Characterising Long Covid: a living systematic review update with controlled studies (preprint)

Background: The clinical sequelae (Long Covid) of acute Covid-19 are recognised globally, yet the risk of developing them is unknown. Methods: A 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. Results Twenty-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). Conclusion: SARS-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.

Characterising long-term covid-19: a rapid living systematic review (preprint)

ObjectiveTo understand the frequency, profile, and duration of persistent symptoms of covid-19 and to update this understanding as new evidence emerges. DesignA living systematic review produced in response to the rapidly evolving evidence base for long covid. Data sourcesMedline and CINAHL (EBSCO), Global Health (Ovid), WHO Global Research Database on covid-19, LitCOVID, and Google Scholar to 28th September 2020. Study selectionStudies reporting long-term symptoms and complications among people with confirmed or suspected covid-19, both in those previously hospitalised and those never hospitalised. Only studies incorporating over 100 participants qualified for data extraction and were assessed for risk of bias. Results were analysed using descriptive statistics. Quality assessmentRisk of bias was assessed using a quality assessment checklist for prevalence studies. ResultsTwenty-eight studies qualified for data extraction; 16 of these were cohort studies, ten cross-sectional, and two large case series. The analysis included 9,442 adults with covid-19 from 13 countries. The longest mean follow-up period was 111 (SD: 11) days post-hospital discharge. A wide range of systemic, cardiopulmonary, gastrointestinal, neurological, and psychosocial symptoms was reported, of which the most common were breathlessness, fatigue, smell and taste disturbance, and anxiety. Persistent symptoms were described across both previously hospitalised and non-hospitalised populations. The quality of evidence was low, with a high risk of bias and heterogeneity in prevalence. The incorporated studies demonstrated limited external validity, a lack of control subjects, and inconsistent data collection methods. Few studies were conducted in primary care, no studies focused solely on children, and no studies were set in low- and middle-income countries. ConclusionOur findings suggest that long covid is a complex, heterogeneous condition; however, the limited evidence base currently precludes a precise definition of its symptoms and prevalence. There is a clear need for robust, controlled, prospective cohort studies, including different at-risk populations and settings, incorporating appropriate investigations, collected and recorded in a standardised way. Systematic review registrationThe protocol was prospectively registered on the PROSPERO database (CRD42020211131). Readers noteThis living systematic review will be updated regularly as new evidence emerges. The search terms and inclusion criteria will be updated in line with new evidence, research priorities and policy needs. This version is the original publication. Updates may occur for up to two years from the date of original publication. When citing this paper please consider adding the version number and date of access for clarity. O_TEXTBOXSection 1: What is already known on this topic? O_LIA significant number of people continue to describe symptoms long after the acute phase of covid-19 is over, so called long covid. C_LIO_LIThere is no case definition for long covid, which appears to be a heterogeneous condition with an uncertain prevalence. C_LI Section 2: What this study adds O_LIThis living systematic review provides a comprehensive summary of the published evidence on persistent symptoms of covid-19 and will be regularly updated. C_LIO_LIThe breadth of reported symptoms suggests a complex, heterogeneous condition affecting both hospitalised patients and those managed in the community. C_LIO_LIHowever, the current evidence base of the clinical spectrum of long covid is of limited quality and is vulnerable to biases. C_LIO_LIOur review identifies those areas where further long covid research is critically needed. C_LI C_TEXTBOX

Development and validation of the 4C Deterioration model for adults hospitalised with COVID-19 (preprint)

Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (-0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.

Early clinical characteristics of Covid-19: scoping review (preprint)

ABSTRACT Background: The Coronavirus disease 2019 (covid-19) pandemic has spread rapidly across the globe. Accurate clinical characterisation studies are essential to informing research, diagnosis and clinical management efforts, particularly early in a pandemic. In this scoping review we identify the clinical characteristics of patients admitted to hospital in the early months of the pandemic, focusing on symptoms, laboratory and imaging findings, and clinical outcomes. Methods: A scoping review. MEDLINE, EMBASE and Global Health databases were searched studies published from January 1st 2020 to April 28th 2020. Studies which reported on at least 100 hospitalised patients with covid-19 of any age were included. Results: Of 1,249 studies identified through the search 78 studies were eligible for inclusion; one randomized control trial and 77 observational studies presenting data on 77,443 patients admitted with covid-19. Most studies were conducted in China (82%), 9% in the US and 10% in Europe and two studies were set in more than one country. No studies included patients from low and middle income countries. Coagulopathy was underrecognised as a complication in the early months of the pandemic. Use of corticosteroids varied widely, and the use of anticoagulants was reported in only one study. Fever, cough and dyspnoea are less common in older adults; gastrointestinal symptoms, as the only presenting feature may be underrecognised. The most common laboratory finding was lymphocytopenia. Inflammatory biomarkers were commonly elevated, including C-reactive protein and interleukin-6. Typical computed tomography findings include bilateral infiltrates however imaging may be normal in early disease. Data on clinical characteristics in children and vulnerable populations were limited. Conclusions: Clinical characterisation studies from early in the pandemic indicated that covid-19 is a multisystem disease, with biomarkers indicating inflammation and coagulopathy. However, early data collection on symptoms and clinical outcomes did not consistently reflect this wide spectrum. Corticosteroid use varied widely, and anticoagulants were rarely used. Clinicians should remain vigilant to the possibility of covid-19 in patients presenting without fever, cough and dyspnoea, particularly in older adults. Further characterisation studies in different at-risk populations is needed. Review registration: Available at https://osf.io/r2ch9 Keywords: Covid-19, clinical characteristics, symptoms, biochemical parameters, imaging, outcomes, pandemic research

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score (preprint)

ObjectivesTo develop and validate a pragmatic risk score to predict mortality for patients admitted to hospital with covid-19. DesignProspective observational cohort study: ISARIC WHO CCP-UK study (ISARIC Coronavirus Clinical Characterisation Consortium [4C]). Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited between 21 May and 29 June 2020. Setting260 hospitals across England, Scotland, and Wales. ParticipantsAdult patients ([≥]18 years) admitted to hospital with covid-19 admitted at least four weeks before final data extraction. Main outcome measuresIn-hospital mortality. ResultsThere were 34 692 patients included in the derivation dataset (mortality rate 31.7%) and 22 454 in the validation dataset (mortality 31.5%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea, and C-reactive protein (score range 0-21 points). The 4C risk stratification score demonstrated high discrimination for mortality (derivation cohort: AUROC 0.79; 95% CI 0.78 - 0.79; validation cohort 0.78, 0.77-0.79) with excellent calibration (slope = 1.0). Patients with a score [≥]15 (n = 2310, 17.4%) had a 67% mortality (i.e., positive predictive value 67%) compared with 1.0% mortality for those with a score [≤]3 (n = 918, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (AUROC range 0.60-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). ConclusionsWe have developed and validated an easy-to-use risk stratification score based on commonly available parameters at hospital presentation. This outperformed existing scores, demonstrated utility to directly inform clinical decision making, and can be used to stratify inpatients with covid-19 into different management groups. The 4C Mortality Score may help clinicians identify patients with covid-19 at high risk of dying during current and subsequent waves of the pandemic. Study registrationISRCTN66726260

ISARIC COVID-19 Clinical Data Report: 8 June 2020 (preprint)

ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global uptake of this resource has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report is a part of a series and includes the results of data analysis on 8 June 2020. We thank all of the data contributors for their ongoing support. As of 8JUN20, data have been entered for 67,130 patients from 488 sites across 37 countries. For this report, we show data for 42,656 patients with confirmed disease who were enrolled >14 days prior. This update includes about 2,400 new cases from France, and we thank these collaborators for this significant addition to the dataset. Some highlights from this report The median time from onset of symptoms to hospital admission is 5 days, but a proportion of patients take longer to get to the hospital (average 14.6 days, standard deviation 8.1). COVID-19 patients tend to require prolonged hospitalisation; of the 88% with a known outcome, the median length of admission to death or discharge is 8 days and the mean 11.5. 17% of patients were admitted to ICU/HDU, about 40% of these on the very day of hospital admission. Antibiotics were given to 83% of patients, antivirals to 9%, steroids to 15%, which becomes 93%, 50% and 27%, respectively for those admitted to ICU/HDU. Attention has been called on overuse of antibiotics and need to adhere to antibiotic stewardship principles. 67% of patients received some degree of oxygen supplementation: of these 23.4% received NIV and 15% IMV. This relatively high proportion of oxygen use will have implications for oxygen surge planning in healthcare facilities. Some centres may need to plan to boost capacity to deliver oxygen therapy if this is not readily available. WHO provides operational advice on surge strategy here https://apps.who.int/iris/bitstream/handle/10665/331746/WHO-2019-nCoV-Oxygen_sources-2020.1-eng.pdf

Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: prospective multicentre observational cohort study (preprint)

ObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). DesignProspective observational cohort study with rapid data gathering and near real time analysis. Setting260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome MeasuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. ResultsMedian age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p<0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p<0.001), myalgia (39% (11/28) vs 7% (12/170), p<0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). ConclusionsOur data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registrationISRCTN66726260