Therapies for Long COVID in non-hospitalised individuals - from symptoms, patient-reported outcomes, and immunology to targeted therapies (The TLC Study): Study protocol
Authors: Haroon Shamil , Nirantharakumar Krishnarajah , Hughes Sarah E , Subramanian Anuradhaa , Aiyegbusi Olalekan Lee , Davies Elin Haf , Myles Puja , Williams Tim , Turner Grace M , Chandan Joht Singh , McMullan Christel , Lord Janet , Wraith David , McGee Kirsty , Denniston Alastair , Taverner Tom , Jackson Louise , Sapey Elizabeth , Gkoutos Georgios , Gokhale Krishna , Leggett Edward , Iles Clare , Frost Christopher , McNamara Gary , Bamford Amy , Marshall Tom , Zemedikun Dawit , Price Gary , Marwaha Steven , Simms-Williams Nikita , Brown Kirsty , Walker Anita , Jones Karen , Matthews Karen , Camaradou Jennifer , Saint-Cricq Michael , Kumar Sumita , Alder Yvonne , Stanton David E. , Agyen Lisa , Baber Megan , Blaize Hannah , Calvert Melanie 
Published: December 2021

AbstractIntroductionIndividuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies.Methods and analysisA cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink (CPRD) and invited by their general practitioners to participate on a digital platform (Atom5™). Individuals will report symptoms, quality of life, work capability, and patient reported outcome measures. Data will be collected monthly for one year.Statistical clustering methods will be used to identify distinct Long COVID symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear sub-study which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.We will review existing evidence on interventions for post-viral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulated evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group.Ethics and disseminationEthical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). The study is registered on the ISRCTN Registry (1567490). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers.Article SummaryStrengths and limitations of the studyThe study will generate a nationally representative cohort of individuals with Long COVID recruited from primary care.We will recruit controls matched on a wide range of demographic and clinical factors to assess differences in symptoms between people with Long COVID and similar individuals without a history of COVID-19.We will use a newly developed electronic patient reported outcome measure (Symptom Burden Questionnaire™) for Long COVID to comprehensively assess a wide range of symptoms highlighted by existing literature, patients, and clinicians.Immunological, proteomic, genetic, and wearable data captured in the study will allow deep phenotyping of Long COVID syndromes to help better target therapies.A limitation is that a significant proportion of non-hospitalised individuals affected by COVID-19 in the first wave of the pandemic will lack confirmatory testing and will be excluded from recruitment to the study.