Article Text

Long Covid: a global health issue – a prospective, cohort study set in four continents
  1. Ekaterina Pazukhina1,
  2. Esteban Garcia-Gallo1,
  3. Luis Felipe Reyes2,3,
  4. Anders Benjamin Kildal4,5,
  5. Waasila Jassat6,7,
  6. Murray Dryden7,
  7. Jan Cato Holter8,9,
  8. Allegra Chatterjee10,
  9. Kyle Gomez11,
  10. Arne Søraas12,
  11. Matteo Puntoni13,
  12. Nicola Latronico14,15,
  13. Fernando A Bozza16,17,
  14. Michael Edelstein18,
  15. Bronner P Gonçalves19,
  16. Christiana Kartsonaki20,
  17. Oksana Kruglova21,
  18. Sérgio Gaião22,
  19. Yock Ping Chow23,
  20. Yash Doshi24,
  21. Sara Isabel Duque Vallejo25,
  22. Elsa D Ibáñez-Prada26,
  23. Yuli V Fuentes26,
  24. Claire Hastie27,
  25. Margaret E O'Hara27,
  26. Valeria Balan1,
  27. Tigist Menkir28,
  28. Laura Merson1,
  29. Sadie Kelly29,
  30. Barbara Wanjiru Citarella1,
  31. Malcolm G Semple30,31,
  32. Janet T Scott32,33,
  33. Daniel Munblit34,35,
  34. Louise Sigfrid1,36
  35. ISARIC Clinical Characterisation Group and ISARIC Global Covid-19 follow up working group
    1. 1ISARIC Global Support Centre, Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
    2. 2Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Chia, Colombia
    3. 3Clinica, Universidad de La Sabana, Chia, Colombia
    4. 4Department of Anesthesiology and Intensive Care, University Hospital of North Norway, Tromso, Troms, Norway
    5. 5Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromso, Troms, Norway
    6. 6Genesis Analytics Pty Ltd, Johannesburg, Gauteng, South Africa
    7. 7National Institute for Communicable Diseases, Johannesburg, South Africa
    8. 8Department of Microbiology, Oslo University Hospital, Oslo, Norway
    9. 9Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    10. 10UK Health Security Agency, London, UK
    11. 11Gibraltar Health Authority, Gibraltar, Gibraltar
    12. 12The Norwegian Corona Cohort, Oslo, Norway
    13. 13Clinical & Epidemiological Research Unit, University Hospital of Parma, Parma, Italy
    14. 14Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
    15. 15Department of Emergency, Spedali Civili University Hospital, Brescia, Italy
    16. 16National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
    17. 17D'Or Institute for Research and Education, Rio de Janeiro, Brazil
    18. 18Bar-Ilan University The Azrieli Faculty of Medicine, Safed, Northern District, Israel
    19. 19Department of Comparative Biomedical Sciences, University of Surrey, Guildford, UK
    20. 20Nuffield Department of Population Health, University of Oxford, Oxford, UK
    21. 21Department of Internal Medicine No 2, Lugansk State Medical University, Rivne, Ukraine
    22. 22São João Hospital Centre, Porto, Portugal
    23. 23Sunway Medical Centre, Bandar Sunway, Selangor, Malaysia
    24. 24Terna Specialty Hospital and Research Centre, Mumbai, India
    25. 25University of Oxford Nuffield Department of Medicine, Oxford, UK
    26. 26Universidad de La Sabana, Chia, Colombia
    27. 27Long COVID Support, London, UK
    28. 28The Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Cambridge, Massachusetts, USA
    29. 29Pandemic Sciences Institute, University of Oxford, Oxford, UK
    30. 30NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool, UK
    31. 31Liverpool Institute for Child Health and Wellbeing, Alder Hey Children’s Hospital, Liverpool, UK
    32. 32MRC, University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
    33. 33RD&I and COVID Recovery Service, NHS Highland, Inverness, UK
    34. 34Division of Care in Long Term Conditions, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK
    35. 35Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child’s Health, I M Sechenov First Moscow State Medical University, Moskva, Moskva, Russian Federation
    36. 36Policy and Practice Research Group, Pandemic Sciences Institute, University of Oxford, Oxford, UK
    37. 37Global Collaborative Platform, Oxford, UK
    1. Correspondence to Dr Louise Sigfrid; louise.sigfrid{at}ndm.ox.ac.uk

    Abstract

    Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).

    Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to <6 and 6 to <12 months post-hospital discharge. A standardised case report form developed by International Severe Acute Respiratory and emerging Infection Consortium’s Global COVID-19 Follow-up working group evaluated the frequency of fever, persistent symptoms, breathlessness (MRC dyspnoea scale), fatigue and impact on daily activities.

    Results Of 11 860 participants (median age: 52 (IQR: 41–62) years; 52.1% females), 56.5% were from HICs and 43.5% were from LMICs. The proportion identified with Long Covid was significantly higher in HICs vs LMICs at both assessment time points (69.0% vs 45.3%, p<0.001; 69.7% vs 42.4%, p<0.001). Participants in HICs were more likely to report not feeling fully recovered (54.3% vs 18.0%, p<0.001; 56.8% vs 40.1%, p<0.001), fatigue (42.9% vs 27.9%, p<0.001; 41.6% vs 27.9%, p<0.001), new/persistent fever (19.6% vs 2.1%, p<0.001; 20.3% vs 2.0%, p<0.001) and have a higher prevalence of anxiety/depression and impact on usual activities compared with participants in LMICs at 2 to <6 and 6 to <12 months post-COVID-19 hospital discharge, respectively.

    Conclusion Our data show that Long Covid affects populations globally, manifesting similar symptomatology and impact on functioning in both HIC and LMICs. The prevalence was higher in HICs versus LMICs. Although we identified a lower prevalence, the impact of Long Covid may be greater in LMICs if there is a lack of support systems available in HICs. Further research into the aetiology of Long Covid and the burden in LMICs is critical to implement effective, accessible treatment and support strategies to improve COVID-19 outcomes for all.

    • COVID-19
    • Global Health
    • Epidemiology
    • Public Health
    • Cohort study

    Data availability statement

    Data are available on reasonable request. The data that underpin this analysis are highly detailed clinical data on individuals hospitalised with COVID-19. Due to the sensitive nature of these data and the associated privacy concerns, they are available via a governed data access mechanism following review of a data access committee. Data can be requested via the IDDO COVID-19 Data Sharing Platform (http://www.iddo.org/covid-19). The Data Access Application, Terms of Access and details of the Data Access Committee are available on the website. Briefly, the requirements for access are a request from a qualified researcher working with a legal entity who have a health and/or research remit; a scientifically valid reason for data access which adheres to appropriate ethical principles. The full terms are at https://www.iddo.org/document/covid-19-data-access-guidelines. A small subset of sites who contributed data to this analysis have not agreed to pooled data sharing as above. In the case of requiring access to these data, please contact the corresponding author in the first instance who will look to facilitate access.

    https://creativecommons.org/licenses/by/4.0/

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Prior to this study, global data on Long Covid were sparse, with most studies focused on high-income countries (HICs).

    • Long Covid sequelae identified in previous studies included a wide range of symptoms, with fatigue, breathlessness, cognitive dysfunction and various physical complications.

    • The lack of precise case definitions, standardised protocols and tools has hindered a comprehensive understanding of Long Covid and its impact globally.

    WHAT THIS STUDY ADDS

    • This study, employing a collaborative harmonised approach to data collection across four continents, reveals key Long Covid characteristics affecting populations worldwide.

    • Although the prevalence was higher in HICs, the individual and broader socioeconomic impact may be higher in resource-limited settings.

    • Codevelopment of a standardised protocol using validated tools facilitated implementation in resource-restricted settings during the pandemic.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Our data highlight the need for further research into underlying aetiologies of Long Covid to inform precise case definitions, trials and evidence-based care pathways to improve equitable COVID-19 outcomes.

    • Further, research to identify the impact of Long Covid globally, to inform targeted strategies to support recovery and mitigate wider socioeconomic impact.

    • Prepositioned standardised follow-up protocols nested in strategic observational and adaptive trial platforms should be incorporated in epidemics and pandemic preparedness plans.

    Introduction

    The COVID-19 pandemic has caused a substantial burden on healthcare systems and economies worldwide, especially in lower-income and middle-income countries (LMICs),1 2 with 774 million confirmed cases globally, 3.42 million in LMICs and 7.02 million deaths worldwide (as of 24 January 2024).3 SARS-CoV-2 can cause prolonged sequelae and complications, as previously documented for other infections.4–8 People affected by long-term sequelae coined the term Long Covid. WHO later defined post-COVID-19 condition/Long Covid as occurring in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis, generally impacting on functionality.9 Since then, a number of studies have documented a broad spectrum of physical and psychological postacute COVID-19 sequelae affecting both adults and children.10 It is estimated that 6%–10% of adults are affected by Long Covid following SARS-CoV-2 infection.11 Post-COVID-19 sequelae affect adults of all ages across acute disease spectra.12 Hospitalisation has been identified as a risk factor for prolonged COVID-19 recovery.12Due to heterogeneous study designs, case definitions, limited research resources and most studies being concentrated in high-income (HICs) countries, underlying aetiology, precise clinical characteristics, optimal care, the global burden and the wider individual and socioeconomic impact remain uncertain. While studies have shown that COVID-19 vaccination can provide protection against Long Covid, the protection is imperfect.13 14 Limited access to treatment trials has led to people resorting to trialling non-evidence-based experimental Long Covid treatments, with associated risks and costs to individuals, creating moral and ethical dilemmas for clinicians and challenges for trial implementation.

    Despite the many studies exploring Long Covid characteristics, the lack of precise case definitions and heterogeneity in study design and outcome measures have been a challenge for meta-analyses.15 Key commonly reported Long Covid sequelae identified include but are not limited to, fatigue, breathlessness, cognitive dysfunction and cardiovascular, muscular and endocrinological complications.16 17 A systematic review including 39 COVID-19 follow-up studies identified 60 physical and psychological signs and symptoms, with 41% of patients reporting weakness, 31% fatigue, 26% concentration difficulties and 25% breathlessness.15 The review did not identify any studies set in LMICs. LMICs might not have sufficient research or surveillance infrastructure to accurately report the magnitude and effect of COVID-19. Limited access to surveillance and healthcare systems may hide a high burden of Long Covid.18 To address this knowledge gap, we convened an International COVID-19 Global Follow-up Working Group of diverse clinical specialists, researchers and Long Covid patient group representatives to develop a standardised, open-access Global COVID-19 follow-up protocol and case report form (CRF) for implementation in any resourced setting during the pandemic.19–22 The primary aim was to characterise Long Covid, explore risk factors for developing Long Covid and the impact on daily activities and quality of life (QoL) in different regions. The data are relevant for informing strategies and policies to improve equitable long-term COVID-19 outcomes globally.

    Methods

    This is a prospective, observational, international cohort study set in 25 sites in 17 countries (Brazil, Colombia, France, The Gambia, Gibraltar, India, Israel, Italy, Malaysia, Norway, Portugal, Russian Federation, South Africa, Spain, Sudan, Ukraine and the UK). The sites were identified through an open call to sites to collaborate via the International Severe Acute Respiratory and emerging Infection Consortium’s (ISARIC’s) clinical research network, website, newsletter and social media and included sites with a capacity to follow up with participants post-COVID-19 hospital discharge. Adults admitted to the hospital due to or identified with SARS-CoV-2 infection during hospital admission were eligible to participate. Participants were contacted at 2 to <6 months and/or 6 to <12 months postdischarge for a follow-up assessment using ISARIC’s Global COVID-19 follow-up protocol and electronic CRF. We established a diverse, inclusive, open-access ISARIC follow-up working group in May 2020, consisting of international multidisciplinary specialist physicians, researchers, public health professionals and people living with Long Covid and developed the protocol through a series of meetings and email iterations.22 The CRF was piloted in three countries before being finalised as described previously. The CRF was designed to facilitate implementation in any resourced setting by focusing on critical key data, using validated tools and enabling a combination of clinician-led assessments (in-clinic or by phone) and patient self-assessment via (post and online) to support wide dissemination and uptake during the pandemic restrictions. The data were entered into a Research Electronic Database Capture system (REDCap, V.8.11.11, Vanderbilt University, Nashville, Tenn23) and linked with data documented previously during the acute COVID-19 admission collated by the ISARIC Clinical Characterisation Group (online supplemental file) for the analysis. Data were shared with ISARIC’s Global Support Centre at the University of Oxford for integration into a central dataset. Each site investigator was responsible for ensuring local ethical and regulatory approvals and conducting the study on-site.

    Supplemental material

    Study population

    Patients aged 18 years and over admitted to a participating hospital between February 2020 and April 2022 were included in this analysis. Participants were identified via convenience sampling. Patients with laboratory or clinically confirmed COVID-19 diagnosed on or during admission, who consented to be contacted for a posthospital follow-up, for whom a valid contact was provided and who were discharged at least 60 days ago, were eligible for inclusion. We included patients with laboratory or clinically diagnosed COVID-19 since laboratory confirmation depended on the local availability of PCR testing. Any patients with demographic data and at least one answer to the follow-up questions were included in the analysis.

    Variables and outcomes

    Explanatory variables at the time of hospital admission, including age, sex and pre-existing comorbidities, were recorded in the acute CRF,24 and the data captured during the follow-up assessment in the linked follow-up CRF.22 Patients receiving ICU care, high-flow nasal cannulation, non-invasive respiratory support, invasive ventilation and/or vasopressors, were defined as having severe acute COVID-19 as described previously.19 25–27 The primary outcome was self-reported recovery at 2 to <6 or 6 to <12 months following hospital discharge. Secondary outcomes included new or persistent symptoms, breathlessness, fatigue, impact on daily functioning and quality of life (QoL). Breathlessness was measured using the Medical Research Centre (MRC) dyspnoea scale, which grades the effect of breathlessness on daily activities. This 5-point scale measures perceived respiratory disability, with 0 representing no breathlessness and 4 representing an inability to undertake activities of daily living due to breathlessness. Fatigue was measured on a 1–10 Visual Analogue Scale (VAS) where 0 represents no fatigue and 10 represents the worst possible fatigue. The impact on functionality, psychosocial complications and QoL was measured using the EuroQol 5-Dimension 5-level (EQ-5D-5L) instrument. This tool covers five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The person indicates his/her health state for each of the five dimensions. New and persistent symptoms not present prior to their COVID-19 illness were categorised into organ systems and systemic symptoms: (a) Cardiological: palpitations; (b) Dermatological: skin rash, Covid toes; (c) Fatigue; (d) Fever (measured or self-reported), (e) Gastrointestinal: abdominal pain, diarrhoea, constipation, vomiting/nausea; (f) Musculoskeletal: muscle aches/joint pain, ankle swelling; (g) Neurocognitive: headache, problems with sleeping, altered consciousness/confusion, dizziness, tinnitus, problems with balance, paraesthesia, tremor, problems with speaking or communicating, fainting/blackouts, loss of sensation, seizures; (h) Respiratory: cough, cough productive, cough non-productive, shortness of breath, pain in breathing, chest pain and (i) Sensory: lost or altered sense of smell, lost or altered sense of taste (online supplemental file 1: box S1). Patients with at least one symptom group affected at the first follow-up assessment, which was not present prior to COVID-19 onset, were categorised as Long Covid in line with WHO’s definition.28

    Statistical analysis

    Categorical data were expressed as counts and percentages, and continuous data as median (25th–75th percentiles). We described the frequencies of the outcomes across demographic groups (age categories and sex), comorbidities and acute disease severity. We grouped all measures by time interval (2 to <6 months and 6 to <12 months postdischarge). Countries were categorised as LMICs or HICs based on the World Bank country income classification29 (HICs included France, Gibraltar, Israel, Italy, Norway, Portugal, Spain and the UK; LMICs included Brazil, Colombia, The Gambia, India, Malaysia, Russian Federation, South Africa, Sudan and Ukraine). To test for differences across groups, we used a two-proportion z-test. Confidence for the means was calculated using a bootstrap procedure with 1000 iterations group. Risk factors were evaluated using logistic regression, with country income included as a separate covariate. The sensitivity analysis for logistic regression is included in online supplemental file 6 table S3. Other covariates were age, gender, comorbidities and severity at hospitalisation. For breathlessness, we calculated the change in value reported by participants at the follow-up assessment versus before COVID-19 onset. For the health state at the follow-up assessment, we used the EQ-5D-5L tool with the English standardised valuation study protocol value set on the composite time trade-off valuation (https://euroqol.org/publications/user-guides). Overall changes in summary health index, before and after COVID-19 onset, were summarised for the cohort using the Paretian Classification of Health Change method. Summary of the EQ-5D-5L indices index was measured on a scale of 0–1, with 0 reflecting the worst health imaginable; 1 reflecting perfect health. We calculated overall estimates and estimates for individual EQ-5D-5L dimensions, as well as changes in the summary index and individual dimensions. All data processing and statistical analysis were performed using secure R V.4.2.0 (R Foundation for Statistical Computing, Vienna, AUT), with the tidvverse, readxl, ggplot2, gtsummary, reshape and forcats packages using SPSS V.29 (IBM). Scales were transformed into binary variables. For fatigue intensity (10-point VAS), scores ≤4 were classified as 0 (none-to-mild, and scores ≥5 as 1 (moderate-to-severe). Incomplete recovery was measured on a 5-point Likert scale converted to numerical values. Values 1–2 (agree and strongly agree) were categorised as 1 (not completely recovered), values 4–5 (disagree and strongly disagree) categorised as 0 (recovered) and value 3 (neither disagree/agree) as unknown. For breathlessness (initial scales 0–4), the values ≤2 were classified as 0 (none-to-mild breathlessness); values >2 as 1 (moderate-to-severe). The components of EQ-5D-5L (initial range 1–5) were classified as 0 (none-to-mild problems) if the initial value was ≤2 and for values >2 as 1 (moderate-to-severe problems).

    Public and patient involvement

    Patients and people living with Long Covid, including the founding members of the UK Charity, Long Covid Support, were involved in informing the CRF design and in the interpretation and representation of the data and review of the manuscript. The CRF was piloted with patients presenting in clinics in three countries and the feedback incorporated into the final version. This included suggestions on the data on symptoms collected, how questions were asked and the patient information.

    Results

    Of 35 637 participants included in the follow-up studies, 11 860 met the inclusion criteria for this analysis. Of these, 64.3% (7625/11860) were assessed at 2 to <6 months, 55.0% (6520/11860) at 6 to <12 months postdischarge; 19.3% (2285/11860) were assessed at both time points (online supplemental file 2: figure S1: Strengthening the Reporting of Observational Studies in Epidemiology flow chart). 56.5% (6698/11 860) were included in sites in HICs, and 43.5% (5162/11 860) in LMICs sites, in countries in Africa (18.8%, 2228/11 860), Asia (15.8%, 1874/11 860), Europe (60.2%, 7141/11 860) and South America (5.2%, 617/11 860) (figure 1, online supplemental file 3: table S1). The median age was 52.0 (IQR: 41–62) years, 52.1% (6147/11860) were female and 48.5% (5751/11860) were of white ethnicity.

    Figure 1

    Geographical distribution of participating sites. The map shows the distribution of the participating sites in Brazil, Colombia, France, The Gambia, Gibraltar, India, Israel, Italy, Norway, Malaysia, Portugal, Russian Federation, South Africa, Spain, Sudan, Ukraine, and the UK, and their country income classification. HIC, high-income country; LMIC, low-income and middle-income country.

    Pre-existing risk factors

    Most participants (87.3%) were classified as having had moderate acute disease. Hypertension (22.4%, 2659/11 860), diabetes mellitus (10.0%, 1187/11 860) and chronic cardiac disease (6.0%, 707/11 860) were the most common comorbidities. 10% (1190/11860) were obese, and 12.7% (1507/11860) were classified as having had a severe illness during acute hospitalisation (table 1). The participants in LMICs and HICs had a similar age distribution, while those included in LMICs had higher rates of pre-existing hypertension, chronic cardiac disease, HIV and obesity. In contrast, HICs reported a higher prevalence of asthma, chronic pulmonary disease and rheumatological disorders.

    Table 1

    Demographic and clinical cohort characteristics stratified by time point and income classification

    Medium-term and longer-term impact on physical and psychosocial health

    The most commonly reported symptoms were fatigue/malaise, headache, shortness of breath and muscle/joint pain at both follow-up assessments, with a higher frequency reported in HICs versus LMICs (online supplemental 4: figure S2). Of the participants, 37.0% (2400/6402) reported not feeling fully recovered at 2 to <6 months and 46.5% (2863/6152) at 6 to <12 months postdischarge. (online supplemental file 5: table S2). At the 2 to <6 months assessment, participants in HICs were significantly more likely to report moderate-to-severe fatigue (42.9 vs 27.9%, p<0.001), feeling not fully recovered (54.3% vs 18.0%, p<0.001), fever (19.6% vs 2.1%, p<0.001) and have at least one persistent or new symptom (69.0% vs 45.3%, p<0.001) compared with those in LMICs. The proportion reporting anxiety/depression (9.2% vs 5.6%, p<0.001), pain/discomfort (11.6% vs 6.7%, p<0.001) and problems doing usual activities (10.0% vs 3.5%, p<0.001) was also higher in HICs compared with LMICs. In contrast, there were no significant differences in the proportion of moderate-to-severe breathlessness across settings and time points, ranging from 8.4% to 11.8%.

    Similar differences were observed at the later follow-up assessment (6 to <12 months), with a higher proportion of participants in HICs reporting fatigue (41.6% vs 27.9%, p<0.001), not feeling fully recovered (56.8% vs 40.1%, p<0.001), fever (20.3% vs 2.0%, p<0.001) and experiencing at least one persistent or new symptom (69.7% vs 42.4 %, p<0.001) compared with in LMICs. This was also reflected in the QoL and psychosocial assessment; a significantly higher proportion of participants in HICs reported depression/anxiety (11.0% vs 6.3%, p<0.001), pain/discomfort (11.9% vs 7.0%, p<0.001) and having problems doing usual activities (10.6% vs 3.8%, p<0.001) compared with those in LMICs.

    When grouping symptoms into physiological symptom clusters, all clusters were significantly more common in the study population in HICs versus LMICs at both time points. Neurocognitive symptoms were the most commonly reported (48.2% vs 21.8%, p<0.001) at 2 to <6 months; (51.5% vs 19.9%, p<0.001) at 6 to <12 months in HIC vs LMIC), followed by respiratory symptoms (32.9% vs 19.8%, p<0.001 at 2 to <6 months; 32.2% vs 18.7%, p<0.001 at 6 to <12 months in HICs vs LMICs) (figure 2, online supplemental file 4:table S2)

    Figure 2

    Post-COVID-19 sequelae post-hospital discharge in HICs compared with LMICs. The figures present the differences in post-COVID-19 manifestations among participants in lower-to-middle-income settings (blue dots) compared with those in high-income settings (orange dots). The grey shading illustrates the level of significance, dark grey=p< 0.01, medium grey=p<0.05, white=non-significant differences. EQ5D5L, EuroQol 5-Dimension 5-level; HICs, high-income countries; LMIC, lower-income and middle-income countries.

    Breathlessness

    There was a significant increase in the proportion of people experiencing breathlessness at the follow-up assessment compared with prior to their COVID-19 illness. Although the frequency was lower at the 6 to 12 months assessment compared with the earlier assessment, a proportion had still not recovered to pre-COVID-19 levels (figure 3). The most considerable deterioration was observed in breathlessness dynamics: the proportion of those whose breathlessness worsened after COVID-19 is larger than those whose breathlessness remained the same or improved.

    Figure 3

    Breathlessness before and after SARS-CoV-2 infection by setting. The graph shows the level of breathlessness before and after developing COVID-19 measured using the Medical Research Council (MRC) dyspnoea scale. 0=no breathlessness; 1=mild breathlessness, 2=breathlessness, 3=moderate breathlessness; 4=severe breathlessness. HIC, high-income country; LMIC, lower-income and middle-income country.

    Risk factors for developing postacute COVID-19 physical sequelae

    Patients with severe acute COVID-19 during hospitalisation had a higher risk of developing Long Covid, moderate-to-severe fatigue, decreased functioning and QoL at 2 to <6 months follow-up than patients with moderate acute COVID-19 (figure 4a–c). Males had a lower risk of developing Long Covid, moderate-to-severe fatigue, with reduced functioning and QoL than females. Participants from LMICs had a lower risk of developing Long Covid, moderate-to-severe fatigue, with decreased functioning and QoL compared with participants in HICs. Being 45–65 years old was associated with a significantly increased risk of experiencing reduced functioning and QoL compared with younger adults. Pre-existing asthma, chronic pulmonary and rheumatological disease were identified as significant risk factors for developing Long Covid and fatigue, hypertension and chronic cardiac disease were additional risk factors for experiencing reduced functioning and QoL.

    Figure 4

    Risk factors for long -term COVID-19 sequelae The graphs present risk factors for experiencing Long Covid (4a), fatigue (4b) and reduced functioning and quality of life (QoL) (4c), respectively, at 2 -to- < 6 months post-COVID-19 hospital discharge. HIC: high-income country; LMIC: lower-income and middle-income country.

    Discussion

    Our data show that Long Covid affects populations globally, manifesting with similar symptomatology and impact on functioning and QoL. Although the frequency of Long Covid was higher in countries in high-income settings, the impact on individuals may be higher in lower-resourced settings where the healthcare and socioeconomic support infrastructure may be more limited. Our data highlight an urgent need for investment into research, care and support, to identify underlying pathophysiology inform treatment and trials and identify effective and accessible treatment strategies to improve long-term COVID-19 outcomes. The higher rates of persistent symptoms, fatigue and reduced functioning observed in participants from HICs compared with LMICs may be explained by multiple factors. Differences in awareness of the condition, limited healthcare access and ability to seek medical care in lower-resourced settings may lead to underdiagnosis and under-reporting of long-term COVID-19 sequelae. Cultural differences in how symptoms are perceived and reported may also contribute to reporting biases. The differences may also be due to varying underlying pandemic trajectories and viral factors such as the dominating circulating strain at different time points and settings. Later circulating SARS-CoV-2 strains, such as Omicron, were associated with a lower risk of COVID-19 sequelae than earlier pandemic strains.30 The first sites to establish Long Covid cohorts in this study were in HICs, which may bias the inclusion of people with early SARS-CoV-2 strains in these settings.31 In addition, the higher rates of risk factors identified, such as hypertension and asthma in HICs, may also play a role. Due to the complexity of recording ethnicity in large international studies due to the rich, diverse ethnic groups in a globalised world, it was not possible to draw any conclusions on the association between ethnicity and the risk of developing Long Covid. Further research is needed to explore the differences in Long Covid burden observed and explore the impact of host and pathogen factors.

    The most commonly reported symptoms were fatigue/malaise, headache, shortness of breath and muscle/joint pain. Neurocognitive symptoms were the most common when grouping symptoms into clusters, followed by respiratory symptoms. These findings are in agreement with other studies.16 17 Prolonged recovery has featured in other postviral and postintensive care syndrome studies, describing some commonality in symptoms such as breathlessness, fatigue, muscle weakness and impact on QoL. However, these studies identified a lower frequency of postviral complications than post-SARS-CoV-2 studies. This may partly be explained by the challenges in comparing patients with different disease severity. When disease severity is similar to when comparing classic acute respiratory distress syndrome (ARDS) versus COVID-19-associated ARDS (CARDS), a study identified that persisting disability may be more common in survivors of classic ARDS compared with CARDS.32 However, cognitive and psychological health status may be relatively less frequently impaired than physical functioning.33

    Interestingly, in contrast to the other outcomes with diverse frequencies between study populations and over time, there were no significant differences in the proportion of participants with moderate-to-severe breathlessness between LMICs and HICs, nor assessment time points. Approximately 1 in 10 participants was affected by moderate-to-severe breathlessness, which aligns with global estimates of Long Covid. Breathlessness was assessed using a validated, well-recognised and tested tool, the MRC dyspnoea scale, recognised as the key instrument for measuring core outcome sets in Long Covid studies.34

    Our data illustrate the importance of implementing standardised and validated tools to identify reliable data and facilitate comparative analysis. The reason for the differences in presentation may relate to wider factors as described earlier, but it also suggests that there may be different underlying aetiology, such as specific organ damage, persistent, infection-triggered autoimmunity and dysautonomia behind different clusters of symptoms. Breathlessness, may be related to direct lung or cardiovascular organ damage, cellular gas exchange and/or diaphragm muscle impairment. Radiological Long Covid abnormalities have been identified in various organs, including the olfactory bulb, brain, heart and lungs35 Micro clots and hypercoagulation biomarkers indicating endothelial activation and abnormal clotting have been implicated as causative agents for some Long Covid symptoms.35 The high proportion of people with new or persistent fever identified in our study might be explained by a persistent infection. Both persistent SARS-CoV-2 infection and reactivation of Epstein-Barr virus have been proposed as possible underlying causative agents of long COVID.35 36 Further research is needed to identify the underlying pathophysiological mechanisms to guide treatment trials and provide more precise case definitions to guide diagnostic and care referral pathways and inclusion in trials.

    The proportion of people reporting newly developed or persistent symptoms not experienced before onset of their COVID-19 illness was higher than those reporting not feeling fully recovered. This indicates that existing Long Covid definitions are too broad, lacking the precision needed to guide clinical and public health management. This poses a risk of Long Covid being misdiagnosed, with associated risks and impact on patients and health systems from both overdiagnosis and underdiagnosis.

    This study has limitations: it was not possible to follow up with all possible participants discharged from the study hospitals due to a combination of factors, including pandemic resource constraints, contact details not being available, patients not responding to the invitation or not consenting to participate. Although efforts were made to facilitate inclusion, such as using multiple contact methods (mail, telephone and online) in different languages, it may be that non-responders were too unwell to respond, did not receive the invite, had died or moved away, had recovered or were not interested in participating. Therefore, the results may not fully represent the population of people hospitalised with COVID-19 in the participating hospitals and countries. This potential completion bias may mean that the data is underestimating or overestimating the prevalence. Further, patients were asked to retrospectively rate their health status before their COVID-19 onset, which may be impacted by recall bias. The different data collection methods (clinician-led assessment in the clinic and by phone or online) designed for broad uptake during the pandemic constraints and cultural interpretation of the questions may add heterogeneity. Due to resource and pandemic constraints, we could not include a control group of participants hospitalised with a non-COVID-19 illness. As the pandemic progressed through waves of new and more transmissible strains, identifying and ascertaining meaningful controls became increasingly difficult. Therefore, it was not possible to fully assess pandemic-related factors impacting QoL. However, similar symptoms presenting in different countries during the study period indicate that pandemic restrictions are not the likely aetiology. Finally, due to the different ethnicity definitions in countries, and regulations in some countries preventing documentation of ethnicity, a sensitive analysis based on different ethnicities was not feasible.

    Despite these limitations, this is, to our knowledge, the largest international study on Long Covid using a standardised data collection form and predominantly clinician-led assessments, enabling characterisation and comparison of Long Covid and its impact on functioning in participants following COVID-19 hospitalisation in different resourced settings globally.

    Reflecting on this study, similar research in future could be improved by (1) developing a pathogen-blind protocol including appropriate control groups, hibernating studies and making logistical provision for swift deployment of a study for future epidemics and pandemics; (2) collecting information about postinfection sequelae in both hospitalised and community cohorts in a single study to facilitate comparison between these groups; (3) linking postinfection studies to studies of the acute illness to facilitate improved data linkage and reduce loss to follow-up and (4) consider strategies to include poorly represented groups such as low-income countries, rural communities, children, the elderly and any minority ethnic groups within countries.

    The data show that a significant proportion of adults hospitalised with COVID-19 in HICs and LMICs are impacted by long-term sequelae 1-year postdischarge, presenting with similar symptoms, illustrating that Long Covid is a universal health issue. The WHO Post-Covid Condition definition is broad and does not distinguish between different underlying pathophysiology. Our data show the urgent need to define Long Covid clusters, to guide clinical referral pathways and inclusion in trials.

    The wide range of symptoms identified indicates that patients may present to multiple specialities within the healthcare system. Highlighting the need to establish clear referral pathway guidelines accessible in front-line primary and secondary care clinics, supported by access to appropriate diagnostics and treatments. Despite the global research effort during the pandemic, most funding was channelled into acute trials. Many research priorities identified at an international stakeholder forum organised by the WHO and GloPID-R in December 2020 remain unanswered, largely due to a lack of investment into and coordination of research during the pandemic.37 In the future, we need to integrate standardised follow-up protocols into clinical studies and adaptive trial platforms to strengthen our capacity for timely data generation to inform the clinical and public health response.

    Conclusions

    Our study shows that Long Covid affects populations globally, with a significant proportion of people experiencing persistent symptoms impacting on functioning and QoL a year after COVID-19 onset. The data emphasise the potential long-term impact on population health globally, which may disproportionately impact economically disadvantaged populations.

    In HICs, the prevalence of Long Covid is higher. This may reflect better awareness, along with a broader range of reported symptoms, including significant neurocognitive and psychosocial issues. This underscores the importance of accessible and comprehensive healthcare systems, as well as robust mental health and social support. In LMICs, the lower reported prevalence may suggest under-reporting due to limited healthcare access and resources, however, the proactive follow-up that this study required may have ameliorated these issues.

    Long Covid may have a disproportionately severe impact on daily functioning in LMICs, compounded by inadequate healthcare infrastructure and higher rates of pre-existing conditions.

    There is an urgent need for significant investment in healthcare capacity building in both HICs and LMICs to improve diagnosis, management and support for Long Covid. As COVID-19 becomes endemic, continuing to infect and reinfect people worldwide, further investments in identifying effective prevention and treatment of acute and long-term complications accessible to all populations are essential to improve outcomes.

    Data availability statement

    Data are available on reasonable request. The data that underpin this analysis are highly detailed clinical data on individuals hospitalised with COVID-19. Due to the sensitive nature of these data and the associated privacy concerns, they are available via a governed data access mechanism following review of a data access committee. Data can be requested via the IDDO COVID-19 Data Sharing Platform (http://www.iddo.org/covid-19). The Data Access Application, Terms of Access and details of the Data Access Committee are available on the website. Briefly, the requirements for access are a request from a qualified researcher working with a legal entity who have a health and/or research remit; a scientifically valid reason for data access which adheres to appropriate ethical principles. The full terms are at https://www.iddo.org/document/covid-19-data-access-guidelines. A small subset of sites who contributed data to this analysis have not agreed to pooled data sharing as above. In the case of requiring access to these data, please contact the corresponding author in the first instance who will look to facilitate access.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and ethical approval was given in the UK by the South Central—Oxford C Research Ethics Committee in England ((ref 13)/SC/0149) and the Scotland A Research Ethics Committee ((ref 20)/SS/0028). Clinica Universidad de La Sabana (MED-309-201). Each site was responsible for ethical approvals before commencing the study in each setting. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We would like to thank all the clinical and research staff, who performed the follow-up assessments and collected this data, and the participants for their individual contributions in these difficult times. We would also like to thank the Long Covid Support and ISARIC's Global Support Centre for their invaluable support, with special thanks to Sarah Moore and Muriel Lunn. The investigators acknowledge the philanthropic support of the donors to the University of Oxford’s COVID-19 Research Response Fund; COVID clinical management team, AIIMS, Rishikesh, India; COVID-19 Clinical Management team, Manipal Hospital Whitefield, Bengaluru, India; Italian Ministry of Health “Fondi Ricerca corrente–L1P6” to IRCCS Ospedale Sacro Cuore–Don Calabria; The dedication and hard work of the Groote Schuur Hospital Covid ICU Team, supported by the Groote Schuur nursing and University of Cape Town registrar bodies coordinated by the Division of Critical Care at the University of Cape Town; the dedication and hard work of the Norwegian SARS-CoV-2 study team; and Preparedness work conducted by the Short Period Incidence Study of Severe Acute Respiratory Infection. This work uses data provided by patients and collected by the NHS as part of their care and support #DataSavesLives. The data used for this research were obtained from ISARIC4C. We are extremely grateful to the 2648 frontline NHS clinical and 22 research staff and volunteer medical students who collected these data in challenging circumstances; and the generosity of the patients and their families for their individual contributions in these difficult times. The COVID19 Clinical Information Network (CO-CIN) data was collated by ISARIC4C Investigators. We also acknowledge the support of Jeremy J Farrar and Nahoko Shindo.

    References

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • EP, EG-G and LFR are joint first authors.

    • JTS, DM and LS are joint senior authors.

    • Handling editor Helen J Surana

    • X @NickLatronico, @epi_michael, @JTSGlobalHealth, @louise_sigfrid

    • Collaborators ISARIC Global Covid-19 follow-up working group: Laurent Abel, Amal Abrous, Younes Ait Tamlihat, Aliya Mohammed Alameen, Marta Alessi, Beatrice Alex, Kévin Alexandre, Adam Ali, Kazali Enagnon Alidjnou, Clotilde Allavena, Nathalie Allou, Claire Andrejak, Andrea Angheben, François Angoulvant, Séverine Ansart, Jean-Benoît Arlet, Elise Artaud-Macari, Jean Baptiste Assie, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Eyvind W. Axelsen, Laurène Azemar, Cecile Azoulay, Benjamin Bach, Delphine Bachelet, Claudine Badr, John Kenneth Baillie, Firouzé Bani-Sadr, Wendy S. Barclay, Marie Bartoli, Joaquín Baruch, Romain Basmaci, Jules Bauer, Alexandra Bedossa, Husna Begum, Marine Beluze, Nicolas Benech, Delphine Bergeaud, José Luis Bernal Sobrino, Giulia Bertoli, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Krishna Bhavsar, Zeno Bisoffi, Laurent Bitker, Mathieu Blot, Laetitia Bodenes, Debby Bogaert, Anne-Hélène Boivin, Isabela Bolaños, Pierre-Adrien Bolze, Raphaël Borie, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Anne-Sophie Boureau, Maude Bouscambert, Aurore Bousquet, Marielle Boyer-Besseyre, Axelle Braconnier, Sonja Hjellegjerde Brunvoll, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Ingrid G. Bustos, Denis Butnaru, Roar Bævre-Jensen, André Cabie, Eder Caceres, Cyril Cadoz, Jose Andres Calvache, Valentine Campana, Pauline Caraux-Paz, Nicolas Carlier, Thierry Carmoi, Marie-Christine Carret, Gail Carson, Maire-Laure Casanova, Guylaine Castor-Alexandre, François-Xavier Catherine, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chakveatze, Meera Chand, Jean-Marc Chapplain, Charlotte Charpentier, Julie Chas, Léo Chenard, Antoine Cheret, Thibault Chiarabini, Catherine Chirouze, Bernard Cholley, Marie-Charlotte Chopin, Yock Ping Chow, Barbara Wanjiru Citarella, Sara Clohisey, Gwenhaël Colin, Marie Connor, Graham S. Cooke, Hugues Cordel, Andrea Cortegiani, Grégory Corvaisier, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Juan Luis Cruz Bermúdez, Jaime Cruz Rojo, Elodie Curlier, Eric D'Ortenzio, Ana da Silva Filipe, Charlene Da Silveira, Andrew Dagens, John Arne Dahl, Jo Dalton, Etienne De Montmollin, Cristina De Rose, Thushan de Silva, Nathalie DeCastro, Alexa Debard, Marie-Pierre Debray, Romain Decours, Eve Defous, Isabelle Delacroix, Karen Delavigne, Christelle Delmas, Pierre Delobel, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Diane Descamps, Mathilde Desvallées, Alpha Diallo, Sylvain Diamantis, Fernanda Dias Da Silva, Kévin Didier, Jean-Luc Diehl, Vincent Dinot, Fara Diop, Alphonsine Diouf, Félix Djossou, Annemarie B. Docherty, Christl A. Donnelly, Céline Dorival, Nathalie Dournon, Thomas Drake, Amiel A. Dror, Vincent Dubee, François Dubos, Alexandre Ducancelle, Susanne Dudman, Paul Dunand, Jake Dunning, Bertrand Dussol, Xavier Duval, Anne Margarita Dyrhol-Riise, Michael Edelstein, Linn Margrete Eggesbø, Mohammed El Sanharawi, Brigitte Elharrar, Merete Ellingjord-Dale, Philippine Eloy, Isabelle Enderle, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Marc Fabre, Isabelle Fabre, Cameron J. Fairfield, Karine Faure, Raphaël Favory, François-Xavier Ferrand, Eglantine Ferrand Devouge, Nicolas Ferriere, Céline Ficko, William Finlayson, Thomas Flament, Tom Fletcher, Aline-Marie Florence, Victor Fomin, Erwan Fourn, Christophe Fraser, Stéphanie Fry, Valérie Gaborieau, Rostane Gaci, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Linda Gail Skeie, Sérgio Gaião, Carrol Gamble, Esteban Garcia-Gallo, Noelia García Barrio, Denis Garot, Valérie Garrait, Anatoliy Gavrylov, Alexandre Gaymard, Eva Geraud, Louis Gerbaud Morlaes, Jade Ghosn, Tristan Gigante, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Petr Glybochko, François Goehringer, Kyle Gomez, Marie Gominet, Yanay Gorelik, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Pascal Granier, Christopher A. Green, William Greenhalf, Segolène Greffe, Fiona Griffiths, Jérémie Guedj, Martin Guego, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Thomas Guimard, Ali Hachemi, Nadir Hadri, Matthew Hall, Sophie Halpin, Rebecca Hamidfar, Bato Hammarström, Hayley Hardwick, Ewen M. Harrison, Janet Harrison, Lars Heggelund, Ross Hendry, Maxime Hentzien, Diana Hernandez, Rupert Higgins, Hikombo Hitoto, Antonia Ho, Alexandre Hoctin, Isabelle Hoffmann, Jan Cato Holter, Peter Horby, Ikram Houas, Jean-Sébastien Hulot, Samreen Ijaz, Patrick Imbert, Mariachiara Ippolito, Margaux Isnard, Mette Stausland Istre, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Stéphane Jaureguiberry, Florence Jego, Synne Jenum, Cédric Joseph, Mercé Jourdain, Silje Bakken Jørgensen, Ouifiya Kafif, Florentia Kaguelidou, Sabina Kali, Karl Trygve Kalleberg, Christiana Kartsonaki, Seán Keating, Sadie Kelly, Kalynn Kennon, Younes Kerroumi, Antoine Khalil, Saye Khoo, Beathe Kiland Granerud, Anders Benjamin Kildal, Antoine Kimmoun, Eyrun Floerecke Kjetland Kjetland, Paul Klenerman, Gry Kloumann Bekken, Stephen R Knight, Arsène Kpangon, Oksana Kruglova, Galyna Kutsyna, Marie Lachatre, Marie Lacoste, Nadhem Lafhej, Marie Lagrange, Fabrice Laine, Olivier Lairez, Antonio Lalueza, Marc Lambert, Marie Langelot-Richard, Vincent Langlois, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Sylvie LeGac, Jennifer Lee, Gary Leeming, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefèvre, Jean-Daniel Lelievre, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Marc Leone, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Sophie Letrou, Bruno Levy, Yves Levy, Claire Levy-Marchal, Geoffrey Liegeon, Wei Shen Lim, Bruno Lina, Andreas Lind, Guillaume Lingas, Sylvie Lion-Daolio, Marine Livrozet, Paul Loubet, Bouchra Loufti, Guillame Louis, Jean-Christophe Lucet, Carlos Lumbreras Bermejo, Miles Lunn, Liem Luong, Dominique Luton, Moïse Machado, Gabriel Macheda, Guillermo Maestro de la Calle, Rafael Mahieu, Sophie Mahy, Mylène Maillet, Thomas Maitre, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Julie Mankikian, Aldric Manuel, Samuel Markowicz, Laura Marsh, Guillaume Martin-Blondel, Martin Martinot, Olga Martynenko, Mathieu Mattei, Laurence Maulin, Thierry Mazzoni, Sarah E. McDonald, Kenneth A. McLean, Cécile Mear-Passard, France Mentré, Alexander J. Mentzer, Emmanuelle Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Laura Merson, Roberta Meta, Agnès Meybeck, Alison M. Meynert, Vanina Meysonnier, Mehdi Mezidi, Isabelle Michelet, Shona C. Moore, Sarah Moore, Lina Morales Cely, Lucia Moro, Clara Mouton Perrot, Julien Moyet, Jimmy Mullaert, Daniel Munblit, Marlène Murris, Srinivas Murthy, Alamin Mustafa, Karl Erik Müller, Fredrik Müller, Ebrahim Ndure, Nadège Neant, Nikita Nekliudov, Anthony Nghi, Duc Nguyen, Mahdad Noursadeghi, Saad Nseir, Elsa Nyamankolly, Anders Benteson Nygaard, Piero L. Olliaro, Wilna Oosthuyzen, Peter Openshaw, Claudia Milena Orozco-Chamorro, Paul Otiku, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Maïder Pagadoy, Justine Pages, Massimo Palmarini, Carlo Palmieri, Nathalie Pansu, Aurélie Papadopoulos, Jérémie Pasquier, Bruno Pastene, Christelle Paul, William A. Paxton, Jean-François Payen, Miguel Pedrera Jiménez, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Daniel Perez, Thomas Perpoint, Vincent Pestre, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Walter Picard, Olivier Picone, Lionel Piroth, Chiara Piubelli, Riinu Pius, Laurent Plantier, Julien Poissy, Ryadh Pokeerbux, Georgios Pollakis, Diane Ponscarme, Sébastien Preau, Mark G. Pritchard, Víctor Quirós González, Else Quist-Paulsen, Christian Rabaud, Marie Rafiq, Blandine Rammaert, Christophe Rapp, Stanislas Rebaudet, Sarah Redl, Dag Henrik Reikvam, Anne-Sophie Resseguier, Matthieu Revest, Luis Felipe Reyes, Antonia Ricchiuto, Laurent Richier, Patrick Rispal, Karine Risso, Stephanie Roberts, David L. Robertson, Olivier Robineau, Paola Rodari, Amanda Rojek, Roberto Roncon-Albuquerque Jr, Mélanie Roriz, Manuel Rosa-Calatrava, Andrea Rossanese, Patrick Rossignol, Carine Roy, Benoît Roze, Clark D. Russell, Aleksander Rygh Holten, Nadia Saidani, Charlotte Salmon Gandonniere, Hélène Salvator, Olivier Sanchez, Vanessa Sancho-Shimizu, Pierre-François Sandrine, Benjamine Sarton, Egle Saviciute, Arnaud Scherpereel, Marion Schneider, Janet T. Scott, Nicholas Sedillot, Malcolm G. Semple, Eric Senneville, Pablo Serrano Balazote, Catherine A. Shaw, Victoria Shaw, Nassima Si Mohammed, Jeanne Sibiude, Louise Sigfrid, Dario Sinatti, Vegard Skogen, Sue Smith, Lene Bergendal Solberg, Tom Solomon, Agnès Sommet, Albert Sotto, Edouard Soum, Elisabetta Spinuzza, Shiranee Sriskandan, Sarah Stabler, Trude Steinsvik, Birgitte Stiksrud, David Stuart, Charlotte Summers, Andrey Svistunov, Arne Søraas, Renaud Tamisier, Coralie Tardivon, Pierre Tattevin, Marie-Capucine Tellier, Olivier Terrier, Nicolas Terzi, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Emma C. Thomson, Mathew Thorpe, Ryan S. Thwaites, Vadim Tieroshyn, Peter S Timashev, Jean-François Timsit, Noémie Tissot, Kristian Tonby, Cécile Tromeur, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Lance C.W. Turtle, Anders Tveita, François Téoulé, Timothy M. Uyeki, Piero Valentini, Sylvie Van Der Werf, Noémie Vanel, Charline Vauchy, Aurélie Veislinger, Fanny Vuotto, Steve Webb, Jia Wei, Murray Wham, Paul Henri Wicky, Aurélie Wiedemann, Natalie Wright, Yazdan Yazdanpanah, Cécile Yelnik, Hodane Yonis, Marion Zabbe, Maria Zambon, David Zucman.

    • Contributors JTS and LS developed the initial concept of the ISARIC Global follow-up study, convened and chaired the ISARIC Global Follow-up Working Group of site investigators, multidisciplinary clinical specialists, researchers and Long Covid support representatives. LS and JTS led on developing the protocol and case report form in collaboration with the ISARIC Global Follow-up Working Group and members of Long COVID support (CH and MO'H). The individual site investigators led on setting up and implementing the study in their respective sites. Local site investigators identified participants during the acute admission, ensured consent and entered acute and follow-up patient data into the database. LM managed the REDCap database, VB central trial project management, SK and EG-G data curation. EP and EG-G led the data analysis. EP, LS, EG-G, LFR, DM, BPG, CK, ABK and JTS led the data visualisation and interpretation of the data. EP, DM, LFR, ABK, JTS and LS led on drafting of the manuscript, with input from all the coauthors. All coauthors informed the data representation and reviewed the manuscript before submission. LS is the guarantor In accordance with BMJ’s policy on the use of artificial intelligence (AI) in academic literature, we declare that AI technology was used in a limited capacity during the preparation of this manuscript. Specifically, we used Claude 3.5 Sonnet, an AI language model developed by Anthropic, for the following purposes: proofreading and grammatical corrections. Minor text refinements to improve clarity and readability. Assistance in structuring responses to reviewer comments. Claude 3.5 Sonnet was used to enhance the clarity and readability of the text while maintaining the integrity of the authors’ original work and ideas. It was not used for data analysis, interpretation of results or generation of scientific content. All original ideas, research design, data collection, analysis and primary writing were conducted by the human authors. We did not use AI technologies in any research underpinning this manuscript or in the creation of key sources cited. The AI outputs were carefully reviewed and edited by the authors to ensure accuracy and appropriateness. The authors take full responsibility for the content of this manuscript, including any text refined with the assistance of Claude 3.5 Sonnet.

    • Conceptualization

    • Data curation

    • Formal analysis

    • Methodology

    • Writing – original draft

    • Writing – review and editing

    • Funding This work was made possible with the support of the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z and 220757/Z/20/Z]; the Bill & Melinda Gates Foundation [OPP1209135]; the philanthropic support of the donors to the University of Oxford’s COVID-19 Research Response Fund (0009109); grants from the National Institute for Health Research (NIHR; award CO-CIN-01/DH_/Department of Health/United Kingdom), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award ISBRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support; the Comprehensive Local Research Networks (CLRNs) of which PJMO is an NIHR Senior Investigator (NIHR201385); Cambridge NIHR Biomedical Research Centre (award NIHR203312); a Research Council of Norway grant no 312780, and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner; the South Eastern Norway Health Authority and the Research Council of Norway; Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115523, COMBACTE, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013) and EFPIA companies, in-kind contribution; grants from Instituto de Salud Carlos III, Ministerio de Ciencia, Spain; the French COVID cohort (NCT04262921) is sponsored by INSERM and is funded by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n°20-0424); Brazil, National Council for Scientific and Technological Development Scholarship number 303953/2018-7; Institute for Clinical Research (ICR), National Institutes of Health (NIH) supported by the Ministry of Health Malaysia; and The Universidad de La Sabana (MED-309-201).This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z], the Bill & Melinda Gates Foundation [OPP1209135], the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), the National Institute for Health Research (NIHR) (CSA2022GloPID-R -3387) using UK Aid from the UK Government to support global health research, as part of the EDCTP2 Programme supported by the European Union. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, the UK Department of Health and Social Care or EDCTP. The Universidad de La Sabana (MED-309-201), the Research Council of Norway (grant number 312780). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

    • Disclaimer The study sponsors and funders had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication. Investigators were independent of funders, and the corresponding authors had full access to all the data in the study and were responsible for the decision to submit it for publication.

    • Map disclaimer The inclusion of any map (including the depiction of any boundaries therein), or of any geographic or locational reference, does not imply the expression of any opinion whatsoever on the part of BMJ concerning the legal status of any country, territory, jurisdiction or area or of its authorities. Any such expression remains solely that of the relevant source and is not endorsed by BMJ. Maps are provided without any warranty of any kind, either express or implied.

    • Competing interests JTS was Co-Chair of the ISARIC COVID Global follow up group. NL received a grant from the Italian Ministry of Health to support this work and received support from the National Congress of the Italian Society of Anesthesia and Critical Care Medicine SIAARTI for travel and accommodation expenses to attend a meeting. MoH Trustee is a Trustee of Long Covid Support.

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.