key: cord-0700819-ce1a9k8b authors: Sigfrid, L.; Drake, T. M.; Pauley, E.; Jesudason, E. C.; Olliaro, P.; Lim, W. S.; Gillesen, A.; Berry, C.; Lowe, D.; McPeake, J.; Lone, N.; Munblit, D.; Casey, A.; Bannister, P.; Russell, C. D.; Goodwin, L.; Ho, A.; Turtle, L.; Hara, M. O.; Hastie, C.; Donohue, C.; Spencer, R.; Donegan, C.; Gummery, A.; Harrison, J.; Hardwick, H.; Hastie, C. E.; Carson, G.; Merson, L.; Baillie, J. K.; Openshaw, P.; Harrison, E. M.; Docherty, A.; Semple, M. G.; Scott, J. T. title: Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. date: 2021-03-23 journal: nan DOI: 10.1101/2021.03.18.21253888 sha: 0e983e2d025bca8b296e8cba7db8b6d4b11c1fcd doc_id: 700819 cord_uid: ce1a9k8b Structured Abstract Objectives: The long-term consequences of severe Covid-19 requiring hospital admission are not well characterised. The objective of this study was to establish the long-term effects of Covid-19 following hospitalisation and the impact these may have on patient reported outcome measures. Design: A multicentre, prospective cohort study with at least 3 months follow-up of participants admitted to hospital between 5th February 2020 and 5th October 2020. Setting: 31 hospitals in the United Kingdom. Participants: 327 hospitalised participants discharged alive from hospital with confirmed/high likelihood SARS-CoV-2 infection. Main outcome measures and comparisons: The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, new or increased disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). We compared these outcome measures across age, comorbidity status and in-hospital Covid-19 severity to identify groups at highest risk of developing long-term difficulties. Multilevel logistic and linear regression models were built to adjust for the effects of patient and centre level risk factors on these outcomes. Results: In total 53.7% (443/824) contacted participants responded, yielding 73.8% (327/443) responses with follow-up of 90 days or more from symptom onset. The median time between symptom onset of initial illness and completing the participant questionnaire was 222 days (Interquartile range (IQR) 189 to 269 days). In total, 54.7% (179/327) of participants reported they did not feel fully recovered. Persistent symptoms were reported by 93.3% (305/325) of participants, with fatigue the most common (82.8%, 255/308), followed by breathlessness (53.5%, 175/327). 46.8% (153/327) reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24.2% (79/327) of participants. Overall (EQ5D-5L) summary index was significantly worse at the time of follow-up (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Conclusions: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present even in young, previously healthy working age adults, and were most common in younger females. Policymakers should fund further research to identify effective treatments for long-Covid and ensure healthcare, social care and welfare support is available for individuals with long-Covid. • Long-term symptoms after hospitalisation for Covid-19 have been reported, but it is not clear what impact this has on quality of life. • It is not known which patient groups are most likely to have long-term persistent symptoms following hospitalisation for Covid-19, or if this differs by disease severity. • More than half of patients reported not being fully recovered 7 months after onset of Covid-19 symptoms. • Previously healthy participants and those under the age of 50 had higher odds of worse long-term outcomes compared to older participants and those with comorbidities. • Younger women and those with more severe acute disease in-hospital had the worst long-term outcomes. • Policy makers need to ensure there is long-term support for people experiencing long-Covid and should plan for lasting long-term population morbidity. Funding for research to understand mechanisms underlying long-Covid and identify potential interventions for testing in randomised trials is urgently required. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 23, 2021. ; https://doi.org/10.1101/2021.03.18.21253888 doi: medRxiv preprint Objectives: The long-term consequences of severe Covid-19 requiring hospital admission are not well characterised. The objective of this study was to establish the long-term effects of Covid-19 following hospitalisation and the impact these may have on patient reported outcome measures. Design: A multicentre, prospective cohort study with at least 3 months follow-up of participants admitted to hospital between 5th February 2020 and 5th October 2020. Setting: 31 hospitals in the United Kingdom. Participants: 327 hospitalised participants discharged alive from hospital with confirmed/high likelihood SARS-CoV-2 infection. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, new or increased disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). We compared these outcome measures across age, comorbidity status and in-hospital Covid-19 severity to identify groups at highest risk of developing long-term difficulties. Multilevel logistic and linear regression models were built to adjust for the effects of patient and centre level risk factors on these outcomes. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 8 times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Conclusions: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present even in young, previously healthy working age adults, and were most common in younger females. Policymakers should fund further research to identify effective treatments for long-Covid and ensure healthcare, social care and welfare support is available for individuals with long-Covid. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 23, 2021. Our understanding of long-term outcomes after acute Covid-19 disease remains limited. It is becoming increasingly evident that some patients who have had acute Covid-19 go on to experience persistent symptoms, known as long-Covid or post-covid syndrome [1] . Several studies in hospitalised and community settings have identified that those with Covid-19 frequently develop long-term symptoms and a range of sequelae affecting the kidneys, lungs and heart [2] [3] [4] . These symptoms appear to overlap with other post-viral syndromes and with the challenges faced by patients recovering from other critical illness with post-intensive care syndrome (PICS), such as muscle weakness, fatigue, and sleep disturbance [5] [6] [7] [8] [9] . Yet, understanding the impact Covid-19 has on patient reported outcome measures, including quality of life, has not yet been fully characterised [10]. Many clinical trials or studies that aim to characterise the immediate course of Covid-19 have used mortality as a primary outcome [11, 12] . This has demonstrated that patients in older age groups and those who have pre-existing comorbidities are at higher risk of dying from the disease[13-16] . Nonetheless, most people with Covid-19 will survive the initial acute infection and data on what happens to these individuals in the long-term are lacking. The large number of people affected by Covid-19 and the growing evidence of long-term sequelae highlights the importance for policy makers, society and healthcare systems to understand the difficulties faced by those suffering from long-Covid [17] [18] [19] [20] . Understanding the burden of disease, and who is at greatest risk of developing long-term complications, may help to target preventative strategies and provide effective support for affected individuals to improve Covid-19 outcomes and reduce risk of widening health inequalities by inadequate rehabilitation and recovery support. Identifying which patient groups are most likely to be affected could provide data to guide policy and aid future research to identify disease mechanisms, formulate and test new interventions. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The ISARIC WHO CCP protocol was first developed by international consensus in 2012 to respond to any emerging or re-emerging pathogen of public health interest [22] . It was activated in the UK in response to the SARS-CoV-2 pandemic on 17th January 2020. Study information including the CCP-UK and follow-up protocol, standardised case report forms, study information and consent forms, are available on the ISARIC4C.net website. Hospitals providing acute care throughout the United Kingdom are eligible to enrol participants into the study. This analysis is reported in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines[23]. Patients aged 18 years and over, admitted to hospital between 17 th January to 5 th October 2020 with confirmed or highly suspected SARS-CoV-2 infection at 31 centres, who consented to be contacted for follow-up and were discharged at least 90 days ago were eligible for inclusion. Confirmation of SARS-CoV-2 was by reverse-transcriptase polymerase chain reaction (RT-PCR). Individuals with highly suspected, Covid-19 were also eligible for inclusion, given that SARS-CoV-2 was an emergent pathogen in the earlier stages of the pandemic and laboratory confirmation was dependent on local availability of PCR testing. Patient questionnaires for adults were developed by a multidisciplinary team of researchers, clinicians and psychologists through a series of meetings and e-mail iterations [22] . These is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint were piloted in three countries before being finalised. The UK version was piloted with patients at sites in Liverpool and Glasgow. Patient questionnaires were designed to allow selfassessment via post, or clinician led follow up via telephone, or in outpatient clinic, to support wide dissemination. All surviving patients who consented to be contacted following discharge and for which a valid address or phone number were provided were contacted. Questionnaires were posted from the Outbreak Laboratory coordinating centre at the University of Liverpool, UK, with a prepaid, self-addressed envelope for returning the questionnaire. A combination of postal and telephone follow-up was used to improve response rates. Those who did not respond by post and who had a valid phone number were followed up by telephone or in outpatient clinic by local study investigators. Participants completed one questionnaire as part of this study, so there were no repeat measures. Data from responses were entered onto a Research Electronic Capture (REDCap) Database system hosted at the University of Oxford and linked with data documented during the admission with acute Covid-19 for the analysis. Explanatory variables at the time of hospital admission, including age, sex, pre-existing comorbidities, and treatment received during the hospital admission were recorded. Maximum severity of Covid-19 during the acute hospital admission with Covid-19 was classified using the WHO COVID-19 ordinal severity scale [24] . This scale comprised of 4 levels of severity which were relevant to our in-hospital cohort; level 3 -did not receive supplemental oxygen, level 4 -received supplemental oxygen, level 5 -received high flow oxygen or NIV noninvasive ventilation (HFNC, NIV), and levels 6 and 7 -received invasive mechanical ventilation or admission to critical care) [24] . We also used the WHO severity scale to account for inhospital severity in our modelling approach [24, 25] . The primary outcome was self-reported recovery at 3 to 12 months following initial Covid-19 symptoms. Secondary outcomes included persistent or new symptoms, new or worsened is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Categorical data were summarised as frequencies and percentages, and continuous data as median, alongside the corresponding interquartile range (IQR) presented as the 25 th and 75 th centile values. To test for differences across comparison groups in categorical data, we used Fisher's exact test and for continuous data, used the Wilcoxon rank-sum test for two-sample testing and Kruskal-Wallis where there were more than 2 groups. For disability, breathlessness, and EQ5D-5L index (health state), we calculated the change in value reported by participants before onset of their Covid-19 illness compared to the follow up assessment. For health state at the follow up assessment, we used the EQ5D-5L with the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint and change in summary EQ5D-5L index were measured on a scale of 0 to 1, with 1 being perfect health and 0 being worst health imaginable. We calculated both the overall estimates and estimates for individual EQ5D-5L dimensions. We created models to adjust for age, sex, presence of comorbidities and in-hospital severity of Covid-19, according to the maximum level of respiratory support that was required. Multilevel logistic regression was used for binary outcomes, and linear regression models were used for continuous outcomes. In both model types, we adjusted for the effects of explanatory variables using fixed-effects and centre by including a random-effects term. Final model selection was guided by minimisation of the Akaike information criterion (AIC). Variables were only included in the model if they were present during the first hospital admission for Covid-19. All models were checked for first order interactions and any meaningful interactions were retained and incorporated as dummy variables. Effect estimates are presented as odds ratios for binary outcomes or mean differences for continuous outcomes, alongside the corresponding 95% confidence interval (95% CI). Statistical analyses were performed using R version 3.6.3 (R Foundation for Statistical Computing, Vienna, AUT) with the tidyverse, finalfit, eq5d and Hmisc packages. Statistical significance was taken at the level of P ≤ 0.05. This was an urgent public health research study in response to a public health emergency of international concern. Patients and the public were therefore not involved in the design, of the acute phase rapid response research. However, patients and people living with long covid were involved in the design, conduct and interpretation of the follow up study. The follow up is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 23, 2021. ; https://doi.org/10.1101/2021.03.18.21253888 doi: medRxiv preprint data collection survey and associated patient information was informed by the founding members of the Long Covid support group, who themselves are living with long Covid. The survey was also piloted in several settings in the UK with patients affected by Covid-19 from different demographics, and feedback incorporated into the final version. This included suggestions on the data on symptoms collected and the way questions were asked as well as on the patient information. The results and interpretation of the findings and final manuscript were informed by members of the Long Covid support group. Of the 2150 eligible people in the CCP-UK study who were discharged from their acute is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Of 327 participants, 54.7% (179/327) did not feel they had fully recovered at the time of followup. At the univariable level, there were no associations between not feeling recovered and the risk factors of age, sex, ethnicity, and comorbidities (table 1) but we found patients with a higher severity of acute disease were significantly more likely not to feel recovered. Persistent is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Overall, intensity of fatigue was unrelated to age or disease severity in hospital (figure 3, table 2 ), but females were found to have significantly increased levels of fatigue compared with males (median fatigue 0-10 VAS score, males 4.0, IQR 2.0 to 6; versus females 6.0, IQR 2.0 to 7.0, supplementary table 2, supplementary figure 1). New or worsened disability in at least one Washington Group domain was experienced by 24.2% (79/327). This did not change by in-hospital Covid-19 severity ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Using multilevel regression models, we adjusted for the effects of age by sex (as this was identified as a significant interaction and retained in our models), the presence of comorbidity 4) . Similarly, those who received invasive mechanical ventilation were 3.6 times less likely to feel fully recovered (figure 4). For the secondary outcomes, age did not appear to be associated with better or worse long-term outcomes (table 3) . Females under 50 were more likely than men to experience persistent fatigue and seven times more likely to experience greater breathlessness, twice as likely to develop new disability and had a significantly poorer health state (EQ5D-5L), all of which persisted in adjusted analyses (table 3 ). Participants with one or more comorbidities were more likely to experience greater fatigue, disability, and a poorer health state (EQ5D-5L, table 3). We found high rates of long-term symptoms and poor long-term outcomes, which were present several months after hospitalisation for Covid-19. Women under 50, and those with severe acute disease requiring critical care had the worst long-term outcomes even after adjusting for severity of the initial illness. Interestingly, our findings were largely unaffected by existing patient comorbidities or disability. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Our findings add considerably to the current literature, as we identify the main risk factor for worse long-term outcomes are being female and under the age of 50. We also have been able to quantify the significant deterioration in disability and breathlessness-related disability in detail. Many of our findings are largely in agreement with other recent studies in Chinese and Russian populations, which also found high rates of breathlessness and fatigue [17, 32] . In the community setting, a recent mobile application-based study, described very high rates of breathlessness (71%) and fatigue (98%) in those reporting symptoms persisting over 28 days [2] . Interestingly, in our population, the presence of symptoms many months after initial infection are higher than the 76% reported by Huang et al. and three times higher than that Compared with these studies, our data contain far higher numbers of patients who required critical care and is likely to be more generalisable to these groups. In our study, being young, female and having a high severity of acute disease were the strongest independent predictors of poor long-term outcomes. It is unclear why females had the worst outcomes. This could be to do with the effects of initial exposure, where females are more likely to be in industries where exposure to SARS-CoV-2 may be higher [37], however is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . Another explanation is that females are more likely to survive severe acute disease than men, so could have worse long-term outcomes as a result. However, in our data, we could not find any differences by sex across several measures of disease severity. A further possibility is that men felt less able or inclined to disclose symptoms. From our findings it is clear more research is required into why females have worse long-term outcomes, particularly as sectors where females are likely to have greater exposure to SARS-CoV-2 are beginning to reopen (e.g. education, hospitality and healthcare). There are several limitations to our study. First, we were not able to follow all the cases that were discharged from hospital, either because they did not give permission or because they did not respond to repeated requests for information. We attempted to reach non-responders to the survey via telephone follow-up to limit potential for selection bias, but not all could be reached. It is possible that those who did not respond might have been well and therefore uninterested in responding, but it could also be that some were too unwell to respond, had died or moved away. Our results may therefore not be fully representative of with the entire population of those hospitalised with Covid-19. Secondly, we did not include patients hospitalised with other non-Covid-19 illness or a contemporaneous control group, therefore it is unknown if the changes in our outcomes e.g. quality of life, are specific to recovery from is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Future research should focus on establishing the optimal care of this cohort, identifying interventions to test in randomised trials and to identify the mechanisms underlying adverse long-term outcomes. The PHOSP-Covid (Post-HOSPitalisation Covid-19) study is ongoing and will inform patient care by adding to our data on the long-term sequelae of Covid-19, looking at the impact on these of acute and post-discharge interventions, and exploring possible mechanisms [40] . In our study of 327 patients who were discharged alive from hospital, we found most participants reported symptoms months after acute Covid-19 infection. The most common symptoms were fatigue and breathlessness. Participants reported significant difficulties, including increased breathlessness, new or worsened disability and worse quality of life following Covid-19. These symptoms were largely independent of age and prior comorbidity, suggesting that the long-term effects of Covid-19 are determined by factors that differ from those that predict increased mortality. Moreover, the high frequency and severity of long-term symptoms emphasise the importance of long-Covid symptoms and the potential long-term impact on population health and wellbeing. This work uses data provided by patients and collected by the NHS as part of their care and support #DataSavesLives. We are extremely grateful to the 2,648 frontline NHS clinical and research staff and volunteer medical students, who collected this data in challenging circumstances; and the generosity of the participants and their families for their individual contributions in these difficult times. In particular, the ISARIC Global Covid-19 Follow up working group and the ISARIC global support centre. We would like to thank Sarah Moore, Romans Matulevics, and James Lee for administrative, data management and dissemination support. We also acknowledge the support of Jeremy J Farrar and NahokoShindo. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The lead author (the manuscript's guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Dissemination plans: Dissemination to participants and related patient and public communities: ISARIC4C has a public facing website [ISARIC4C.net] and twitter account (@CCPUKstudy). We are engaging with print and internet press, television, radio, news, and documentary programme makers. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The study sponsors and funders had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication. Investigators were independent from funders and the authors have full access to all of the data, including any statistical analysis and tables. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Numbers are N (%). . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Numbers are N (%). . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Numbers are N (%). . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 23, 2021. ; https://doi.org/10.1101/2021.03.18.21253888 doi: medRxiv preprint Persistent Symptoms in Patients After Acute COVID-19 Attributes and predictors of long COVID Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App Long-term Pulmonary Consequences of Coronavirus Disease 2019 (COVID-19): What We Know and What to Expect Post-Ebola syndrome Post-Ebola Syndrome The Uncertainty Surrounding the Burden of Post-acute Consequences of Dengue Infection Brief Report: Management of Chronic Post-Chikungunya Rheumatic Disease: The Martinican Experience Post-intensive care syndrome: An overview