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

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

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.

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

IntroductionAs 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 analysisThis 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 disseminationEthical 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. RegistrationResearchregistry: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/6246bfeeeaaed6001f08dadc/.

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

Post-COVID assessment in a specialist clinical service: a 12-month, single-centre analysis of symptoms and healthcare needs in 1325 individuals. (preprint)

Background. Complications following SARS-CoV-2 infection 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 clinical service to include both hospitalised and non-hospitalised patients. Methods. In a single-centre, observational analysis, we report outcomes for 1325 individuals assessed in the University College London Hospitals NHS Foundation Trust Post-COVID service between April 2020 and April 2021. Demography, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation were compared by referral route ('post hospitalisation', 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. Findings. 1325 individuals were assessed (PH 547 [41.3%], PED 212 [16%], NH 566 [42.7%]. Compared with PH and PED groups, NH were younger (median 44.6 [35.6-52.8] vs 58.3 [47.0-67.7] and 48.5 [39.4-55.7] years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be from an ethnic minority (30.9%, 52.7% and 41.0%) and seen later after symptom onset (median [IQR]:194 [118-298], 69 [51-111] and 76 [55-128] days) (all p<0.0001). NH patients had similar rates of onward specialist referral as PH and PED groups (18.7%, 16.1% and 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%, 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% of optimal health (median [IQR] 70% [55%-85%]). Overall, less than half of employed individuals felt able to return to work full-time at first assessment. Interpretation. Symptoms following SARS-CoV-2 infection were significant in both post- and non-hospitalised patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required.