Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Stratification Of LIver Disease (SOLID): protocol for a prospective observational cohort study to determine the optimum biomarker strategies for the detection of advanced liver disease at the primary-secondary care interface.

INTRODUCTION: Undiagnosed fatty liver disease is prevalent in the community, due to high rates of harmful alcohol consumption and/or obesity. Fatty liver disease can progress to cirrhosis and its complications. Early identification of liver disease and treatment may prevent progression to cirrhosis. Biomarkers including FIB-4, enhanced liver fibrosis (ELF), PRO-C3 and vibration controlled transient elastography (VCTE) can stage liver fibrosis, but it is not known how well they perform in a primary care population. Moreover, no assessment of long-term prognostic ability of these biomarkers has been conducted in primary care. We aim to evaluate the performance of fibrosis biomarkers in primary care to develop a pathway to detect advanced fibrosis. METHODS AND ANALYSIS: This prospective, observational cohort study will recruit 3000 individuals with fatty liver disease risk factors (obesity, type 2 diabetes or hazardous alcohol consumption) at their primary care 'annual chronic disease review'. Participants will have a 'liver health check'. Two pathways will be evaluated: (1) all have FIB-4, ELF and VCTE performed, and (2) patients have an initial assessment with FIB-4 and ELF, followed by VCTE in only those with increased FIB-4 and/or ELF. Individuals with suspected significant/advanced liver fibrosis (liver stiffness measurement>8 kPa), will be reviewed in secondary care to confirm their fibrosis stage and institute treatment. The performance of FIB-4, ELF, PRO-C3, VCTE and novel biomarkers alone or in combination for advanced fibrosis/cirrhosis will be evaluated. Participants will be followed longitudinally via their electronic health records to assess long-term clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Chelsea Research Ethics Committee (22/PR/0535; 27 June 2022). Recruitment began on 31 October 2022. Outcomes of this study will be published in peer-reviewed journals and presented at scientific meetings. A lay summary of the results will be available for study participants and will be disseminated widely by LIVErNORTH.

COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study.

BACKGROUND: A subset of patients with severe COVID-19 develop a hyperinflammatory syndrome, which might contribute to morbidity and mortality. This study explores a specific phenotype of COVID-19-associated hyperinflammation (COV-HI), and its associations with escalation of respiratory support and survival. METHODS: In this retrospective cohort study, we enrolled consecutive inpatients (aged ≥18 years) admitted to University College London Hospitals and Newcastle upon Tyne Hospitals in the UK with PCR-confirmed COVID-19 during the first wave of community-acquired infection. Demographic data, laboratory tests, and clinical status were recorded from the day of admission until death or discharge, with a minimum follow-up time of 28 days. We defined COV-HI as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 µg/L. Respiratory support was categorised as oxygen only, non-invasive ventilation, and intubation. Initial and repeated measures of hyperinflammation were evaluated in relation to the next-day risk of death or need for escalation of respiratory support (as a combined endpoint), using a multi-level logistic regression model. FINDINGS: We included 269 patients admitted to one of the study hospitals between March 1 and March 31, 2020, among whom 178 (66%) were eligible for escalation of respiratory support and 91 (34%) patients were not eligible. Of the whole cohort, 90 (33%) patients met the COV-HI criteria at admission. Despite having a younger median age and lower median Charlson Comorbidity Index scores, a higher proportion of patients with COV-HI on admission died during follow-up (36 [40%] of 90 patients) compared with the patients without COV-HI on admission (46 [26%] of 179). Among the 178 patients who were eligible for full respiratory support, 65 (37%) met the definition for COV-HI at admission, and 67 (74%) of the 90 patients whose respiratory care was escalated met the criteria by the day of escalation. Meeting the COV-HI criteria was significantly associated with the risk of next-day escalation of respiratory support or death (hazard ratio 2·24 [95% CI 1·62-2·87]) after adjustment for age, sex, and comorbidity. INTERPRETATION: Associations between elevated inflammatory markers, escalation of respiratory support, and survival in people with COVID-19 indicate the existence of a high-risk inflammatory phenotype. COV-HI might be useful to stratify patient groups in trial design. FUNDING: None.