To the Editor — There is now a rich body of knowledge on acute COVID-19, but much less is known about the risk factors, clinical presentation, duration and management of persistent or new symptoms following recovery from initial infection, often termed long COVID1. Post-infection follow-up data show that a significant proportion of hospitalized and non-hospitalized patients experience persistent symptoms and organ dysfunction2,3,4.

The UK Office for National Statistics (ONS) estimates that the number of people in the UK that are self-reporting symptoms lasting more than 4 weeks currently stands at 1.1 million (1.7% of the population)3, while the real-time assessment of community transmission (REACT) study in England estimated the overall number of people who reported at least one symptom lasting for 12 or more weeks as more than 2 million by February 2021 (ref. 5). Patients globally have reported a range of new, returning and/or ongoing symptoms, including (but not limited to) fatigue, shortness of breath, altered smell and taste, cough, myalgia, cognitive impairment and diarrhea following COVID-19 infection6. Of great concern are data from imaging studies that report single or multiple organ impairment, even in non-hospitalized patients7.

To build greater understanding of long COVID, a wide range of nationally funded studies has been launched in the UK (see Fig. 1 and Table 1). The post-hospitalisation COVID-19 study (PHOSP-COVID) was the first such study, securing £8.4 million in July 2020 from UK Research and Innovation (UKRI), and aims to understand and improve long-term outcomes for people who survive hospitalization with COVID-19.

Fig. 1: Timeline of major funded epidemiological studies on long COVID in the UK.
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*PHOSP-COVID has ethical approval for 25-year follow-up and REACT-LC for 20-year follow-up, with plans highlighting how each study will evolve, ask new questions and seek further resources. #REACT-LC is funded from February 2021 but the timeline of the project starts in May 2020 with the use of the first baseline data from REACT participants, which form the sampling for follow-up.

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Table 1 Summary of major funded epidemiological studies on long COVID in the UK
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Another study that started early in the pandemic was the REACT programme, which was commissioned by the Department of Health and Social Care in April 2020. The REACT studies are nationally representative prevalence surveys of SARS-CoV-2 in the community in England. REACT was then extended to include REACT-long COVID (REACT-LC) in February 2021 via the National Institute for Health Research (NIHR) and UKRI funding. REACT-LC aims to characterize the genetic, biological, social and environmental determinants, and the corresponding inter-relationships, that underpin progression to long COVID, and to understand the natural history and long-term sequelae after SARS-CoV-2 infection. In early 2021, the NIHR and UKRI funded four research studies (totalling £18.5 million) to better understand and address longer-term effects of SARS-CoV-2 infection on physical and mental health. In summer 2021, NIHR funded a further 15 projects (totalling £19.6 million) to improve the diagnosis of long COVID, as well as treatment, rehabilitation and recovery.

From this cohort of funded projects, as well as other key national projects, nine major epidemiology-focused long COVID studies are currently running in the UK (see Fig. 1 and Table 1). These studies cover population epidemiology, symptomatology, phenotyping, operational definition, health impacts post-hospitalization, determinants, mechanisms and consequences of the long-term effects, and genetic, biological, social and environmental signatures and pathways. Researchers on these studies have formed the National Long COVID Research working group, to share key findings and promote rapid knowledge exchange and efficient timely research. Key outputs of the group are shared with the Chief Medical Officer for England. An example of this knowledge exchange in action is an open science repository platform8 that the National Long COVID working group has formed to collate and index the latest research on long COVID.

There are a wide range of outstanding research priorities, including defining long COVID, identifying its pathogenesis, describing its clinical presentation and health impacts, characterizing the longer-term burden and predictive risk factors and developing clinical interventions. The primary areas of knowledge that the studies outlined in Table 1 will advance are: the prevalence and phenotyping of symptom clusters (TLC, CIS, CONVALESCENCE, REACT-LC and PHOSP-COVID; see Table 1 for full study names), identification of the short- and long-term mental and physical health sequelae of long COVID (TLC, CIS, CLoCk, PHOSP-COVID, CONVALESCENCE, REACT-LC, STIMULATE-ICP and OpenPROMPT), prevalence, phenotyping and operational research definition of long COVID in children and young people (CLoCk), the immunological causes and consequences of long COVID (TLC and REACT-LC), identifying mechanisms that underpin the development of long COVID (TLC, CONVALESCENCE and REACT-LC), and identifying and trialling potential therapies and interventions to treat and manage long COVID (TLC, PHOSP-COVID and STIMULATE-ICP). The CLoCk study is the largest study of long COVID specifically in children that we know of globally, uniquely uses child-reported symptoms, a control group and standardized measures, and is longitudinal and based on a national cohort.

A particular strength of several of the studies (TLC, CLoCk, CONVALESCENCE and the REACT cohort follow-up) is the use of control groups, which allows comparison of symptom profiles and burden in individuals with confirmed SARS-CoV-2 infection compared to those without infection who may experience symptoms due to comorbidities, and because some reported long-COVID symptoms are non-specific and prevalent in the general population9. There is a huge burden of ill health from long COVID in the UK and globally. People living with long COVID were the first to identify and describe long COVID10. The research community have joined patient researchers in their efforts to improve understanding of long COVID, including its symptoms, health impacts, pathophysiology and treatments. Patient and public involvement is a feature of all the studies described above, with research teams working with patient partners from diverse backgrounds, as well as engaging with national long-COVID support groups. Multidisciplinary research collaboration with patients at the core, as well as co-producing the research as equal partners, is crucial for developing a comprehensive approach to unraveling the complexity and heterogeneity of long COVID. This co-production will be fundamental in the development of targeted therapeutic approaches and to inform health service provision to meet the large unmet need from long COVID.