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BackgroundSleep disturbance is common following hospitalisation both for COVID-19 and other causes. The clinical associations are poorly understood, despite it altering pathophysiology in other scenarios. We, therefore, investigated whether sleep disturbance is associated with dyspnoea along with relevant mediation pathways. MethodsSleep parameters were assessed in a prospective cohort of patients (n=2,468) hospitalised for COVID-19 in the United Kingdom in 39 centres using both subjective and device-based measures. Results were compared to a matched UK biobank cohort and associations were evaluated using multivariable linear regression. Findings64% (456/714) of participants reported poor sleep quality; 56% felt their sleep quality had deteriorated for at least 1-year following hospitalisation. Compared to the matched cohort, both sleep regularity (44.5 vs 59.2, p<0.001) and sleep efficiency (85.4% vs 88.5%, p<0.001) were lower whilst sleep period duration was longer (8.25h vs 7.32h, p<0.001). Overall sleep quality (effect estimate 4.2 (3.0-5.5)), deterioration in sleep quality following hospitalisation (effect estimate 3.2 (2.0-4.5)), and sleep regularity (effect estimate 5.9 (3.7-8.1)) were associated with both dyspnoea and impaired lung function (FEV1 and FVC). Depending on the sleep metric, anxiety mediated 13-42% of the effect of sleep disturbance on dyspnoea and muscle weakness mediated 29-43% of this effect. InterpretationSleep disturbance is associated with dyspnoea, anxiety and muscle weakness following COVID-19 hospitalisation. It could have similar effects for other causes of hospitalisation where sleep disturbance is prevalent. FundingUK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.
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BackgroundThe clinical sequelae (Long Covid) of acute Covid-19 are recognised globally, yet the risk of developing them is unknown. MethodsA living systematic review (second version). Bibliographical records from the C19 Living Map Long Covid segment (22nd February 2022), Medline, CINAHL, Global Health, WHO Covid-19 database, LitCOVID, and Google Scholar (18th November 2021). We included studies with at least 100 people at 12 weeks or more post-Covid-19 onset and with a control group without confirmed Covid-19. Risk of bias was assessed using the Newcastle-Ottawa scale. Symptoms are aligned with the Post Covid-19 Condition Core Outcome Set. We present descriptive statistics and use meta-analysis to estimate the relative risk of experiencing Long Covid. ResultsTwenty-eight studies were included: 20 cohort, five case-controls, three cross-sectional. Studies reported on 242,715 people with Covid-19 (55.6% female) and 276,317 controls (55.7% female) in 16 countries. Most were of moderate quality (71%). Only two were set in low-middle-income countries and few included children (18%). The longest mean follow-up time was 419.8 (standard deviation 49.4) days post-diagnosis. The relative risk (RR) of experiencing persistent or new symptoms in cases compared with controls was 1.53 (95% CI: 1.50 to 1.56). The core outcomes with the highest increased risk were cardiovascular (RR 2.53 95% CI: 2.16 to 2.96), cognitive (RR 1.99; 95% CI: 1.82 to 2.17), and physical functioning (RR 1.85; 95% CI: 1.75 to 1.96). ConclusionSARS-CoV-2 infection is associated with a higher risk of new or persistent symptoms when compared with controls that can last over a year following acute Covid-19. There is still a lack of robust studies set in lower resourced settings and current studies have high heterogeneity and potential misclassifications of cases and controls. Future research should explore the role of vaccination and different variants on the risk of developing Long Covid. Systematic review registrationThe protocol was prospectively registered on the PROSPERO database (CRD42020211131). O_TEXTBOXO_TEXTBOXNOSection 1:C_TEXTBOXNO What is already known?O_LIPublished evidence indicates a high prevalence of people affected by post-acute SARS-CoV-2 sequelae often referred to as Long Covid; yet these estimates are impacted by heterogeneity in study design and a lack of controlled studies and core outcome sets. C_LIO_LIOur first version of this review, looking at studies till March 2021, identified a breadth of reported symptoms of Long Covid affecting both those who were hospitalised during the acute phase and those managed in the community. We also identified a lack of studies including children and set in low-middle income countries. C_LIO_LIThe most commonly reported symptoms identified were weakness, general malaise, fatigue, concentration difficulties, and breathlessness, suggesting Long Covid is a complex, heterogeneous condition. C_LI O_TEXTBOXNOSection 2:C_TEXTBOXNO What are the new findings?O_LITo address the limitations identified, this first update of our living systematic review provides a comprehensive summary of peer-reviewed published studies with a control group (till 22nd February 2022) on the risk of experiencing Covid-19 sequelae. C_LIO_LIDespite study limitations identifying control groups, our findings suggest that people with a confirmed previous SARS-CoV-2 infection are 1.5 times more likely to experience new or persisting symptoms at 12 or more weeks post-onset when compared to a control group. C_LIO_LIMapped to the new Core Outcome set for Post-Covid-19 Condition, a framework for standardised assessment, our review identifies cardiovascular functioning, cognitive functioning, and physical functioning as the outcomes with highest increased risk for people post-SARS-CoV-2 infection compared to controls. C_LI O_TEXTBOXNOSection 3:C_TEXTBOXNO What do the new findings imply?O_LIOur findings point to a clear association between exposure to SARS-CoV-2 and the risk of developing new or persistent symptoms, for some lasting longer than 12 months after the initial infection. C_LIO_LIControlled studies on Long Covid should focus on improving quality to enable multisite metaanalysis by using standardised research protocols and by evaluating participants with multiple standardised diagnostic tests at various time points to capture transitory and intermittent symptoms and complications. C_LIO_LITo help inform health system planning and rehabilitation to improve outcomes for those affected, Long Covid research should focus on estimating the burden of post-acute SARS-CoV-2 in lower resourced settings, investigating the impact of vaccination and variants on Long Covid, and investigating therapeutic strategies. C_LI C_TEXTBOX
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BackgroundRemdesivir has been evaluated in clinical trial populations, but there is a sparsity of evidence evaluating effectiveness in general populations. MethodsAdults eligible to be treated with remdesivir, requiring oxygen but not ventilated, were identified from UK patients hospitalised with COVID-19. Patients treated with remdesivir within 24h of hospitalisation were compared with propensity-score matched controls; estimates of effectiveness were calculated for short-term outcomes (14-day mortality, 28-day mortality, time-to-recovery among others) using multivariable modelling. Results9,278 out of 39,330 patients satisfied eligibility criteria. 1,549 patients were identified as treated and matched with 4,964 controls. Patients were 62% male, mean (SD) age 63.1 (15.6) years, 80% White ethnicity, and symptomatic for a median of 6 days prior to baseline. There was no statistically significant benefit of remdesivir at 14 days in terms of mortality or clinical status; there were signals of effectiveness in time-to-recovery after day 9, and a reduction in 28-day mortality. ConclusionIn a real-world setting, initiation of remdesivir within 24h of hospitalisation in conjunction with standard of care was not associated with a benefit at 14 days but supports clinical trial evidence of a potential reduction in 28-day mortality.
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BackgroundWe aimed to compare the prevalence and severity of fatigue in survivors of Covid-19 versus non-Covid-19 critical illness, and to explore potential associations between baseline characteristics and worse recovery. MethodsWe conducted a secondary analysis of two prospectively collected datasets. The population included was 92 patients who received invasive mechanical ventilation (IMV) with Covid-19, and 240 patients who received IMV with non-Covid-19 illness before the pandemic. Follow-up data was collected post-hospital discharge using self-reported questionnaires. The main outcome measures were self-reported fatigue severity and the prevalence of severe fatigue (severity >7/10) 3 and 12-months post-hospital discharge. ResultsCovid-19 IMV-patients were significantly younger with less prior comorbidity, and more males, than pre-pandemic IMV-patients. At 3-months, the prevalence (38.9% [7/18] vs. 27.1% [51/188]) and severity (median 5.5/10 vs. 5.0/10) of fatigue was similar between the Covid-19 and pre-pandemic populations respectively. At 6-months, the prevalence (10.3% [3/29] vs. 32.5% [54/166]) and severity (median 2.0/10 vs. 5.7/10) of fatigue was less in the Covid-19 cohort. In the Covid-19 population, women under 50 experienced more severe fatigue, breathlessness, and worse overall health state compared to other Covid-19 IMV-patients. There were no significant sex differences in long-term outcomes in the pre-pandemic population. In the total sample of IMV-patients included (i.e. all Covid-19 and pre-pandemic patients), having Covid-19 was significantly associated with less severe fatigue (severity <7/10) after adjusting for age, sex, and prior comorbidity (adjusted OR 0.35 (95%CI 0.15-0.76, p=0.01). ConclusionFatigue may be less severe after Covid-19 than after other critical illness.
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BackgroundThe long-term sequelae of coronavirus disease 2019 (Covid-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with Covid-19 and associated risk factors. MethodsThis is a prospective cohort study of children ([≤]18 years old) admitted with confirmed Covid-19 to Z.A. Bashlyaeva Childrens Municipal Clinical Hospital in Moscow, Russia. Children admitted to the hospital during the first wave of the pandemic, between April 2, 2020 and August 26, 2020, were included. Telephone interview using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Covid-19 Health and Wellbeing paediatric follow up survey. Persistent symptoms (>5 months) were further categorised by system(s) involved. FindingsOverall, 518 of 853 (61%) of eligible children were available for the follow-up assessment and included in the study. Median age was 10.4 years (IQR, 3-15.2) and 270 (52.1%) were girls; median follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%,) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: age "6-11 years" (odds ratio 2.74 (95% confidence interval 1.37 to 5.75) and "12-18 years" (2.68, 1.41 to 5.4), and a history of allergic diseases (1.67, 1.04 to 2.67). InterpretationA quarter of children experienced persistent symptoms months after hospitalization with acute covid-19 infection, with almost one in ten experiencing multi-system involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up. Our findings highlight the need for replication and further investigation of potential mechanisms as well as clinical support to improve long term outcomes in children. FundingNone. O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that Covid-19 may result in short- and long-term consequences to health. Studies in children and adolescents are limited and available evidence is scarce. We searched Embase for publications from inception to April, 25, 2021, using the following phrases or combinations of phrases "post-covid condition" or "post-covid syndrome" or "covid sequalae" or "post-acute covid" or "long covid" or "long hauler" with "pediatric*" or "paediatric*" or "child*" or "infant*" or "newborn*" or "toddler*" or "neonate*" or "neonatal" or "adolescent*" or "teen*". We found small case series and small cohort studies looking at Covid-19 consequences in children. No large cohort studies of previously hospitalised children, assessing symptom duration, categorisation or attempting multivariable analyses to identify independent risk factors for long Covid development were identified. Added value of this studyTo our knowledge, this is the largest cohort study with the longest follow-up since hospital discharge of previously hospitalised children. We found that even months after discharge from the hospital, approximately a quarter of children experience persistent symptoms with one in ten having multi-system involvement. Older age and allergic diseases are associated with Covid-19 consequences. Parents of some children report emotional and behavioural changes in their children after Covid-19. Implications of all the available evidenceOur findings highlight the need for continued global research of Covid-19 consequences in the paediatric population. Older children admitted to the hospital should be carefully monitored upon discharge. Large, controlled studies aiming to identify risk groups and potential intervention strategies are required to fill knowledge gaps. C_TEXTBOX
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Structured AbstractO_ST_ABSObjectivesC_ST_ABSThe 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. DesignA multicentre, prospective cohort study with at least 3 months follow-up of participants admitted to hospital between 5th February 2020 and 5th October 2020. Setting31 hospitals in the United Kingdom. Participants327 hospitalised participants discharged alive from hospital with confirmed/high likelihood SARS-CoV-2 infection. Main outcome measures and comparisonsThe 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. ResultsIn 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. ConclusionsSurvivors 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. Section 1: What is already known on this topicO_LILong-term symptoms after hospitalisation for Covid-19 have been reported, but it is not clear what impact this has on quality of life. C_LIO_LIIt 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. C_LI Section 2: What this study addsO_LIMore than half of patients reported not being fully recovered 7 months after onset of Covid-19 symptoms. C_LIO_LIPreviously 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. C_LIO_LIYounger women and those with more severe acute disease in-hospital had the worst long-term outcomes. C_LIO_LIPolicy 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. C_LI
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BackgroundSARS-CoV-2 infection, the causative agent of COVID-19, has resulted in over 2,500,000 deaths to date1. Although vaccines are becoming available, treatment options remain limited. Repurposing of compounds could reduce the time, cost, and risks associated with the development of new drugs and has been the focus of many clinical studies. Here, we summarise available evidence on 29 FDA-approved compounds, from in vitro results to clinical trials, focussing on remdesivir, galidesivir and favipiravir, and test 29 antiviral compounds activity in vitro. MethodsA comprehensive search strategy was used to retrieve trials and publications related to antiviral compounds with potential efficacy to treat coronaviruses. These data were used to prioritise testing of a panel of antiviral drugs in vitro against patient isolates of SARS-CoV-2. An in vitro screen was carried out to determine the activity of 29 FDA-approved compounds. Results625 clinical trials investigated 16 repurposed antiviral candidate compounds for the treatment of COVID-19. In vitro studies identified ten drug candidates with demonstrable anti-SARS-CoV-2 activity, including favipiravir, remdesivir, and galidesivir. To validate these findings, a drug screen was conducted using two cell lines and wildtype isolates of SARS-CoV-2 isolated from patients in the UK. While eight drugs with anti-SARS-CoV-2 activity were identified in vitro, activity in clinical trials has, as yet failed to demonstrate a strong effect on mortality. ConclusionsSo far, no repurposed antiviral has shown a strong effect on mortality in clinical studies. The urgent need for novel antivirals in this pandemic is clear, despite the costs and time associated with their development. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSRepurposing of existing compounds for the treatment of COVID-19 has been the focus of many in vitro studies and clinical trials, saving time, costs and risks associated with the research and development of new compounds. Added value of this studyWe reviewed the literature for 29 FDA-approved compounds with previously reported (or suspected) anti-SARS-CoV-2 activity and found 625 clinical trials that have been undertaken on 16 different drugs. We determined if repurposed antivirals are suitable for clinical trials based on previously published data, and conducted an additional in vitro screen using locally circulating strains in the UK (PHE2 and GLA1). We report the difference in IC50 from published data using Wuhan1/Wash1 strains with PHE2 and GLA1, including IC50 values below 100M for galidesivir in wild-type virus. Given the limited success of repurposed compounds in the treatment of COVID-19, we comment on the urgent need for new antivirals specifically targeting SARS-CoV-2. Implications of all the available evidenceOur data show that most prospective compounds for repurposing show no anti-SARS-CoV-2 activity, and antiviral activity in vitro does not always translate to clinical benefit. So far, no repurposed compound has shown a strong effect on mortality in clinical studies. Drugs, including monoclonal antibody therapies, that have been developed to target SARS-CoV-2 virus itself have shown most promise.
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BackgroundThe long-term sequalae of COVID-19 remain poorly characterised. In this study, we aimed to assess long-standing symptoms (LS) (symptoms lasting from the time of discharge) in previously hospitalised patients with COVID-19 and assess associated risk factors. MethodsThis is a longitudinal cohort study of adults ([≥]18 years of age) with clinically diagnosed or laboratory-confirmed COVID-19 admitted to Sechenov University Hospital Network in Moscow, Russia. Data were collected from patients discharged between April 8 and July 10, 2020. Participants were interviewed via telephone using Tier 1 ISARIC Long-term Follow-up Study CRF and the WHO CRF for Post COVID conditions. Reported symptoms were further categorised based on the system(s) involved. Additional information on dyspnoea, quality of life and fatigue was collected using validated instruments. Multivariable logistic regressions were performed to investigate risk factors for development of LS categories. FindingsOverall, 2,649 of 4,755 patients discharged from the hospitals were available for the follow-up and included in the study. The median age of the patients was 56 years (IQR, 46-66) and 1,353 (51.1%) were women. The median follow-up time since hospital discharge was 217.5 (200.4-235.5) days. At the time of the follow-up interview 1247 (47.1%) participants reported LS. Fatigue (21.2%, 551/2599), shortness of breath (14.5%, 378/2614) and forgetfulness (9.1%, 237/2597) were the most common LS reported. Chronic fatigue (25%, 658/2593) and respiratory (17.2% 451/2616) were the most common LS categories. with reporting of multi-system involvement (MSI) less common (11.3%; 299). Female sex was associated with LS categories of chronic fatigue with an odds ratio of 1.67 (95% confidence interval 1.39 to 2.02), neurological (2.03, 1.60 to 2.58), mood and behaviour (1.83, 1.41 to 2.40), dermatological (3.26, 2.36 to 4.57), gastrointestinal (2.50, 1.64 to 3.89), sensory (1.73, 2.06 to 2.89) and respiratory (1.31, 1.06 to 1.62). Pre-existing asthma was associated with neurological (1.95, 1.25 to 2.98) and mood and behavioural changes (2.02, 1.24 to 3.18) and chronic pulmonary disease was associated with chronic fatigue (1.68, 1.21 to 2.32). Interpretation6 to 8 months after acute infection episode almost a half of patients experience symptoms lasting since hospital discharge. One in ten individuals experiences MSI. Female sex is the main risk factor for majority of the LS categories. chronic pulmonary disease is associated with a higher risk of chronic fatigue development, and asthma with neurological and mood and behaviour changes. Individuals with LS and MSI should be the main target for future research and intervention strategies. FundingThis study is supported by Russian Fund for Basic Research and UK Embassy in Moscow. The ISARIC work is supported by grants from: the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], and the Bill and Melinda Gates Foundation [OPP1209135], EU Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525] This research was funded in part, by the Wellcome Trust. The views expressed are those of the authors and not necessarily those of the DID, NIHR, Wellcome Trust or PHE. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that COVID-19 may result in short- and long-term consequences to health. Most studies do not provide definitive answers due to a combination of short follow-up (2-3 months), small sample size, and use of non-standardised tools. There is a need to study the longer-term health consequences of previously hospitalised patients with COVID-19 infection and to identify risk factors for sequalae. Added value of this studyTo our knowledge, this is the largest cohort study (n=2,649) with the longest follow-up since hospital discharge (6-8 months) of previously hospitalised adult patients. We found that 6-8 months after discharge from the hospital, around a half (47.1%) of patients reported at least one long-standing symptom since discharge. Once categories of symptoms were assessed, chronic fatigue and respiratory problems were the most frequent clusters of long-standing symptoms in our patients. Of those patients having long-term symptoms, a smaller proportion (11.3%) had multisystem involvement, with three or more categories of long-standing symptoms present. Although most patients developed symptoms since discharge, a smaller number of individuals experienced symptom beginning symptom appearing weeks or months after the acute phase. Female sex was a predictor for most of the symptom categories at the time of the follow-up interview, with chronic pulmonary disease associated with chronic fatigue-related symptoms, and asthma with a higher risk of neurological symptoms, mood and behaviour problems. Implications of all the available evidenceThe majority of patients experienced long-lasting symptoms 6 to 8 months after hospital discharge and almost half reported at least one long-standing symptom, with chronic fatigue and respiratory problems being the most frequent. A smaller number reported multisystem impacts with three or more long-standing categories present at follow-up. A higher risk was found for women, for chronic pulmonary disease with chronic fatigue, and neurological symptoms and mood and behaviour problems with asthma. Patterns of the symptom development following COVID-19 should be further investigated in future research.
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BackgroundWhile it is now apparent clinical sequelae (often called Long Covid) may persist after acute Covid-19, their nature, frequency, and aetiology are poorly characterised. This study aims to regularly synthesise evidence on Long Covid characteristics, to inform clinical management, rehabilitation, and interventional studies to improve long term outcomes. MethodsA living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research Database on Covid-19, LitCOVID, and Google Scholar were searched up to 17th March 2021. Published studies including at least 100 people with confirmed or clinically suspected Covid-19 at 12 weeks or more post-onset were included. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence with 95% confidence intervals (CIs). ResultsThirty-nine studies were included: 32 cohort, six cross-sectional, and one case-control. Most showed high or moderate risk of bias. None were set in low-income countries, limited studies included children. Studies reported on 10,951 people (48% female) in 12 countries. Most followed-up post hospital discharge (78%, 8520/10951). The longest mean follow-up was 221.7 (SD: 10.9) days post Covid-19 onset. An extensive range of symptoms with wide prevalence was reported, most commonly weakness (41%; 95% CI 25% to 59%), malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%), and breathlessness (25%; 95% CI 18% to 34%). Other frequent symptoms included musculoskeletal, neurological, and psychological. 37% (95% CI 18% to 60%) of people reported reduced quality of life. ConclusionLong Covid is a complex condition with heterogeneous symptoms. The nature of the studies precludes a precise case definition or evaluation of risk factors. There is an urgent need for prospective, robust, standardised controlled studies into aetiology, risk factors, and biomarkers to characterise Long Covid in different at-risk populations and settings. Systematic review registrationThe protocol was prospectively registered on the PROSPERO database (CRD42020211131). Section 1: What is already known?O_LIA significant number of people continue to describe ongoing symptoms long after the acute phase of Covid-19, often referred to as Long Covid. C_LIO_LILong Covid is a heterogeneous condition with an uncertain prevalence, for which there is currently no precise case definition. C_LI Section 2: What are the new findings?O_LIThis living systematic review provides a comprehensive summary of peer-reviewed published evidence on persistent symptoms of Covid-19 and will be regularly updated as new evidence emerges. C_LIO_LIThe breadth of reported symptoms suggests a complex, heterogeneous condition affecting both those who were hospitalised and those managed in the community. C_LIO_LIOur review identifies weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% confidence interval 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%) as the most common symptoms. C_LI Section 3: What do the new findings imply?O_LIThe current evidence base of the clinical spectrum of Long Covid is limited, based on heterogenous data, and vulnerable to biases, hence caution should be used when interpreting or generalising the results. C_LIO_LIOur review identifies areas where further Long Covid research is critically needed to help characterise Long Covid in different populations and define its aetiology, risk factors, and biomarkers, as well as the impact on variants of concern and vaccination on long term outcomes. C_LI
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IntroductionVery little is known about possible clinical sequelae that may persist after resolution of the acute Coronavirus Disease 2019 (COVID-19). A recent longitudinal cohort from Italy including 143 patients recovered after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60 day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical ICU patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. Methods and analysisThis is an international open-access prospective, observational multi-site study. It will enrol patients following a diagnosis of COVID-19. Tier 1 is developed for following up patients day 28 post-discharge, additionally at 3 to 6 months intervals. This module can be used to identify sub-sets of patients experiencing specific symptomatology or syndromes for further follow up. A Tier 2 module will be developed for in-clinic, in-depth follow up. The primary aim is to characterise physical consequences in patients post-COVID-19. Secondary aim includes estimating the frequency of and risk factors for post-COVID-19 medical sequalae, psychosocial consequences and post-COVID-19 mortality. A subset of patients will have sampling to characterize longer term antibody, innate and cell-mediated immune responses to SARS-CoV-2. Ethics and disseminationThis collaborative, open-access study aims to characterize the frequency of and risk factors for long-term consequences and characterise the immune response over time in patients following a diagnosis of COVID-19 and facilitate standardized and longitudinal data collection globally. The outcomes of this study will inform strategies to prevent long term consequences; inform clinical management, direct rehabilitation, and inform public health management to reduce overall morbidity and improve outcomes of COVID-19. Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIAs an international prospective, observational study we provide open-access standardised tools that can be adapted by any site interested in following up patients with COVID-19, for independent or combined analysis, to forward knowledge into short and long term consequences of COVID-19. C_LIO_LIThis study aims to inform strategies to prevent longer term sequalae; inform clinical management, rehabilitation, and public health management strategies to reduce morbidity and improve outcomes. C_LIO_LIThe protocol will be used for a sub-set of patients, already included in the existing cohort of more than 85,973 individuals hospitalized with confirmed COVID-19 infection across 42 countries (as of 20 July 2020), using the ISARIC/WHO standardized Core- or RAPID Case Report Forms (CRFs). C_LIO_LIThe data will be linked with data on pre-existing comorbidities, presentation, clinical care and treatments documented in the existing cohort already documented using the ISARIC/WHO standardized Core- or RAPID CRFs. C_LIO_LIThe data collection tool is developed to facilitate wide dissemination and uptake, by enabling patient self-assessment, however, follow up of patients requires consent and resources, which might limit the uptake and bias the data towards countries /sites with capacity to follow up patients over time. C_LI
