STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: a structured protocol (preprint)

Introduction: Long COVID (LC), the persistent symptoms >=12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway (ICP) approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. Methods and analysis: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an ICP (Coverscan, a multi-organ MRI, and Living with COVID Recovery, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that ICP interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 NHS LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes (e.g. EQ-5D-5L, GAD-7, PHQ-9, WSAS, PDQ-5, CFQ, SF-12, MRC Dyspnoea score) at 3 months. The trial also includes an economic evaluation which will be described separately. Ethics and dissemination: The protocol was reviewed by South Central - Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan has UKCA certification (752965). The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. Trial registration number: ISRCTN10665760

Cardiac impairment in Long Covid 1-year post-SARS-CoV-2 infection (preprint)

Background Long Covid is associated with multiple symptoms and impairment in multiple organs. Cardiac impairment has been reported to varying degrees by varying methodologies in cross-sectional studies. Using cardiac magnetic resonance (CMR), we investigated the 12-month trajectory of cardiac impairment in individuals with Long Covid. Methods 534 individuals with Long Covid underwent baseline CMR (T1 and T2 mapping, cardiac mass, volumes, function, and strain) and multi-organ MRI at 6 months (IQR 4.3,7.3) since first post-COVID-19 symptoms and 330 were rescanned at 12.6 (IQR 11.4, 14.2) months if abnormal findings were reported at baseline. Symptoms, standardised questionnaires, and blood samples were collected at both timepoints. Cardiac impairment was defined as one or more of: low left or right ventricular ejection fraction (LVEF and RVEF), high left or right ventricular end diastolic volume (LVEDV and RVEDV), low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in [≥]3 cardiac segments. A significant change over time was reported by comparison with 92 healthy controls. Results The technical success of this multiorgan assessment in non-acute settings was 99.1% at baseline, and 98.3% at follow up, with 99.6% and 98.8% for CMR respectively. Of individuals with Long Covid, 102/534 [19%] had cardiac impairment at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing cardiac impairment at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms, or clinical outcomes. At baseline, low LVEF, high RVEDV and low GLS were associated with cardiac impairment. Low LVEF at baseline was associated with persistent cardiac impairment at 12 months. Conclusion Cardiac impairment, other than myocarditis, is present in 1 in 5 individuals with Long Covid at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers are unable to identify cardiac impairment in Long COVID. Subtypes of disease (based on symptoms, examination, and investigations) and predictive biomarkers are yet to be established. Interventional trials with pre-specified subgroup analyses are required to inform therapeutic options.

Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study (preprint)

Importance: Multi-organ impairment associated with Long COVID is a significant burden to individuals, populations and health systems, presenting challenges for diagnosis and care provision. Standardised assessment across multiple organs over time is lacking, particularly in non-hospitalised individuals. Objective: To determine the prevalence of organ impairment in Long COVID patients at 6 and at 12 months after initial symptoms and to explore links to clinical presentation. Design: This was a prospective, longitudinal study in individuals following recovery from acute COVID-19. We assessed symptoms, health status, and multi-organ tissue characterisation and function, using consensus definitions for single and multi-organ impairment. Physiological and biochemical investigations were performed at baseline on all individuals and those with organ impairment were reassessed, including multi-organ MRI, 6 months later. Setting: Two non-acute settings (Oxford and London). Participants: 536 individuals (mean 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post-COVID-19). 331 (62%) with organ impairment or incidental findings had follow up, with reduced symptom burden from baseline (median number of symptoms: 10 and 3, at 6 and 12 months). Exposure: SARS-CoV-2 infection 6 months prior to first assessment. Main outcome: Prevalence of single and multi-organ impairment at 6 and 12 months post-COVID-19. Results: Extreme breathlessness (36% and 30%), cognitive dysfunction (50% and 38%) and poor health-related quality of life (EQ-5D-5L<0.7; 55% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single organ impairment. At baseline, there was fibro-inflammation in the heart (9%), pancreas (9%), kidney (15%) and liver (11%); increased volume in liver (7%), spleen (8%) and kidney (9%); decreased capacity in lungs (2%); and excessive fat deposition in the liver (25%) and pancreas (15%). Single and multi-organ impairment were present in 59% and 23% at baseline, persisting in 59% and 27% at follow-up. Conclusion and Relevance: Organ impairment was present in 59% of individuals at 6 months post-COVID-19, persisting in 59% of those followed up at 1 year, with implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID. Trial Registration: ClinicalTrials.gov NCT04369807

Impact of Interventional Policies Including Vaccine on Covid-19 Propagation and Socio-Economic Factors (preprint)

A novel coronavirus disease has emerged (later named COVID-19) and caused the world to enter a new reality, with many direct and indirect factors influencing it. Some are human-controllable (e.g. interventional policies, mobility and the vaccine); some are not (e.g. the weather). We have sought to test how a change in these human-controllable factors might influence two measures: the number of daily cases against economic impact. If applied at the right level and with up-to-date data to measure, policymakers would be able to make targeted interventions and measure their cost. This study aims to provide a predictive analytics framework to model, predict and simulate COVID-19 propagation and the socio-economic impact of interventions intended to reduce the spread of the disease such as policy and/or vaccine. It allows policymakers, government representatives and business leaders to make better-informed decisions about the potential effect of various interventions with forward-looking views via scenario planning. We have leveraged a recently launched open-source COVID-19 big data platform and used published research to find potentially relevant variables (features) and leveraged in-depth data quality checks and analytics for feature selection and predictions. An advanced machine learning pipeline has been developed armed with a self-evolving model, deployed on a modern machine learning architecture. It has high accuracy for trend prediction (back-tested with r-squared) and is augmented with interpretability for deeper insights.

Multi-organ impairment in low-risk individuals with long COVID (preprint)

Background: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection has disproportionately affected older individuals and those with underlying medical conditions. Research has focused on short-term outcomes in hospital, and single organ involvement. Consequently, impact of long COVID (persistent symptoms three months post-infection) across multiple organs in low-risk individuals is yet to be assessed. Methods: An ongoing prospective, longitudinal, two-centre, observational study was performed in individuals symptomatic after recovery from acute SARS-CoV-2 infection. Symptoms and organ function (heart, lungs, kidneys, liver, pancreas, spleen) were assessed by standardised questionnaires (EQ-5D-5L, Dyspnoea-12), blood investigations and quantitative magnetic resonance imaging, defining single and multi-organ impairment by consensus definitions. Findings: Between April and September 2020, 201 individuals (mean age 44 (SD 11.0) years, 70% female, 87% white, 31% healthcare workers) completed assessments following SARS-CoV-2 infection (median 140, IQR 105-160 days after initial symptoms). The prevalence of pre-existing conditions (obesity: 20%, hypertension: 6%; diabetes: 2%; heart disease: 4%) was low, and only 18% of individuals had been hospitalised with COVID-19. Fatigue (98%), muscle aches (88%), breathlessness (87%), and headaches (83%) were the most frequently reported symptoms. Ongoing cardiorespiratory (92%) and gastrointestinal (73%) symptoms were common, and 42% of individuals had ten or more symptoms. There was evidence of mild organ impairment in heart (32%), lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and spleen (6%). Single (66%) and multi-organ (25%) impairment was observed, and was significantly associated with risk of prior COVID-19 hospitalisation (p<0.05). Interpretation: In a young, low-risk population with ongoing symptoms, almost 70% of individuals have impairment in one or more organs four months after initial symptoms of SARS-CoV-2 infection. There are implications not only for burden of long COVID but also public health approaches which have assumed low risk in young people with no comorbidities.

HIGH LIVER FAT ASSOCIATES WITH HIGHER RISK OF DEVELOPING SYMPTOMATIC COVID-19 INFECTION - INITIAL UK BIOBANK OBSERVATIONS (preprint)

Background A high proportion of COVID-19 patients develop acute liver dysfunction. Early research has suggested that pre-existing fatty liver disease may be a significant risk factor for hospitalisation. Liver fat, in particular, is a modifiable parameter and can be a target for public health policy and individual patient plans. In this study we aimed to assess pre-existing liver disease as a risk factor for developing symptomatic COVID-19. Methods From 502,506 participants from the UK Biobank, 42,146 underwent MRI (aged 45-82), and had measures of liver fat, liver fibroinflammatory disease and liver iron. Patients were censored on May 28th to determine how many had tested for COVID-19 with symptomatic disease. UK testing was restricted to those with symptoms in hospital. COVID-19 symptoms included fever, dry cough, sore throat, diarrhoea and fatigue. Univariate analysis was performed on liver phenotypic biomarkers to determine if these variables increased risk of symptomatic COVID-19, and compared to previously described risk factors associated with severe COVID-19, including to age, ethnicity, gender and obesity, Findings Increased liver fat was associated with a higher risk for symptomatic confirmed COVID-19 in this population in univariate analysis(OR:1.85, p=0.03). In obese participants, only those with concomitant fatty liver([≥]10%) were at increased risk(OR:2.96, p=0.02), with those having normal liver fat (<5%) showing no increased risk(OR:0.36, p=0.09). Conclusions UK Biobank data demonstrated an association between pre-existing liver disease and obesity with severe COVID-19, with higher proportions of liver fat in obese individuals a likely risk factor for symptomatic disease and severity. Public policy measures to protect patients with liver disease who may have almost double the risk of the general population should be considered, especially as dietary and pharmacological strategies to reduce body weight and liver fat already exist. Funding University of Oxford, Innovate UK, UK Biobank. Authors are employees of Perspectum Ltd.