Abstract
Background In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge.
Methods Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions–Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias.
Findings Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI −0.026–0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change −0.12±0.22 versus −0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups.
Interpretation Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.
Shareable abstract
Systemic corticosteroids given for acute COVID-19 do not affect health-related quality of life or other patient-reported outcomes, physical and mental health outcomes, or organ function 1 year after hospital discharge. https://bit.ly/3XR45Ln
Introduction
The discovery of vaccines and effective treatments for acute coronavirus disease 2019 (COVID-19) (corticosteroids (dexamethasone), anti-interleukin (IL)-6 agents, monoclonal antibodies and Janus kinase inhibitors) have reduced progression to invasive mechanical ventilation and improved mortality [1–4]. However, many survivors experience persistent symptoms, physical and mental health effects, cognitive impairment, and multi-system organ damage, which can reduce health-related quality of life (HRQoL) for years after the initial infection (at least 4 years to date) [5–7].
Definitions for post-COVID-19 sequelae vary [8, 9], but the patient-derived term “long COVID” is now commonly used to describe persistent symptoms beyond 4 weeks after the acute infection [10]. The mechanisms underlying long COVID are complex, multifaceted and not yet fully understood, but potentially include persistent inflammation, which is associated with the severity of ongoing health impairments [5, 11]. Corticosteroids prescribed for acute COVID-19 requiring supplemental oxygen may potentially reduce the risk and severity of long COVID by attenuating the acute inflammatory burden [12].
Many of the large acute COVID-19 therapeutic trials, including RECOVERY [1–4], did not have detailed follow-up, which limits understanding of the longer-term effects, and it would now be unethical to randomise patients to placebo rather than corticosteroids. Adults previously randomised to receive acute corticosteroids on intensive care showed no improvement in HRQoL at 6 months compared to usual care [13], although a small observational study suggested a modest benefit in some quality of life domains and persistence of symptoms in patients who had received corticosteroids [12]. We have previously reported no acute corticosteroid effect on patient-perceived recovery at 1 year [6]. However, it is unknown whether corticosteroids during acute COVID-19 requiring supplemental oxygen affect other longer-term sequelae.
Using data from the PHOSP-COVID (Post-hospitalisation COVID-19) [14] and ISARIC (International Severe Acute Respiratory and emerging Infection Collaboration) [15] studies, we aimed to investigate whether treatment with corticosteroids in patients with COVID-19 requiring oxygen supplementation was associated with improved HRQoL 1 year after hospital discharge. Additionally, we aimed to investigate the effect of acute corticosteroids on a broad range of secondary health outcomes.
Methods
Study design
This was a longitudinal cohort study using data from two UK multicentre prospective cohort studies. Adults discharged from hospital after COVID-19 between 1 February 2020 and 31 March 2021 were recruited from 36 UK National Health Service (NHS) hospital sites as part of the PHOSP-COVID study previously described [14]. Data were collected 1 year after hospital discharge, including patient-reported recovery, physical and mental health status, and measures of organ impairment (detailed below). Pre-hospital EuroQol-Five Dimensions–Five Levels utility index (EQ-5D-5L UI) was completed retrospectively at a study visit 2–7 months after hospital discharge, with participants considering their quality of life prior to admission for COVID-19.
For the sensitivity analysis, we used data from the ISARIC study [15], which included more than 300 000 patients admitted to over 200 NHS hospitals across England, Scotland and Wales with COVID-19.
Participants
Eligibility criteria for PHOSP-COVID have been previously described in detail [14]. For this analysis we selected participants who required supplemental oxygen therapy (World Health Organization (WHO) clinical progression scale 5), noninvasive ventilatory support (WHO clinical progression scale 6) or invasive mechanical ventilation (WHO clinical progression scale 7–9) [16] during their hospital admission in accordance with current guideline requirements for corticosteroid use in COVID-19 [17] and who had completed an EQ-5D-5L UI at their 1 year study visit. We excluded patients on pre-existing immunosuppressant medications (including systemic corticosteroids in the 14 days prior to hospital admission) and where corticosteroid exposure was unknown or not recorded (figure 1).
Consort diagram demonstrating study population included in co-primary outcomes of the EuroQol-Five Dimensions–Five Levels utility index (EQ-5D-5L UI) at 1 year (A), and change in EQ-5D-5L UI from pre-hospital to 1 year (B), and sensitivity analysis (C). “Tier 1” participants had collection of routine clinical data with linkage to retrospective and prospective health and social care records only. “Tier 2” participants underwent enhanced clinical data collection and research-specific biosampling at two further research visits following hospital discharge, including collection of the study outcomes. ISARIC: International Severe Acute Respiratory and emerging Infection Consortium cohort; PHOSP: Post-hospitalisation cohort.
For the sensitivity analysis, we analysed a subset of the ISARIC study cohort, who were admitted with COVID-19 in the same study period and meeting the same WHO clinical progression scale criteria [15] (figure 1).
Exposure
Patients who received any systemic (oral or intravenous) corticosteroid during their hospital admission for COVID-19 were compared to those who did not.
Outcomes
The primary outcome was HRQoL, assessed by the EQ-5D-5L UI [18]. EQ-5D-5L UI 1 year after hospital discharge and change in EQ-5D-5L UI from pre-hospital to 1 year were compared between corticosteroid exposed and nonexposed patients.
Secondary outcomes were patient-perceived recovery (patient-reported recovery rate, symptom count, fatigue visual analogue scale (VAS), breathlessness VAS), physical health status (dyspnoea-12 score [19], Functional Assessment of Chronic Illness Therapy fatigue score [20], Washington Group Short Set on Functioning score [21], incremental shuttle walk test distance [22], Short Physical Performance Battery score [23]), cognitive impairment and mental health status (Montreal Cognitive Assessment) score) [24], Generalised Anxiety Disorder-7 score [25], Patient Health Questionnaire-8 score [26], Post-traumatic Stress Disorder Checklist-5 score [27]) and organ function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, carbon monoxide transfer coefficient, transfer factor of the lung for carbon monoxide, brain-natriuretic peptide, haemoglobin A1C, estimated glomerular filtration rate, C-reactive protein, fibrinogen).
Bias
Several potential sources of bias were considered a priori, as follows: 1) bias in treatment decisions made by clinicians (prior to corticosteroids becoming standard care in June 2020); 2) selection bias regarding who participated in the PHOSP-COVID study; and 3) survivor bias due to participants being recruited to PHOSP-COVID after hospital discharge (i.e., survivors). A statistical analysis plan was developed including the use of propensity weighting to ensure balance between treatment groups in the primary analysis and sensitivity analyses using data from the ISARIC study.
Statistical analysis
The main analysis was undertaken using the PHOSP-COVID cohort. A logistic regression model was fitted to estimate propensity for exposure to corticosteroids. An average treatment effect of corticosteroid treatment on the outcomes (primary and secondary) was calculated weighted by the inverse of propensity for exposure using either linear or logistic regression, depending on the distribution of the outcome. The following variables, which potentially influence treatment decisions, were included in the propensity model: age, sex, obesity status, ethnicity, index of multiple deprivation [28], WHO Clinical Progression Scale status, smoking status, presence of specific comorbidities (cardiovascular, respiratory, metabolic/endocrine/renal, neurological/psychiatric (defined in table S1)) and total number of comorbidities. Multiple Imputation by Chained Equations was performed to deal with missing data for the variables used in the propensity model. Summary statistics tables were produced for patients by exposure status, visually inspecting the distribution of propensity scores and evaluating imbalance between groups by standardised mean difference (SMD).
Sensitivity analyses
Sensitivity analyses were performed using the ISARIC dataset to address selection, treatment and survivor biases in PHOSP-COVID (supplementary methods). In summary, a propensity score weighting for corticosteroid treatment was developed in the ISARIC cohort (survivors and nonsurvivors) using logistic regression. The PHOSP-COVID dataset was used to develop a prediction model for EQ-5D-5L UI at 1 year. We used this model to calculate predicted 1-year EQ-5D-5L UI values for those that survived COVID-19 hospitalisation in the ISARIC cohort (1000 estimates per patient). Adults that did not survive were assigned an EQ-5D-5L UI value of zero. Participants who were in both ISARIC and PHOSP-COVID cohorts were assigned their PHOSP-COVID EQ-5D-5L UI value. The 1000 datasets created were sub-sampled down to the PHOSP-COVID dataset size to ensure robust standard errors (1000 random samples of each dataset). These datasets were used to produce an average treatment effect of corticosteroid exposure on EQ-5D-5L UI weighted by the inverse of propensity for exposure using linear regression.
The sensitivity analysis addressed selection and survivor bias by using the structure of the ISARIC population (assuming the ISARIC population was similar to all hospitalised patients with COVID-19 eligibility to receive corticosteroids). The ISARIC cohort included participants who did not survive hospitalisation with COVID-19. Biased treatment assignment was accounted for by developing a propensity score with corticosteroid as the dependent variable, which was developed in the ISARIC cohort and therefore independent of survival status at hospital discharge.
Statistical analysis was undertaken using R (version 4.2.0) with the tidyverse, tidymodels, mice, finalfit, WeightIt and tableone packages for all statistical analyses. The study is reported using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Permissions
PHOSP-COVID was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107). ISARIC was approved by the South Central – Oxford C Research Ethics Committee in England and the Scotland A Research Ethics Committee.
Results
The relevant PHOSP-COVID cohort consisted of 2697 participants, of whom 2248 required at least supplemental oxygen and were discharged from hospital between 1 February 2020 and 31 March 2021. There were 1888 participants with nonmissing corticosteroid information not prescribed immunosuppressant medication pre-hospital, of which 1149 (60.9%) were corticosteroid-exposed and 739 (39.1%) were corticosteroid-nonexposed. 1226 participants had an EQ-5D-5L UI score at their 1-year visit and 1057 participants had both pre-hospital and 1-year EQ-5D-5L UI scores (figure 1). There were no meaningful differences in baseline characteristics between included participants and those excluded due to absent 1-year EQ-5D-5L UI data (table S2).
Baseline characteristics for the 1888 included participants demonstrated a mean age of 58.6 years with 64.4% being male. 75.1% were white, 10.1% South Asian, 7.3% black and 7.5% other ethnicity. 58.6% were obese (body mass index ≥30 kg·m−2), and 43.8% had two or more comorbidities (table S3). Prior to propensity weighting some baseline characteristics were imbalanced between treatment groups, as demonstrated by an SMD of >0.1 (table S3). Participants treated with corticosteroids were slightly younger compared to those not receiving corticosteroids (58.0 versus 59.7 years) and had greater prevalence of white ethnicity (76.8% versus 72.5%), deprivation (49.5% versus 41.0% in lowest two deprivation index quintiles) and obesity (61.0% versus 55.8%). The corticosteroid group had a lower proportion of “never-smokers” (54.9% versus 56.4%). There were also differences in the level of respiratory support required between patients treated with corticosteroid and those not: 51.5% versus 54.7% received low-flow oxygen (WHO scale 5), 33.3% versus 22.6% received noninvasive respiratory support (WHO scale 6) and 15.1% versus 22.7% received invasive mechanical ventilation (WHO scale 7–9).
Propensity weighting successfully achieved balance between the treatment groups, as demonstrated by an SMD <0.1 for all recorded baseline outcomes (table 1).
Baseline characteristics after propensity weighting
Primary outcomes
After propensity weighting for treatment, there was no statistically significant difference in EQ-5D-5L UI at 1 year between corticosteroid exposed (mean±sd 0.72±0.25) and nonexposed (0.71±0.25) groups (mean difference 0.004, 95% CI −0.026–0.034, p=0.77) (table 2 and figures 2 and 3).
Primary and secondary outcomes: patient-reported outcomes, mental health status and cognitive assessments
EuroQol-Five Dimensions–Five Levels utility index at 1 year after hospital discharge in corticosteroid exposed versus nonexposed patients. Between-group mean difference and 95% confidence interval shown for main analysis (Post-hospitalisation coronavirus disease 2019 (PHOSP-COVID) cohort) and sensitivity analysis (International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort).
EuroQol-Five Dimensions–Five Levels (EQ-5D-5L) utility index change from pre-hospital (baseline) to 1 year in corticosteroid-exposed versus nonexposed patients.
There was a large reduction in EQ-5D-5L UI from pre-hospital to 1 year, with no significant difference between corticosteroid exposed (mean change −0.12 (0.22)) and nonexposed (−0.11 (0.22)) groups (mean difference 0.01, 95% CI −0.01–0.04, p=0.32) (table 2 and figure 3).
Secondary outcomes
Secondary outcomes, assessing patient-reported outcomes, physical, cognitive and mental health status, and measurements of organ impairment, were not significantly different between treatment groups at 1 year (tables 2 and 3, and figure 4), except breathlessness VAS, which was lower in patients who had received corticosteroids (median (interquartile range) 1.0 (0.0–4.0) versus 1.0 (0.0–5.0), p=0.043).
Secondary outcomes: physical impairment and organ function
Secondary outcomes. a) Patient-perceived recovery, b) Short Physical Performance Battery (SPPB) score, c) symptom count and d) Montreal Cognitive Assessment (MoCA) score (corrected) 1 year after hospital discharge in corticosteroid exposed versus nonexposed patients.
Sensitivity analysis
In the sensitivity analysis, there was no significant difference in the EQ-5D-5L UI at 1 year between patients who received corticosteroids and those who did not (between-group difference 0.021, 95% CI −0.033–0.074, p=0.45) (figure 2).
Discussion
To our knowledge, this is the first report investigating the effect of acute corticosteroids on HRQoL, other patient-reported outcomes, physical and mental health status, and multi-system organ effects 1 year after hospitalisation for COVID-19. We observed large reductions in HRQoL at 1 year and report novel findings that there was neither a difference in EQ-5D-5L UI at 1 year, nor in EQ-5D-5L UI change pre-hospital to 1 year, between patients who did or did not receive corticosteroids for their acute illness. There remained no difference in HRQoL at 1 year after adjusting for survivor and selection bias using a large cohort of patients admitted with COVID-19 (ISARIC cohort). We also found no difference between receipt of acute corticosteroids or not across a range of secondary end-points assessing patient-reported outcomes, physical, cognitive and mental health status, and measurements of multi-system organ impairment. Despite the observational longitudinal nature of our study, it is likely to be the most comprehensive and robust data available, as the large acute randomised controlled trials of therapeutics in COVID-19 were unable to perform in-person follow-up assessments [1–4] and corticosteroids are now standard of care for COVID-19 requiring supplemental oxygen, meaning a placebo-controlled trial would now be unethical [17]. Our recruitment period encompassed time before and after systemic corticosteroids became standard care for patients requiring oxygen due to COVID-19 (June 2020), allowing comparison between corticosteroid exposed and nonexposed groups.
Our data demonstrate the significant negative impact on HRQoL and other health outcomes 1 year after hospital discharge in this population, similar to our previous reports but in a larger sub-set [6]. Pre-hospital our cohort reported EQ-5D-5L UI scores in line with normal values (reported as 0.81 for men and 0.79 for women aged 55–59 years) [29]. 1 year after discharge from hospital, the EQ-5D-5L UI was comparable to long-term health conditions such as COPD [30].
Developments in treatments for acute COVID-19 (including pharmacological therapies, such as corticosteroids, and ventilation strategies), combined with effective vaccines, have significantly reduced the risk of in-hospital COVID-19 mortality. However, the risk of long COVID remains, and although risk increases with more severe acute illness [5], many people with mild acute COVID-19 develop persistent health problems. We have previously shown that elevated inflammatory proteins 5 months after COVID-19 hospital discharge are associated with increased risk of very severe health impairments at 1 year [5]; therefore, it was reasonable to hypothesise that the anti-inflammatory effect of corticosteroids could mitigate the risk of long COVID. A previous study found no difference in HRQoL 180 days after hospital discharge from a higher 12 mg dose of dexamethasone compared to the standard 6 mg dose [31], but HRQoL comparisons between corticosteroid treated or not were not available. Another recent study showed a reduction in the duration of post-COVID-19 symptoms reported by patients who had received dexamethasone, compared to those who did not [32]. This was not consistent with our own data, which showed no significant difference in presence of any symptoms, or the number of symptoms, at 1 year.
Other acute pharmacological interventions have shown promising effects on the risk of long COVID. Anti-IL-6 (tocilizumab) improves HRQoL at 6 months in COVID-19 survivors admitted to intensive care [13], although whether this benefit applies to patients outside of intensive care is unknown. The antiviral remdesivir is associated with a reduction in rates of long COVID at 180 days, although the study excluded severely unwell patients so this benefit may not apply to a broader population [33]. The antivirals nirmatrelvir and molnupiravir both reduce the risk of post-acute sequelae of COVID-19, including fatigue, muscle pain and neurocognitive impairment at 180 days [34, 35]. Post hoc analysis of nebulised interferon-beta-1a for COVID-19 showed reductions in fatigue/malaise and loss of taste or smell at 60–90 days compared to placebo and further investigations are ongoing [36]. Metformin reduces the risk of long COVID in nonhospitalised overweight and obese patients, although the effect in more severe disease is unknown [37]. While the results of these trials are encouraging, it is noteworthy that each has limitations to their applicability in a wider patient population and none have provided strong enough evidence to change treatment guidelines with the aim of reducing long COVID. The HEAL-COVID study reported no benefit from 2 weeks of anticoagulation (apixaban) on post-discharge mortality or hospital readmission but has not yet reported quality of life outcomes [38]. A second study arm investigating 12 months of atorvastatin is underway [39].
Trials of potential treatments for patients with persistent health problems beyond the acute COVID-19 illness are being undertaken, although are few in number. In a phase 2 placebo-controlled trial, 4 weeks of AXA1125 (an endogenous metabolic modulator comprising five amino acids and N-acetylcysteine) improved fatigue scores in patients with persistent fatigue at least 12 weeks after COVID-19 [40]. The STIMULATE-ICP (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways) study will investigate the effect of antihistamine (famotidine/loratidine), anticoagulation (rivaroxaban) and anti-inflammatory (colchicine) medications on long COVID recovery, in addition to interventions such as rehabilitation strategies [41]. The PHOSP-I study will investigate tocilizumab in patients with persistent symptoms at least 3 months after COVID-19 and evidence of persistent systemic inflammation [42]. Given the evidence for acute interventions not reducing long COVID across a broad patient population, these trials and others are urgently needed to reduce post-COVID-19 sequelae including long COVID. Additionally, although COVID-19 vaccination prior to infection reduces the risk of developing long COVID, it does not appear to improve long COVID in those already affected [43].
Our study has a number of strengths. We included a large cohort of patients discharged from hospital after receiving oxygen for COVID-19 and our sensitivity analysis uses ISARIC data to verify our findings in a much larger hospitalised cohort also requiring oxygen. Therefore, we are confident that our findings are applicable to patients meeting guideline criteria for corticosteroid treatment for COVID-19. Additionally, we used propensity weighting to ensure balance between groups prior to analysing 1-year outcomes in an attempt to replicate the effect of randomised allocation and account for elements of biasing. We are confident, therefore, that the lack of benefit from acute corticosteroids observed here is genuine.
Our study has some limitations. First, despite using propensity-weighting methods, this is an observational study and therefore unable to fully replicate a randomised trial. Our statistical methods were designed to minimise potential biases related to this, but some residual effect may remain. Second, we included patients admitted to hospital over a 14-month period, spanning waves of different COVID-19 variants and the early stages of the vaccine rollout. We cannot exclude potential effects due to these factors, particularly as our corticosteroid nonexposed participants were predominantly hospitalised before June 2020 and corticosteroid-exposed participants predominantly after June 2020. Third, the PHOSP-COVID cohort had a more severe acute illness than the general hospitalised COVID-19 population and only includes patients who survived at least 5 months after discharge; it is therefore subject to selection and survivor biases. We have attempted to address these in our sensitivity analysis, using the ISARIC cohort which includes patients who died. Fourth, there is a significant amount of missing lung function data due to variable infection prevention restrictions during the study period. Therefore, we cannot fully exclude a possible effect on lung function. Finally, pre-hospital EQ-5D-5 L UI was assessed retrospectively using patient recollection of their quality of life prior to hospitalisation with COVID-19. These data are therefore subject to recall bias, although the effect is likely equal between the treatment groups.
There remains a large reduction in HRQoL and other health outcomes 1 year after hospitalisation for COVID-19. Studies to identify pharmacological and nonpharmacological interventions given after the acute COVID-19 illness are essential to address this. It is also important to seek better mechanistic understanding of post-COVID-19 sequelae and improve phenotyping of patients who may respond to specific interventions.
In conclusion, we found no long-term benefit on HRQoL or other health outcomes from corticosteroids given to treat acute COVID-19. There remains an urgent need for effective interventions that reduce the long-term burden of health issues following COVID-19.
Acknowledgements
This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, healthcare and social-care professionals who contributed to setting up and delivering the study at all of the 36 National Health Service trusts/health boards and 25 research institutions across the UK, as well as all the supporting staff at the National Institute for Health and Care Research Clinical Research (NIHR) Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland and Public Health England, and support from the International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma and Lung UK, the British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, the McPin Foundations and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group, and Long Covid Support.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: The PHOSP-COVID study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107). ISARIC was approved by the South Central Oxford C Research Ethics Committee in England and the Scotland A Research Ethics Committee. Individual sites are responsible for ensuring that local sponsorship and ethical approvals are in place.
Conflict of interest: O.C. Leavy declares that their institute received joint funding from UKRI and NIHR (MR/V027859/1 and COV0319) to complete this work. A.B. Docherty declares that they were awarded funding from a Wellcome Clinical Research Career Development Fellowship (216606/Z/19/Z) to complete this work. A Sheikh declares that their institute was awarded grant funding from NIHR and UKRI to complete this work; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca's Thrombotic Thrombocytopenic Taskforce; and leadership or fiduciary roles for UK and Scottish Government COVID-19 advisory groups. C.E. Bolton declares that their institute received grant funding from NIHR/UKRI and NIHR to complete this work; and their institute received grant funding from Nottingham Hospitals Charity and University of Nottingham. G. Choudhury declares funding from GlaxoSmithKline and AstraZeneca; received honoraria for delivering talks from GSK, AZ, Chiesi and BI; participation on a Data Safety Monitoring Board or Advisory Board as Chair on the Act on COPD Programme for AZ in Scotland; and a leadership or fiduciary role as Chair for the Lothian Respiratory Managed Clinical Network. N.D. Bakerly declares they have received nonrestrictive educational grants from Chiesi, AZ and Teva for attending conferences; honoraria from Teva, AZ and GSK; support for attending meetings and/or travel from Chiesi and AZ; participation on a Data Safety Monitoring Board or Advisory Board for Teva; and receipt of equipment from Global Access Diagnostics (previously Mologic Inc). A. Shikotra declares that their institute was awarded joint funding from UKRI and the NIHR (MR/V027859/1 and COV0319) to complete this work. R. Aul declares lecture fees and support for attending a meeting from Boehringer Ingelheim. C. Echevarria declares a grant from GSK. J.R. Hurst declares funding from AstraZeneca; consulting fees from AstraZeneca and GSK; payment for lectures and presentations from AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi and Takeda; support for attending meetings and/or travel from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca; and receipt of equipment from Nonin. M. Jones declares funding from the MRC to complete this work; funding from the MRC, British Lung Foundation and Boehringer Ingelheim; consulting fees from Skyhawk Therapeutics; and a leadership or fiduciary role in the AAIR Charity Scientific Committee. P. Pfeffer declares funding from NIHR. S. Rowland-Jones declares that their institute received funding from UKRI to complete this work; and their institute received funding from NIHR Sheffield Biomedical Research centre, Bill and Melinda Gates Foundation, UKRI (MRC) and EDCTP. D. Parekh declares funding from NIHR and MRC; and a leadership or fiduciary role for the Faculty of Intensive Care Medicine Board. A.A.R. Thompson declares that their institute was awarded a fellowship from the British Heart Foundation, and grant funding from Heart Research UK and the National Institute for Health and Care Research; payment for lectures and presentations from Janssen-Cilag Ltd; and support for attending meetings from Janssen-Cilag Ltd. M.J. Davies declares grant funding from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen; consulting fees from Eli Lilly, Boehringer Ingelheim, Novo Nordisk and Sanofi; payment for speaking for Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, AstraZeneca, Amgen, Napp Pharmaceuticals and Novartis; and is an advisory board member for Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc., and Zealand Pharma. A. De Soyza declares that their institute was awarded grant funding from AstraZeneca, Bayer, GSK, Chiesi, Novartis and Pfizer, outside the submitted manuscript; consulting fees from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed and Gilead; payment for lectures and presentations from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead and 30T; participation on a Data Safety Monitoring Board or Advisory Board for Bayer; and receipt of drugs from GSK outside the submitted manuscript. S. Heller declares consulting fees from NovoNordisk; and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly with payments made to their institution. J. Jacob declares funding from Gilead, Microsoft Research and GlaxoSmithKline; consulting fees from Boehringer Ingelheim, Roche, GlaxoSmithKline and NHSX; payment for lectures and presentations received from Boehringer Ingelheim, Roche, GlaxoSmithKline and Takeda; support for attending meetings and/or travel from Boehringer Ingelheim; patents planned, issued or pending (UK patent application number 2113765.8 and UK patent application number GB2211487.0); and participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim and Roche. R.G. Jenkins declares that their institute received funding from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant; consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics and Pliant; payment for lectures and presentations received from Boehringer Ingelheim, Chiesi, Roche, PatientMPower and AstraZeneca; payment for expert testimony from Pinsent Masons LLP; participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Galapagos and Vicore; and a leadership or fiduciary role for NuMedii and is president for Action for Pulmonary Fibrosis. W.D-C. Man declares that their institute received funding from National Institute for Health Research and NHS Accelerated Access Collaborative; and is Honorary President of the Association for Respiratory Technology and Physiology, and an associate editor of ERJ Open Research. G.P. McCann declares funding from NIHR (RP-2017-ST2-007) to complete this work; funding from the British Heart Foundation, Wellcome Trust and NIHR; and research support from Resonance Health, Circle CVi and Perspectum. S. Neubauer declares grant funding from Oxford NIHR Biomedical Research centre. P.J.M. Openshaw declares funding from UKRI-MRC/DHSC NIHR and UKRI-BEIS. M.J. Rowland declares support for attending meetings and/or travel from Novartis Pharmaceuticals; stock or stock options from Novartis Pharmaceuticals and Roche Pharmaceuticals; and is employed full time as a Senior Clinical Development Medical Director at Novartis Pharmaceuticals. J. Porter declares funding from Breathing Matters and UCL/H BRC (NIHR), and consulting fees from The Limbic. L.G. Heaney declares that their institute received funding from GSK, AstraZeneca and Roche/Genentech; payment for lectures received from AstraZeneca, Novartis, Roche/Genentech, Sanofi, Circassia, GlaxoSmithKline, Chiesi and Teva; support to travel to meetings from AstraZeneca and GSK; participation on a Data Safety Monitoring Board or Advisory Board for Novartis, Roche/Genentech, GSK, Teva and Celltrion; and funding from the NIHR (RfPB grant PB-PG-0317-20032). J.T. Scott declares funding from UKRI. M.G. Semple declares grant funding from National Institute of Health Research UK, Medical Research Council UK and Health Protection Research Unit in Emerging and Zoonotic Infections, and University of Liverpool to complete this work; participation on a Data Safety Monitoring Board or Advisory Board for Pfizer; leadership or fiduciary roles as Chair of Infectious Disease Scientific Advisory Board Integrum Scientific LLC and Director of MedEx Solutions Ltd; stock or stock options as minority owner of Integrum Scientific LLC and majority owner of MedEx Solutions Ltd; receipt of equipment, materials, drugs, medical writing, gifts or other services from Chiesi Farmaceutici SpA; and is a nonremunerated independent member of HMG UK Scientific Advisory Group for Emergencies (SAGE), COVID-19 Response (March 2020 to March 2022) and a nonremunerated independent member of HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG) (2014 to July 2023). S.J. Singh declares grants or contracts from NIHR (programme grant (NIHR 202020), Wellcome Doctoral Training Programme, HTA Project Grant (NIHR 131015), NIHR DHSC/UKRI COVID-19 Rapid Response Initiative, NIHR Global Research Group (NIHR 17/63/20)), Actegy Limited and NIHR Senior Investigator; payment for presentations for GSK, Ministry of Justice, CIPLA, Sherbourne Gibbs; participation on NICE Expert Adviser Panel (long COVID), Wales Long COVID Advisory Board and NHS-E Long Covid Your Covid Recovery working group; and leadership or fiduciary roles as ATS Pulmonary Rehabilitation Assembly Chair, Clinical Lead RCP Pulmonary Rehabilitation Accreditation Scheme and Clinical Lead NACAP Audit for Pulmonary Rehabilitation. M. Toshner declares grant funding from the NIHR Cambridge BRC and NIHR HTA to complete this work; consulting fees from Janssen; support for attending meetings and/or travel from GSK and Janssen; and participation on a Data Safety Monitoring Board or Advisory Board for ComCov and FluCov. A. Horsley declares that their institute was awarded funding from UK Research and Innovation (MR/V027859/1), the National Institute of Health Research (NIHR) (COV0319) and NIHR Manchester BRC; and is Chair for the NIHR Translational Research Collaboration. M. Marks declares that their institute received joint funding from UKRI and NIHR to complete this work. K. Poinasamy declares funding from UKRI and NIHR to complete this work. A. Briggs declares consulting fees from Roche, Merck, Sanofi and GSK. J.K. Quint declares that their institute received funding from the Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GSK, BI, Asthma+Lung UK and AZ; and consulting fees from GlaxoSmithKline, Evidera, Chiesi, AstraZeneca and Insmed. J.D. Chalmers declares funding from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead Sciences, Insmed, Genentech and GlaxoSmithKline; consulting fees from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead Sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon and Trudell; and leadership or fiduciary roles as Chief Editor of the European Respiratory Journal and associate editor of ERJ Open Research, Chair of the British Thoracic Society Science and Research Committee, and Trustee of the British Thoracic Society. L.V. Wain declares funding from UK Research and Innovation (MR/V027859/1), GSK/Asthma+Lung UK (Professorship (C17-1)) and National Institute of Health Research (COV0319) to complete this work; funding from Orion Pharma, GSK, Genentech, AstraZeneca, Nordic Bioscience and Sysmex (OGT); consulting fees Galapagos, Boehringer Ingelheim and GSK; support for attending meetings and/or travel Genentech; participation on Advisory Board for Galapagos; leadership or fiduciary roles as an associate editor for the European Respiratory Journal, and Medical Research Council Board member and Deputy Chair. C.E. Brightling declares that their institute received grant funding from MRC/NIHR and NIHR to complete this work; their institute received grant funding from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma and Mologic; and consulting fees from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic and Areteia. R.A. Evans declares funding from UKRI/MRC/NIHR to complete this work; funding from Wolfson Foundation and Genentech/Roche; consulting fees from AstraZeneca/Evidera; speaking fees from Boehringer and Moderna; support for attending meetings from Chiesi; and leadership or fiduciary roles as ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary, and ATS Pulmonary Rehabilitation Assembly Chair. All other authors declare no conflicts of interest.
Support statement: This study was supported by the National Institute for Health Research and Medical Research Council UK Research and Innovation. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received May 8, 2024.
- Accepted May 15, 2024.
- Copyright ©The authors 2024
This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
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