Background Physical inactivity is a risk factor for severe COVID-19 and often worsens after hospitalisation. Clinicians need quick, accurate assessments to target interventions. We aimed to assess the validity of the General Practice Physical Activity Questionnaire (GPPAQ) in adults recovering one year after COVID-19 hospitalisation . Methods Post-hospitalisation for COVID-19, adults attended a one-year-visit and completed the GPPAQ Physical Activity Index (PAI-4 active), 14-day wrist-worn accelerometry (Moderate-Vigorous PA [MVPA]- active), and other health outcomes. Validity was examined via : (i) internal consistency (factor analysis); (ii) measurement invariance across sex, age, and ethnicity using differential item functioning (DIF); (iii) convergent validity (GPPAQ sensitivity/specificity versus accelerometry); and (iv) construct validity (correlations with health outcomes). Results 752 participants had GPPAQ and accelerometry (265 female, mean± sd age 60.9±11.6 years, MVPA 18.75 min·day −1 (IQR 7.55, 36.11), PAI-1 46.8%, PAI-2 15.6%, PAI-3 19.4%, PAI-4 18.2%. Factor analyses supported good internal consistency with two factors (daily activities, physical exercise). Confirmatory factor Index (CFI) showed excellent fit (CFI 0.965). DIF indicated moderate variability by sex and age. GPPAQ-PAI showed limited sensitivity (26.3%) for correctly classifying physically active individuals, but higher specificity (88.4%) for classifying physical inactivity, and weak-to-moderate correlations with health outcomes. Conclusions GPPAQ demonstrates internal consistency, with construct and convergent validity in adults 1-year post-COVID-19 hospitalisation. GPPAQ effectively identifies inactive individuals to support clinical care; however, its sensitivity suggests underestimation of activity relative to accelerometry. Future pathways should combine GPPAQ with device-based assessment to optimise evaluation of physical activity to guide pulmonary rehabilitation and targeted interventions.

Background In patients with 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) one 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. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one 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 In 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI: -0.026 to 0.034, p = 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change -0.12 (0.22) vs -0.11 (0.22), p = 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. Interpretation Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL one year after hospital discharge. Treatments to address this are urgently needed. ### Competing Interest Statement AART declares that their institute was awarded a fellowship from British Heart Foundation and grant funding from Heart Research UK and National Institute for Health and Care Research; payment for lectures and presentations received from Janssen-Cilag Ltd; support for attending meetings from Janssen-Cilag Ltd. AH​ declares that their institute was awarded funding from UK Research and Innovation (MR/V027859/1), National Institute of Health Research (COV0319) and NIHR Manchester BRC; leadership or fiduciary role as Chair for NIHR Translational Research Collaboration. AS declares that their institute was awarded joint funding from UKRI & NIHR (MR/V027859/1 and COV0319) to complete this work. AB declares consulting fees from Roche, Merck, Sanofi and GSK. ABD​ declares that they were awarded funding from Wellcome Clinical Research Career Development Fellowship (216606/Z/19/Z) to complete this work. ADS​ declares that their institute was awarded grant funding from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer outside the submitted manuscript; consulting fees from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead; payment for lectures and presentations received by AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead, 30T; participation on a Data Safety Monitoring Board or Advisory Board for Bayer; receipt of drugs from GSK outside the submitted manuscript. AShe 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 Astra-Zenecas Thrombotic Thrombocytopenic Taskforce; leadership or fiduciary role for UK and Scottish Government COVID-19 advisory groups. CE declares a grant from GSK. CEB declares that their institute received grant funding from NIHR/UKRI and NIHR to complete this work; their institute received grant funding from Nottingham Hospitals Charity and University of Nottingham. CEBr 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, Mologic; consulting fees from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic, Areteia. DP declares funding from NIHR and MRC; leadership or fiduciary role for Faculty of Intensive Care Medicine Board. GPM declares funding from NIHR (RP-2017-ST2-007) to complete this work; funding from British Heart Foundation, Wellcome Trust and NIHR; research support from Resonance Health, Circle CVi and Perspectum. RGJ declares that their institute received funding from Astra Zeneca, 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, AstraZeneca; payment for expert testimony from Pinsent Masons LLP; participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Galapagos, Vicore; leadership or fiduciary role for NuMedii and president for Action for Pulmonary Fibrosis. GC declares funding from GlaxoSmithKline and AstraZeneca; received honoraria for delivering talks from GSK, AZ, Chiesi, BI; participation on a Data Safety Monitoring Board or Advisory Board as Chair on the Act on COPD Programme for AZ in Scotland; leadership or fiduciary role as Chair for the Lothian Respiratory Managed Clinical Network. JDC declares funding from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead sciences, Insmed, Genentech, Glaxosmithkline; consulting fees from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon, Trudell; leadership or fiduciary roles as Chief Editor of European Respiratory Journal, Chair of British Thoracic Society Science and Research Committee and Trustee of the British Thoracic Society. JTS declares funding from UKRI. JKQ declares that their institute received funding from Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GSK, BI, asthma+lung UK, AZ; consulting fees from GlaxoSmithKline, Evidera, Chiesi, AstraZeneca, Insmed. JP declares funding from Breathing Matters and UCL/H BRC (NIHR); consulting fees from The Limbic. JJ declares funding from Gilead, Microsoft Research, GlaxoSmithKline; consulting fees from Boehringer Ingelheim, Roche, GlaxoSmithKline, NHSX; payment for lectures and presentations received from Boehringer Ingelheim, Roche, GlaxoSmithKline, 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); participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim and Roche. JRH declares funding from AstraZeneca; consulting fees from AstraZeneca and GSK; payment for lectures and presentations received from AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi, Takeda; support for attending meetings and/or travel from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca; Receipt of equipment from Nonin. LGH declares that their institute received funding from GSK, Astra Zeneca, Roche/Genentech; payment for lectures received from Astra Zeneca, Novartis, Roche / Genentech, Sanofi, Circassia, GlaxoSmithKline, Chiesi, 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. LH-W declares funding from NIHR (RfPB grant PB-PG-0317-20032). LVW 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, Sysmex (OGT); Consulting fees Galapagos, Boehringer Ingelheim, GSK; support for attending meetings and/or travel Genentech; participation on Advisory Board for Galapagos; leadership or fiduciary roles as Associate Editor for European Respiratory Journal and Medical Research Council Board member and Deputy Chair. MGS declares grant funding from National Institute of Health Research UK, Medical Research Council UK and Health Protection Research Unit in Emerging & Zoonotic Infections, 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 S.p.A.; non-remunerated independent member of HMG UK Scientific Advisory Group for Emergencies (SAGE), COVID-19 Response (March 2020 to March 2022) and non-remunerated independent member of HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG) (2014 to July 2023). MJ declares funding from MRC to complete this work; funding from MRC, British Lung Foundation and Boehringher Ingelheim; consulting fees from Skyhawk therapeutics; leadership or fiduciary role in AAIR Charity Scientific Committee. MT declares grant funding from NIHR Cambridge BRC and NIHR HTA to complete this work; consulting fees from Jansen; support for attending meetings and/or travel from GSK, Jansen; participation on a Data Safety Monitoring Board or Advisory Board for ComCov and FluCov. MJR declares support for attending meetings and/or travel from Novartis Pharmaceuticals; stock or stock options from Novartis Pharmaceuticals and Roche Pharmaceuticals; employed full time as a Senior Clinical Development Medical Director at Novartis Pharmaceuticals. MJD 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; advisory Board Member for Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc., Zealand Pharma. MM declares that their institute received joint funding from UKRI & NIHR to complete this work. NDB declares they have received non-restrictive 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. NE declares receipt of equipment from Global Access Diagnostics (previously Mologic Inc). OCL declares that their institute received joint funding from UKRI & NIHR- grant (MR/V027859/1 and COV0319) to complete this work. PEP declares funding from NIHR. PJMO declares funding from UKRI-MRC/DHSC NIHR and UKRI-BEIS. RAE declares funding from UKRI/MRC/NIHR to complete this work; funding from Wolfson Foundation and Genentech/Roche; consulting fees from AstraZeneca/Evidera; payment for speaking fees from Boeringher and Moderna; support for attending meetings from Chiesi; leadership or fiduciary role as ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary and ATS Pulmonary Rehabilitation Assembly Chair. RA declares lecture fees from Boehringer Ingelheim; support for attending meeting from Boehringer Ingelheim. SJS 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; leadership or fiduciary role as ATS Pulmonary Rehabilitation Assembly Chair, Clinical Lead RCP Pulmonary Rehabilitation Accreditation Scheme and Clinical Lead NACAP Audit for Pulmonary Rehabilitation. SR-J declares that their institute received funding from UKRI to complete this work; their institute received funding from NIHR Sheffield Biomedical Research centre, Bill & Melinda Gates Foundation, UKRI (MRC) and EDCTP. SH declares consulting fees from NovoNordisk; participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly with payments made Institution. SN declares grant funding from Oxford NIHR Biomedical Research centre. WD-CM declares that their institute received funding from National Institute for Health Research and NHS Accelerated Access Collaborative; leadership or fiduciary role as Honorary President of the Association for Respiratory Technology and Physiology. ### Clinical Protocols ### Funding Statement PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: PHOSP-COVID was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry ([ISRCTN10980107][1]). ISARIC was approved by the South Central - Oxford C Research Ethics Committee in England and the Scotland A Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The PHOSP-COVID study website (https://www.phosp.org) contains an overview of the study, resources, information about people involved, and publications. Research activity using the study is organised across a series of Working Groups. These were established at the outset of the study to coordinate research, minimise duplication of efforts, and facilitate communication across research and clinical specialties. Researchers interested in undertaking research using PHOSP-COVID are encouraged to contact the relevant Working Group leads (https://www.phosp.org/working-group/) in the first instance. The data are currently held in the Outbreak Data Analysis Platform (ODAP, https://odap.ac.uk/). Researchers seeking to access these data are directed to https://www.phosp.org/resource/ for information and forms. Correspondence to be directed to Dr Rachael A Evans, the Co-Principal Investigator of PHOSP-COVID study phosp@leicester.ac.uk. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN10980107

Background Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK. Methods We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved 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), and is registered on the ISRCTN Registry (ISRCTN66726260). Findings 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (524%) were male, 84 418 (475%) were female, and in 248 (139%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (317%) died at 30 days, compared with 30 901 (180%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 52 [95% CI 40-66], p<00001; vs 50-69 years 24 [22-26], p<00001; 70-79 years 18 [16-20], p<00001; and >80 years 15 [13-16], p<00001) but a lower absolute risk (51 [67%] of 763 patients <50 years died compared with 459 [302%] of 1522 patients aged >80 years). In -hospital mortality decreased for all patients during the pandemic but was higher for patients on cancer treatment than for those without cancer throughout the study period. Interpretation People with cancer have a higher risk of mortality from COVID-19 than those without cancer. Patients younger than 50 years with cancer treatment have the highest relative risk of death. Continued action is needed to mitigate the poor outcomes in patients with cancer, such as through optimising vaccination, long-acting passive immunisation, and early access to therapeutics. These findings underscore the importance of the ISARIC-WHO pandemic preparedness initiative.

ObjectiveEndocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies.Design/PatientsSamples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study).MeasurementsPlasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD).ResultsIn the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores.ConclusionsCirculating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

### Competing Interest Statement Full COI statement included in the submitted manuscript. ### Clinical Protocols ### Funding Statement This work was supported by a joint funding from the UK Research and Innovation and National Institute of Health Research [grant references: MR/V027859/1 and COV0319]. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry ([ISRCTN10980107][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The PHOSP-COVID study website () contains an overview of the study, resources, information about people involved, and publications. Research activity using the study is organised across a series of Working Groups ([Figure 3][2]). These were established at the outset of the study to coordinate research, minimise duplication of efforts, and facilitate communication across research and clinical specialties. Researchers interested in undertaking research using PHOSP-COVID are encouraged to contact the relevant Working Group leads () in the first instance. The data are currently held in the Outbreak Data Analysis Platform (ODAP, ). Researchers seeking to access these data are directed to for information and forms. Correspondence to be directed to Dr Rachael A Evans, the Co-Principal Investigator of PHOSP-COVID study phosp{at}leicester.ac.uk. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN10980107 [2]: #F3

Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 ( International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study ), and at follow-up 5 months after hospitalisation ( Post-hospitalisation COVID-19 study ). Plasma steroids were quantified by liquid chromatography–mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). In the acute cohort ( n  = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p  < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p  < .001). In the follow-up cohort ( n  = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121–192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

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.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

BackgroundImmunocompromised patients may be at higher risk of mortality if hospitalised with Coronavirus Disease 2019 (COVID-19) compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death and how this risk changed over the pandemic.Methods and findingsWe included patients > = 19 years with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK prospective cohort study. We defined immunocompromise as immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination, and comorbidities. We used Bayesian logistic regression to explore mortality over time. Between 17 January 2020 and 28 February 2022, we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. In total, 29% (n = 6,499) of immunocompromised and 21% (n = 28,608) of immunocompetent patients died in hospital. The odds of in-hospital mortality were elevated for immunocompromised patients (adjusted OR 1.44, 95% CI [1.39, 1.50], p < 0.001). Not all immunocompromising conditions had the same risk, for example, patients on active cancer treatment were less likely to have their care escalated to intensive care (adjusted OR 0.77, 95% CI [0.7, 0.85], p < 0.001) or ventilation (adjusted OR 0.65, 95% CI [0.56, 0.76], p < 0.001). However, cancer patients were more likely to die (adjusted OR 2.0, 95% CI [1.87, 2.15], p < 0.001). Analyses were adjusted for age, sex, socioeconomic deprivation, comorbidities, and vaccination status. As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50 to 69 years was 88% for men and 83% for women, and for those >80 years was 99% for men and 98% for women. The study is limited by a lack of detailed drug data prior to admission, including steroid doses, meaning that we may have incorrectly categorised some immunocompromised patients as immunocompetent.ConclusionsImmunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses, monoclonal antibodies, and nonpharmaceutical preventive interventions should be continually encouraged for this patient group.Trial registrationISRCTN 66726260.

Background It is unclear what effect the pattern of health-care use before admission to hospital with COVID-19 (index admission) has on the long-term outcomes for patients. We sought to describe mortality and emergency readmission to hospital after discharge following the index admission (index discharge), and to assess associations between these outcomes and patterns of health-care use before such admissions.Methods We did a national, retrospective, complete cohort study by extracting data from several national databases and linking the databases for all adult patients admitted to hospital in Scotland with COVID-19. We used latent class trajectory modelling to identify distinct clusters of patients on the basis of their emergency admissions to hospital in the 2 years before the index admission. The primary outcomes were mortality and emergency readmission up to 1 year after index admission. We used multivariable regression models to explore associations between these outcomes and patient demographics, vaccination status, level of care received in hospital, and previous emergency hospital use.Findings Between March 1, 2020, and Oct 25, 2021, 33 580 patients were admitted to hospital with COVID-19 in Scotland. Overall, the Kaplan-Meier estimate of mortality within 1 year of index admission was 296% (95% CI 291-302). The cumulative incidence of emergency hospital readmission within 30 days of index discharge was 144% (95% CI 140-148), with the number increasing to 356% (349-363) patients at 1 year. Among the 33 580 patients, we identified four distinct patterns of previous emergency hospital use: no admissions (n=18 772 [559%]); minimal admissions (n=12 057 [359%]); recently high admissions (n=1931 [58%]), and persistently high admissions (n=820 [24%]). Patients with recently or persistently high admissions were older, more multimorbid, and more likely to have hospital-acquired COVID-19 than patients with no or minimal admissions. People in the minimal, recently high, and persistently high admissions groups had an increased risk of mortality and hospital readmission compared with those in the no admissions group. Compared with the no admissions group, mortality was highest in the recently high admissions group (post-hospital mortality HR 270 [95% CI 235-281]; p<00001) and the risk of readmission was highest in the persistently high admissions group (323 [289-361]; p<00001).Interpretation Long-term mortality and readmission rates for patients hospitalised with COVID-19 were high; within 1 year, one in three patients had died and a third had been readmitted as an emergency. Patterns of hospital use before index admission were strongly predictive of mortality and readmission risk, independent of age, pre-existing comorbidities, and COVID-19 vaccination status. This increasingly precise identification of individuals at high risk of poor outcomes from COVID-19 will enable targeted support.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post–COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP–COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP–COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83–155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05–1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00–1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07–1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6–9.5), rising to 11.7% (95% CrI, 10.3–13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19–related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

BACKGROUND:Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS:CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS:2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION:Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING:UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

One in ten SARS-CoV-2 infections result in prolonged symptoms termed ‘long COVID’, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Background There are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. Methods PHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35.6% were female, mean age 58.7 (SD 12.5) years, and 27.8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/165 (25.6%) and one year 232/804 (28.9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0.68 (95% CI 0.46-0.99), obesity OR 0.50 (95%CI 0.34-0.74) and IMV OR 0.42 (95%CI 0.23-0.76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0.88 (0.74-1.00), five months 0.74 (0.60-0.88) to one year: 0.74 (0.59-0.88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

COVID-19 may predispose patients to arterial and venous thrombotic disorders due to endothelial dysfunction and platelet activation [1]. High rates of in-hospital arterial/venous thromboembolism have been reported [2] and are likely to persist post-discharge. Current UK guidelines suggest prophylactic anticoagulation for a minimum of 7 days, including after hospital discharge [3]. A recent trial found benefit in extending prophylaxis for 35 days after discharge in high-risk patients [4]. We aimed to identify the risk of arterial/venous thromboembolism in a national population in the 12 months after hospital discharge following COVID-19 in order to inform prophylaxis strategies, including anticoagulation decisions and duration. We used routine healthcare data to identify all COVID-19 hospital survivors from the adult Scottish population of 5.5 million and without documented contraindications to anticoagulation (online Supporting Information, Appendix S1), discharged before 23 August 2021. All patients were followed-up until 23 September 2021 or until death. Approval for access to datasets was granted by the Public Benefit and Privacy Panel for Health and Social Care. Our primary outcome was a composite of mortality or hospital readmission for arterial/venous thromboembolism (online Supporting Information, Appendix S1). We used cumulative incidence, accounting for competing risk events, to report mortality and time to first readmission. We stratified our findings by sex and the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) associative score, used to identify high venous thromboembolism risk in acutely ill medical patients for extended thromboprophylaxis (low (0–1), moderate (2–3) and high (4+) risk) [5]. The IMPROVE score comprises seven criteria: previous VTE; known thrombophilia; lower-limb paralysis/paresis; history of cancer; immobilisation ≥ 1 day; critical care stay; and age > 60 y (online Supporting Information, Table S1). The dataset was cleaned and analysed using R v3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). Cell counts < 5 were suppressed. Between 1 February 2020 and 23 August 2021, 22,969 patients were discharged alive from hospital after admission with COVID-19 in Scotland; 22,230 had no contraindications to anticoagulation (Table 1, online Supporting Information, Table S2). The IMPROVE score classified 7494 (37.0%) patients as low risk, 10,844 (53.6%) as moderate risk and 1898 (9.4%) as high risk of VTE. Patients in the high-risk group were older (age 80+ y: high risk 35.1% vs. low risk < 0.1%), and had more comorbidities (2+ Charlson comorbidities: high risk 62.2% vs. low risk 10.0%). Less than 0.1% of the low-risk group were admitted to ICU during their index admission, compared with 19.7% of the moderate-risk group and 10.1% of the high-risk group. 1 n = 7494 2–3 n = 10,844 4+ n = 1898 The overall cumulative incidence for arterial/venous thromboembolism was 1.2% (95%CI 1.1 - 1.4%) at 35 days and 4.1% (95%CI 3.8 - 4.5%) at 12 months (Fig. 1, online Supporting Information, Figs. S1 and S2); however, this rose to 2.3% (95%CI 1.7 - 3.0%) at 35 days and 7.5% (95%CI 6.2 -8.9%) for patients in the high-risk group, and was consistently higher for men than women. Pulmonary embolism was the commonest event resulting in readmission or death across all risk strata (online Supporting Information, Table S3). The arterial/venous thromboembolism events resulting in readmission were significantly higher than those causing death. The rate of events was similar across all strata for the first 30 days (Fig. 1), after which there was a plateau in the low-risk group. However, there was no similar fall in the moderate- or high-risk groups, and the majority of events occurred after 35 days post-discharge. The risk of arterial/venous thromboembolism after discharge from hospitalisation with COVID-19 was high, and considerably greater across all IMPROVE strata compared with the cohort in which the score was derived when restricted to a comparable outcome (VTE 0.4% at 3 months post discharge vs. our cohort VTE incidence of 1.6% (95%CI 1.4 - 1.7%)) [5]. Rates were lower than observed in the enriched control arm of Nishiga et al. [1], where asymptomatic arterial/venous thromboembolism detected by screening accounted for a third of the events. A strength of our study is its population-based approach in a real-world setting, where routine healthcare data can enable identification of clinically significant events. We were unable to account for in-hospital management, such as treatment with steroids or tocilizumab. Even in the low-risk group, the 2.0% risk of arterial/venous thromboembolism at 12 months was high enough to justify offering patients anticoagulation treatment, in line with treatment thresholds for other conditions with thrombotic risk such as atrial fibrillation [6]. Consideration should be given to the role of anticoagulation in all patients with severe COVID-19 when discharged from hospital, with a shared decision-making approach taken when balancing risks of arterial/venous thromboembolism against bleeding. The mechanism of arterial/venous thromboembolism in COVID-19 may include immunothrombosis in addition to the non-immunological venous thromboembolism seen in other conditions, raising the possibility that anticoagulants with anti-inflammatory properties such as heparins may be more effective than direct oral anticoagulants [7]. Although the incidence in the lowest risk group plateaued within the first month, higher risk groups showed no such reduction, and longer-term anticoagulation should be considered for high-risk patients, potentially in line with guidelines suggesting a minimum of 3 months for a provoked pulmonary embolism [8]. The authors acknowledge the support of the eDRIS Team, Public Health Scotland, for its involvement in obtaining approvals, provisioning and linking data and the use of the secure analytical platform within the National Safe Haven. JF and AD are joint first authors; EH and NL are joint last authors. No other competing interests declared. Appendix S1. Methods. Figure S1. Cumulative incidence for arterial/venous thromboembolism (AV-TE) specific readmission and AV-TE specific mortality up to 12 months post hospital discharge. Figure S2. Cumulative incidence for AV-TE specific mortality/readmission stratified by individual strata of IMPROVE score. Table S1. Modified IMPROVE Score, used by MICHELLE trial Investigators. Table S2. Comorbidities and treatment of Scottish hospital COVID-19 survivors without documented contraindications to anticoagulation. Table S3. Cumulative incidence at 12 months for readmission, mortality and composite of readmission and mortality from overall arterial/venous thromboembolism, stroke, acute myocardial infarction, pulmonary embolism, other arterial/venous thromboembolism. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.