19 exists, nor a clear definition of treatment pathway. To assist clinicians, the National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Royal College of General Practitioners (RCGP) have developed the “COVID-19 rapid guideline: managing the long term effects of COVID-19.”2 It covers care for people with signs and symptoms that continue for more than four weeks, and which developed during or after an infection consistent with covid-19, and which are not explained by alternative diagnoses

Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis

Post-COVID syndrome (PCS) or Long-COVID is an increasingly recognised complication of acute SARS-CoV-2 infection, characterised by persistent fatigue, reduced exercise tolerance chest pain, shortness of breath and cognitive slowing. Acute COVID-19 is strongly linked with increased risk of thrombosis; a prothrombotic state, quantified by elevated Von Willebrand Factor (VWF) Antigen (Ag):ADAMTS13 ratio, and is associated with severity of acute COVID-19 infection. We investigated if patients with PCS also had evidence of a pro-thrombotic state associating with symptom severity. In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk including VWF(Ag):ADAMTS13 ratio, was investigated. An elevated VWF(Ag):ADAMTS13 ratio (≥1.5) was raised in nearly one-third of the cohort and four times more likely in patients with impaired exercise capacity as evidenced by desaturation ≥3% and/or rise in lactate level more than 1 from baseline on 1-minute sit to stand test and/or 6-minute walk test (p<0.0001). 20% (56/276) had impaired exercise capacity, of which 55% (31/56) had a raised VWF(Ag):ADAMTS13 ratio ≥1.5 (p<0.0001). FVIII and VWF(Ag) were elevated in 26% and 18% respectively and support a hypercoagulable state in some patients with PCS. These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and highlight a potential role for antithrombotic therapy in the management of these patients

Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome

Background: Post-COVID syndrome (PCS) affects millions of people worldwide, causing a multitude of symptoms and impairing quality of life months or even years after acute COVID-19. A prothrombotic state has been suggested; however, underlying mechanisms remain to be elucidated. / Objectives: To investigate thrombogenicity in PCS using a microfluidic assay, linking microthrombi, thrombin generation, and the von Willebrand factor (VWF):a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS13) axis. / Methods: Citrated blood was perfused through microfluidic channels coated with collagen or an antibody against the VWF A3 domain, and thrombogenicity was monitored in real time. Thrombin generation assays were performed and α(2)-antiplasmin, VWF, and ADAMTS13 activity levels were also measured. / Results: We investigated thrombogenicity in a cohort of 21 patients with PCS with a median time following symptoms onset of 23 months using a dynamic microfluidic assay. Our data show a significant increase in platelet binding on both collagen and anti-VWF A3 in patients with PCS compared with that in controls, which positively correlated with VWF antigen (Ag) levels, the VWF(Ag):ADAMTS13 ratio (on anti-VWF A3), and inversely correlated with ADAMTS13 activity (on collagen). Thrombi forming on collagen presented different geometries in patients with PCS vs controls, with significantly increased thrombi area mainly attributable to thrombi length in the patient group. Thrombi length positively correlated with VWF(Ag):ADAMTS13 ratio and thrombin generation assay results, which were increased in 55.5% of patients. α(2)-Antiplasmin levels were normal in 89.5% of patients. / Conclusion: Together, these data present a dynamic assay to investigate the prothrombotic state in PCS, which may help unravel the mechanisms involved and/or establish new therapeutic strategies for this condition

Time-efficient physical activity intervention for older adolescents with disability : rationale and study protocol for the Burn 2 Learn adapted (B2La) cluster randomised controlled trial

Introduction Physical activity declines during adolescence, with the lowest levels of activity observed among those with disability. Schools are ideal settings to address this issue; however, few school-based interventions have been specifically designed for older adolescents with disability. Our aim is to investigate the effects of a school-based physical activity programme, involving high-intensity interval training (HIIT), on physical, mental and cognitive health in older adolescents with disability. Methods and analysis We will evaluate the Burn 2 Learn adapted (B2La) intervention using a two-arm, parallel group, cluster randomised controlled trial with allocation occurring at the school level (treatment or waitlist control). Secondary schools will be recruited in two cohorts from New South Wales, Australia. We will aim to recruit 300 older adolescents (aged 15–19 years) with disability from 30 secondary schools (10 in cohort 1 and 20 in cohort 2). Schools allocated to the intervention group will deliver two HIIT sessions per week during scheduled specialist support classes. The sessions will include foundational aerobic and muscle strengthening exercises tailored to meet student needs. We will provide teachers with training, resources, and support to facilitate the delivery of the B2La programme. Study outcomes will be assessed at baseline, 6 months (primary endpoint), and 9 months. Our primary outcome is functional capacity assessed using the 6 min walk/push test. Secondary outcomes include physical activity, muscular fitness, body composition, cognitive function, quality of life, physical literacy, and on-task behaviour in the classroom. We will also conduct economic and process evaluations to determine cost-effectiveness, programme acceptability, implementation, adaptability, and sustainability in schools. Ethics and dissemination This study has received approval from the University of Newcastle (H-2021–0262) and the New South Wales Department of Education (SERAP: 2021257) human research ethics committees. Findings will be published in peer-reviewed journals, and key stakeholders will be provided with a detailed report following the study. Trial registration number Australian New Zealand Clinical Trials Registry Number: ACTRN12621000884808

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

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Post-COVID-19 assessment in a specialist clinical service: a 12-month, single-centre, prospective study in 1325 individuals

Introduction: Post-COVID-19 complications require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated post-COVID-19 clinical service to include hospitalised and non-hospitalised patients. Methods: In a single-centre, observational analysis, we report the demographics, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation of 1325 individuals assessed at the University College London Hospitals post-COVID-19 service between April 2020 and April 2021, comparing by referral route: posthospitalised (PH), non-hospitalised (NH) and post emergency department (PED). Symptoms associated with poor recovery or inability to return to work full time were assessed using multivariable logistic regression. Results: 1325 individuals were assessed (PH: 547, 41.3%; PED: 212, 16%; NH: 566, 42.7%). Compared with the PH and PED groups, the NH group were younger (median 44.6 (35.6–52.8) years vs 58.3 (47.0–67.7) years and 48.5 (39.4–55.7) years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be of ethnic minority (30.9%, 52.7% and 41.0%) or seen later after symptom onset (median (IQR): 194 (118–298) days, 69 (51–111) days and 76 (55–128) days; all p<0.0001). All groups had similar rates of onward specialist referral (NH 18.7%, PH 16.1% and PED 18.9%, p=0.452) and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8% and 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities and other organ impairment. 716 (54.0%) individuals reported <75% optimal health (median 70%, IQR 55%–85%). Less than half of employed individuals could return to work full time at first assessment. Conclusion: Post-COVID-19 symptoms were significant in PH and NH patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required

Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD