Profiling post-COVID syndrome across different variants of SARS-CoV-2

AbstractO_ST_ABSBackgroundC_ST_ABSSelf-reported symptom studies rapidly increased our understanding of SARS-CoV-2 during the pandemic and enabled the monitoring of long-term effects of COVID-19 outside the hospital setting. It is now evident that post-COVID syndrome presents with heterogeneous profiles, which need characterisation to enable personalised care among the most affected survivors. This study describes post-COVID profiles, and how they relate to different viral variants and vaccination status. MethodsIn this prospective longitudinal cohort study, we analysed data from 336,652 subjects, with regular health reports through the Covid Symptom Study (CSS) smartphone application. These subjects had reported feeling physically normal for at least 30 days before testing positive for SARS-CoV-2. 9,323 individuals subsequently developed Long-COVID, defined as symptoms lasting longer than 28 days. 1,459 had post-COVID syndrome, defined as more than 12 weeks of symptoms. Clustering analysis of the time-series data was performed to identify distinct symptom profiles for post-COVID patients, across variants of SARS-CoV-2 and vaccination status at the time of infection. Clusters were then characterised based on symptom prevalence, duration, demography, and prior conditions (comorbidities). Using an independent testing sample with additional data (n=140), we investigated the impact of post-COVID symptom clusters on the lives of affected individuals. FindingsWe identified distinct profiles of symptoms for post-COVID syndrome within and across variants: four endotypes were identified for infections due to the wild-type variant; seven for the alpha variant; and five for delta. Across all variants, a cardiorespiratory cluster of symptoms was identified. A second cluster related to central neurological, and a third to cases with the most severe and debilitating multi-organ symptoms. Gastrointestinal symptoms clustered in no more than two specific phenotypes per viral variant. The three main clusters were confirmed in an independent testing sample, and their functional impact was assessed. InterpretationUnsupervised analysis identified different post-COVID profiles, characterised by differing symptom combinations, durations, and functional outcomes. Phenotypes were at least partially concordant with individuals reported experiences. Our classification may be useful to understand distinct mechanisms of the post-COVID syndrome, as well as subgroups of individuals at risk of prolonged debilitation. FundingUK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimers Society, and ZOE Limited, UK. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe conducted a search in the PubMed Central database, with keywords: ("Long-COVID*" OR "post?covid*" OR "post?COVID*" OR postCOVID* OR postCovid*) AND (cluster* OR endotype* OR phenotype* OR sub?type* OR subtype). On 15 June 2022, 161 documents were identified, of which 24 either provided descriptions of sub-types or proposed phenotypes of Long-COVID or post-COVID syndrome(s). These included 16 studies attempting manual sub-grouping of phenotypes, 6 deployments of unsupervised methods for patient clustering and automatic semantic phenotyping (unsupervised k-means=2; random forest classification=1; other=2), and two reports of uncommon presentations of Long-COVID/post-COVID syndrome. Overall, two to eight symptom profiles (clusters) were identified, with three recurring clusters. A cardiopulmonary syndrome was the predominant observation, manifesting with exertional intolerance and dyspnoea (n=10), fatigue (n=8), autonomic dysfunction, tachycardia or palpitations (n=5), lung radiological abnormalities including fibrosis (n=2), and chest pain (n=1). A second common presentation consisted in persistent general autoimmune activation and proinflammatory state (n=2), comprising multi-organ mild sequelae (n=2), gastrointestinal symptoms (n=2), dermatological symptoms (n=2), and/or fever (n=1). A third syndrome was reported, with neurological or neuropsychiatric symptoms: brain fog or dizziness (n=2), poor memory or cognition (n=2), and other mental health issues including mood disorders (n=5), headache (n=2), central sensitization (n=1), paresthesia (n=1), autonomic dysfunction (n=1), fibromyalgia (n=2), and chronic pain or myalgias (n=6). Unsupervised clustering methods identified two to six different post-COVID phenotypes, mapping to the ones described above. 14 further documents focused on possible causes and/or mechanisms of disease underlying one or more manifestations of Long-COVID or post-COVID and identifying immune response dysregulation as a potential common element. All the other documents were beyond the scope of this work. To our knowledge, there are no studies examining the symptom profile of post-COVID syndrome between different variants and vaccination status. Also, no studies reported the modelling of longitudinally collected symptoms, as time-series data, aiming at the characterisation of post-COVID syndrome. Added-value of this studyOur study aimed to identify symptom profiles for post-COVID syndrome across the dominant variants in 2020 and 2021, and across vaccination status at the time of infection, using a large sample with prospectively collected longitudinal self-reports of symptoms. For individuals developing 12 weeks or more of symptoms, we identified three main symptom profiles which were consistent across variants and by vaccination status, differing only in the ratio of individuals affected by each profile and symptom duration overall. Implications of all the available evidenceWe demonstrate the existence of different post-COVID syndromes, which share commonalities across SARS-CoV-2 variant types in both symptoms themselves and how they evolved through the illness. We describe subgroups of patients with specific post-COVID presentations which might reflect different underlying pathophysiological mechanisms. Given the time-series component, our study is relevant for post-COVID prognostication, indicating how long certain symptoms last. These insights could aid in the development of personalised diagnosis and treatment, as well as helping policymakers plan for the delivery of care for people living with post-COVID syndrome.

Vaccination against SARS-CoV-2 in UK school-aged children and young people decreases infection rates and reduces COVID-19 symptoms

BackgroundWe aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and young people (CYP) in the UK during periods of Delta and Omicron variant predominance. MethodsIn this prospective longitudinal cohort study, we analysed data from 115,775 CYP aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CYP with post-vaccination SARS- CoV-2 infection, compared to unvaccinated CYP, and post-vaccination side-effects. FindingsBetween August 5, 2021 and February 14, 2022, 25,971 UK CYP aged 12-17 years received one dose of BNT162b2 vaccine. Vaccination reduced (proxy-reported) infection risk (-80{middle dot}4% and -53{middle dot}7% at 14-30 days with Delta and Omicron variants respectively, and -61{middle dot}5% and -63{middle dot}7% after 61-90 days). The probability of remaining infection-free diverged soon after vaccination, and was greater in CYP with prior SARS-CoV-2 infection. Vaccinated CYP who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CYP; during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CYP. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved quickly. InterpretationOne dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CYP aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CYP also had generally mild disease. Overall, vaccination was well-tolerated. FundingUK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimers Society, and ZOE Limited. Research in context Evidence before this studyWe searched PubMed database for peer-reviewed articles and medRxiv for preprint papers, published between January 1, 2021 and February 15, 2022 using keywords ("SARS-CoV-2" OR "COVID-19") AND (child* OR p?ediatric* OR teenager*) AND ("vaccin*" OR "immunization campaign") AND ("efficacy" OR "effectiveness" OR "symptoms") AND ("delta" or "omicron" OR "B.1.617.2" OR "B.1.1.529"). The PubMed search retrieved 36 studies, of which fewer than 30% specifically investigated individuals <18 years. Eleven studies explored SARS-CoV-2 viral transmission: seroprevalence in children (n=4), including age-dependency of susceptibility to SARS-CoV-2 infection (n=1), SARS-CoV-2 transmission in schools (n=5), and the effect of school closure on viral transmission (n=1). Eighteen documents reported clinical aspects, including manifestation of infection (n=13), symptomatology, disease duration, and severity in children. Other studies estimated emergency department visits, hospitalization, need for intensive care, and/or deaths in children (n=4), and explored prognostic factors (n=1). Thirteen studies explored vaccination-related aspects, including vaccination of children within specific paediatric co-morbidity groups (e.g., children with Down syndrome, inflammatory bowel disease, and cancer survivors, n=4), mRNA vaccine efficacy in children and adolescents from the general population (n=7), and the relation between vaccination and severity of disease and hospitalization cases (n=2). Four clinical trials were conducted using mRNA vaccines in minors, also exploring side effects. Sixty percent of children were found to have side effects after BNT162b2 vaccination, and especially after the second dose; however, most symptoms were mild and transient apart from rare uncomplicated skin ulcers. Two studies focused on severe adverse effects and safety of SARS-CoV-2 vaccines in children, reporting on myocarditis episodes and two cases of Guillain-Barre syndrome. All other studies were beyond the scope of our research. Added value of this studyWe assessed multiple components of the UK vaccination campaign in a cohort of children and young people (CYP) aged 12-17 years drawn from a large UK community-based citizen-science study, who received a first dose of BNT162b2 vaccine. We describe a variant-dependent protective effect of the first dose against both Delta and Omicron, with additional protective effect of pre-vaccination SARS- CoV-2 infection on post-vaccination re-infection. We compare the illness profile in CYP infected post-vaccination with that of unvaccinated CYP, demonstrating overall milder disease with fewer symptoms for vaccinated CYP. We describe local and systemic side-effects during the first week following first-dose vaccination, confirming that local symptoms are common, systemic symptoms uncommon, and both usually transient. Implications of all the available evidenceOur data confirm that first dose BNT162b2 vaccination in CYP reduces risk of infection by SARS-CoV-2 variants, with generally local and brief side-effects. If infected after vaccination, COVID-19 is milder, if manifest at all. The study aims to contribute quantitative evidence to the risk-benefit evaluation of vaccination in CYP to inform discussion regarding rationale for their vaccination and the designing of national immunisation campaigns for this age group; and applies citizen-science approaches in the conduct of epidemiological surveillance and data collection in the UK community. Importantly, this study was conducted during Delta and Omicron predominance in UK; specificity of vaccine efficacy to variants is also illustrated; and results may not be generalizable to future SARS-CoV-2 strains.

COVID-19 due to the B.1.617.2 (Delta) variant compared to B.1.1.7 (Alpha) variant of SARS-CoV-2: two prospective observational cohort studies

BackgroundThe Delta (B.1.617.2) variant became the predominant UK circulating SARS-CoV-2 strain in May 2021. How Delta infection compares with previous variants is unknown. MethodsThis prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. Findings3,581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta vs. Alpha infection (including fever, sore throat and headache) and vice versa (dyspnoea). Symptom burden in the first week was higher with Delta vs. Alpha infection; however, the odds of any given symptom lasting [≥]7 days was either lower or unchanged. Illness duration [≥]28 days was lower with Delta vs. Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1{middle dot}47) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly (69-84%) reduced risk of Delta infection. InterpretationCOVID-19 from Delta or Alpha infections is clinically similar. The Delta variant is more transmissible than Alpha; however, current vaccines show good efficacy against disease. FundingUK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, Alzheimers Society, and ZOE Limited. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence for differences (including illness, transmissibility, and vaccine effectiveness) from SARS-CoV-2 infection due to Alpha (B.1.1.7) and Delta (B.1.617.2) variants, we searched PubMed for peer-reviewed articles and medRxiv for preprint publications between March 1 and November 18, 2021 using keywords ("SARS-CoV-2" OR "COVID-19") AND ("delta variant" OR "B.1.617.2") AND (symptom* OR transmiss* OR "disease duration" OR "illness duration" OR "symptom* duration"). Searches were not restricted by language. Among 169 identified PubMed articles, we found evidence that Delta variant has increased replication capacity (from 4-fold, up to 21-fold, compared with wild-type) and greater transmissibility (estimated between +20% and +97%), compared with previous strains. Currently available vaccines may have 2- to 5-fold lower neutralizing response to Delta vs. previous variants, depending on vaccine formulation, although their protective effect against severe disease and death appears to remain strong. REACT-1 study found that in UK infections were increasing exponentially in the 5-17-year old children in September 2021, coinciding with the start of the autumn school term in England. This was interpreted as an effect of the relatively low rate of vaccinated individuals in this age group. Other studies found that in unvaccinated individuals, Delta variant may be associated with higher odds of pneumonia, oxygen requirement, emergency care requests, ICU admission, and death. In a study of 27 (mainly young) cases, 22 persons were symptomatic, with fever (41%), cough (33%), headache (26%), and sore throat (26%) the commonest symptoms. We found no studies, beyond case series, investigating symptom and/or illness duration due to Delta variant infection otherwise. Added value of this studyUsing data from one of the largest UK citizen science epidemiological initiatives, we describe and compare illness (symptom duration, burden, profile, risk of long illness, and hospital attendance) in symptomatic community-based adults presenting when either the Alpha or Delta variant was the predominant circulating strain of SARS-CoV-2 in the UK. We assess evidence of transmission, reinfection, and vaccine effectiveness. Our data show that the seven most common symptoms with Delta infection were the same as with Alpha infection. Risks of illness duration [≥]7 days and [≥]28 days, and of requiring hospital care, were not increased. In line with previous research, we found increased transmissibility of Delta vs. previous variants; and no evidence of increased re-infection rates. Our data support high vaccine efficacy of BNT162b2 and ChAdOx1 nCoV-19 formulations against Delta variant infection. Overall, our study adds quantitative information regarding meaningful clinical differences in COVID-19 due to Delta vs. other variants. Implications of all the available evidenceOur observational data confirm that COVID-19 disease in UK in adults is generally comparable to infection with the Alpha variant, including in elderly individuals. Our data contribute to epidemiological surveillance from the wider UK population and may capture information from COVID-19 presentation within the community that might be missed in healthcare-based surveillance. Our data may be useful in informing healthcare service planning, vaccination policies, and measures for social protection.

Illness characteristics of COVID-19 in children infected with the SARS-CoV-2 Delta variant

BackgroundThe Delta (B.1.617.2) SARS-CoV-2 variant became the predominant UK circulating strain in May 2021. Whether COVID-19 from Delta infection differs to infection with other variants in children is unknown. MethodsThrough the prospective COVID Symptom Study, 109,626 UK school-aged children were proxy-reported between December 28, 2020 and July 8, 2021. We selected all symptomatic children who tested positive for SARS-CoV-2 and were proxy-reported at least weekly, within two timeframes: December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the main UK circulating variant); and May 26 to July 8, 2021 (Delta the main UK circulating variant). We assessed illness profiles (symptom prevalence, duration, and burden), hospital presentation, and presence of long ([≥]28 day) illness; and calculated odds ratios for symptoms presenting within the first 28 days of illness. Findings694 (276 younger [5-11 years], 418 older [12-17 years]) symptomatic children tested positive for SARS-CoV-2 with Alpha infection and 706 (227 younger and 479 older) children with Delta infection. Median illness duration was short with either variant (overall cohort: 5 days (IQR 2-9.75) with Alpha, 5 days (IQR 2-9) with Delta). The seven most prevalent symptoms were common to both variants. Symptom burden over the first 28 days was slightly greater with Delta compared with Alpha infection (in younger children, 3 (IQR 2-5) with Alpha, 4 (IQR 2-7) with Delta; in older children 5 (IQR 3-8) with Alpha and 6 (IQR 3-9) with Delta infection in older children). The odds of several symptoms were higher with Delta than Alpha infection, including headache and fever. Few children presented to hospital, and long illness duration was uncommon, with either variant. InterpretationCOVID-19 in UK school-aged children due to SARS-CoV-2 Delta strain B.1.617.2 resembles illness due to the Alpha variant B.1.1.7., with short duration and similar symptom burden. FundingZOE Limited, UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimers Society. EthicsEthics approval was granted by KCL Ethics Committee (reference LRS-19/20-18210). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence for differences in COVID-19 due to infection with Alpha (B.1.1.7) or Delta (B.1.617.2) SARS-CoV-2 variants, we searched PubMed for peer-reviewed articles and medRxiv for preprint publications between March 1, and September 17, 2021 using keywords ("SARS-CoV-2" OR "COVID-19") AND (children OR p?ediatric*) AND ("delta variant" OR "B.1.617.2"). We did not restrict our search by language. Of twenty published articles identified in PubMed, we found one case study describing disease presentation associated with Delta variant infection in a child. Another study examining the increase in hospitalization rates of paediatric cases in USA from August 1, 2020 to August 27, 2021 stated that "It is not known whether the B.1.617.2 (Delta) variant [...] causes different clinical outcomes in children and adolescents compared with variants that circulated earlier." Four studies reported cases of transmission of the Delta variant in school and community contexts; and two discussed screening testing in school-aged children (thus not directly relevant to the research question here). Remaining papers did not target paediatric age specifically. We found no studies investigating differences in COVID-19 presentation (e.g., duration, burden, individual symptoms) in school-aged children either in the UK or world-wide. Added value of this studyWe describe and compare illness profiles in symptomatic UK school-aged children (aged 5-17 years) with COVID-19 when either Alpha or Delta strains were the predominant circulating SARS-CoV-2 variant. Our data, collected through one of the largest UK citizen science epidemiological initiatives, show that symptom profile and illness duration of COVID-19 are broadly similar between the strains. Although there were slightly more symptoms with Delta than with Alpha, particularly in older children, this was offset by similar symptom duration (whether considered for symptoms individually or for illness overall). Our study adds quantitative information to the debate on whether there are meaningful clinical differences in COVID-19 due to Alpha vs. Delta variants; and contributes to the discussion regarding rationale for vaccinating children (particularly younger children) against SARS-CoV-2. Implications of all the available evidenceOur data confirm that COVID-19 in UK school-aged children is usually of short duration and similar symptom burden, whether due to Delta or Alpha. Our data contribute to epidemiological surveillance from the wider UK population, and we capture common and generally mild paediatric presentations of COVID-19 that might be missed using clinician-based surveillance alone. Our data will also be useful for the vaccination debate.

App-based COVID-19 surveillance and prediction: The COVID Symptom Study Sweden

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants ([≥]18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Data from 19,161 self-reported PCR tests were used to create a symptom-based model to estimate the individual probability of symptomatic COVID-19, with an AUC of 0.78 (95% CI 0.74-0.83) in an external dataset. These individual probabilities were used to estimate daily regional COVID-19 prevalence, which were in turn used together with current hospital data to predict next week COVID-19 hospital admissions. We found that this hospital prediction model demonstrated a lower median absolute percentage error (MdAPE: 25.9%) across the five most populated regions in Sweden during the first pandemic wave than a model based on case notifications (MdAPE: 30.3%). During the second wave, the error rates were similar. When applying the same model to an English dataset, not including local COVID-19 test data, we observed MdAPEs of 22.3% and 19.0%, respectively, highlighting the transferability of the prediction model.

Illness duration and symptom profile in a large cohort of symptomatic UK school-aged children tested for SARS-CoV-2

BackgroundIn children, SARS-CoV-2 is usually asymptomatic or causes a mild illness of short duration. Persistent illness has been reported; however, its prevalence and characteristics are unclear. We aimed to determine illness duration and characteristics in symptomatic UK school-aged children tested for SARS-CoV-2 using data from the COVID Symptom Study, the largest UK citizen participatory epidemiological study to date. MethodsData from 258,790 children aged 5-17 years were reported by an adult proxy between 24 March 2020 and 22 February 2021. Illness duration and symptom profiles were analysed for all children testing positive for SARS-CoV-2 for whom illness duration could be determined, considered overall and within younger (5-11 years) and older (12-17 years) groups. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed. Findings1,734 children (588 younger, 1,146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study time frame. The commonest symptoms were headache (62.2%) and fatigue (55.0%). Median illness duration was six days (vs. three days in children testing negative), and was positively associated with age (rs 0.19, p<1.e-4) with median duration of seven days in older vs. five days in younger children. Seventy-seven (4.4%) children had illness duration [≥]28 days (LC28), more commonly experienced by older vs. younger children (59 (5.1%) vs. 18 (3.1%), p=0.046). The commonest symptoms experienced by these children were fatigue (84%), headache (80%) and anosmia (80%); however, by day 28 the symptom burden was low (median, two). Only 25 (1.8%) of 1,379 children experienced symptoms for [≥]56 days. Few children (15 children, 0.9%) in the negatively-tested cohort experienced prolonged symptom duration; however, these children experienced greater symptom burden (both throughout their illness and at day 28) than children positive for SARS-CoV-2. InterpretationSome children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 in children is usually asymptomatic or manifests as a mild illness of short duration. Concerns have been raised regarding prolonged illness in children, with no clear resolution of symptoms several weeks after onset, as is observed in some adults. How common this might be in children, the clinical features of such prolonged illness in children, and how it might compare with illnesses from other respiratory viruses (and with general population prevalence of these symptoms) is unclear. Added value of this studyWe provide systematic description of COVID-19 in UK school-aged children. Our data, collected in a digital surveillance platform through one of the largest UK citizen science initiatives, show that long illness duration after SARS-CoV-2 infection in school-aged children does occur, but is uncommon, with only a small proportion of children experiencing illness duration beyond four weeks; and the symptom burden in these children usually decreases over time. Almost all children have symptom resolution by eight weeks, providing reassurance about long-term outcomes. Additionally, symptom burden in children with long COVID was not greater than symptom burden in children with long illnesses due to causes other than SARS-CoV-2 infection. Implications of all the available evidenceOur data confirm that COVID-19 in UK school-aged children is usually of short duration and of low symptom burden. Some children do experience longer illness duration, validating their experience; however, most of these children usually recover with time. Our findings highlight that appropriate resources will be necessary for any child with prolonged illness, whether due to COVID-19 or other illness. Our study provides timely and critical data to inform discussions around the impact and implications of the pandemic on paediatric healthcare resource allocation.

The effect of SARS-CoV-2 variant B.1.1.7 on symptomatology, re-infection and transmissibility

BackgroundSARS-CoV-2 variant B.1.1.7 was first identified in December 2020 in England. It is not known if the new variant presents with variation in symptoms or disease course, if previously infected individuals may become reinfected with the new variant, or how the variants increased transmissibility affects measures to reduce its spread. MethodsUsing longitudinal symptom reports from 36,920 users of the COVID Symptom Study app testing positive for Covid-19 between 28 September and 27 December 2020, we performed an ecological study to examine the association between the regional proportion of B.1.1.7 and reported symptoms, disease course, rates of reinfection, and transmissibility. FindingsWe found no evidence for changes in reported symptoms or disease duration associated with B.1.1.7. We found a likely reinfection rate of 0.7% (95% CI 0.6-0.8), but no evidence that this was higher compared to older strains. We found an increase in R(t) by a factor of 1.35 (95% CI 1.02-1.69). Despite this, we found that R(t) fell below 1 during regional and national lockdowns, even in regions with high proportions of B.1.1.7. InterpretationThe lack of change in symptoms indicates existing testing and surveillance infrastructure do not need to change specifically for the new variant, and the reinfection findings suggest that vaccines are likely to remain effective against the new variant. FundingZoe Global Limited, Department of Health, Wellcome Trust, EPSRC, NIHR, MRC, Alzheimers Society. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence on SARS-CoV-2 variant B.1.1.7 we searched PubMed and Google Scholar for articles between 1 December 2020 and 1 February 2021 using the keywords Covid-19 AND B.1.1.7, finding 281 results. We did not find any studies that investigated B.1.1.7-associated changes in the symptoms experienced, their severity and duration, but found one study showing B.1.1.7 did not change the ratio of symptomatic to asymptomatic infections. We found six articles describing laboratory-based investigations of the responses of B.1.1.7 to vaccine-induced immunity to B.1.1.7, but no work investigating what this means for natural immunity and the likelihood of reinfection outside of the lab. We found five articles demonstrating the increased transmissibility of B.1.1.7. Added value of this studyTo our knowledge, this is the first study to explore changes in symptom type and duration, as well as community reinfection rates, associated with B.1.1.7. The work uses self-reported symptom logs from 36,920 users of the COVID Symptom Study app reporting positive test results between 28 September and 27 December 2020. We find that B.1.1.7 is not associated with changes in the symptoms experienced in Covid-19, nor their duration. Building on existing lab studies, our work suggests that natural immunity developed from previous infection provides similar levels of protection to B.1.1.7. We add to the emerging consensus that B.1.1.7 exhibits increased transmissibility. Implications of all the available evidenceOur findings suggest that existing criteria for obtaining a Covid-19 test in the community need not change for the rise of B.1.1.7. The fact that immunity developed from infection by wild type variants protects against B.1.1.7 provides an indication that vaccines will remain effective against B.1.1.7. R(t) fell below 1 during the UKs national lockdown, even in regions with high levels of B.1.1.7, but further investigation is required to establish the factors that enabled this, to facilitate countries seeking to control the spread of B.1.1.7.

Anosmia and other SARS-CoV-2 positive test-associated symptoms, across three national, digital surveillance platforms as the COVID-19 pandemic and response unfolded: an observation study

BackgroundMultiple participatory surveillance platforms were developed across the world in response to the COVID-19 pandemic, providing a real-time understanding of community-wide COVID-19 epidemiology. During this time, testing criteria broadened and healthcare policies matured. We sought to test whether there were consistent associations of symptoms with SARS-CoV-2 test status across three national surveillance platforms, during periods of testing and policy changes, and whether inconsistencies could better inform our understanding and future studies as the COVID-19 pandemic progresses. MethodsFour months (1st April 2020 to 31st July 2020) of observation through three volunteer COVID-19 digital surveillance platforms targeting communities in three countries (Israel, United Kingdom, and United States). Logistic regression of self-reported symptom on self-reported SARS-CoV-2 test status (or test access), adjusted for age and sex, in each of the study cohorts. Odds ratios over time were compared to known changes in testing policies and fluctuations in COVID-19 incidence. FindingsAnosmia/ageusia was the strongest, most consistent symptom associated with a positive COVID-19 test, based on 658,325 tests (5% positive) from over 10 million respondents in three digital surveillance platforms using longitudinal and cross-sectional survey methodologies. During higher-incidence periods with broader testing criteria, core COVID-19 symptoms were more strongly associated with test status. Lower incidence periods had, overall, larger confidence intervals. InterpretationThe strong association of anosmia/ageusia with self-reported SARS-CoV-2 test positivity is omnipresent, supporting its validity as a reliable COVID-19 signal, regardless of the participatory surveillance platform or testing policy. This analysis highlights that precise effect estimates, as well as an understanding of test access patterns to interpret differences, are best done only when incidence is high. These findings strongly support the need for testing access to be as open as possible both for real-time epidemiologic investigation and public health utility. FundingNIH, NIHR, Alzheimers Society, Wellcome Trust Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAs the COVID-19 pandemic has evolved, testing capacity expanded and governmental guidelines adapted, generally encouraging testing with a broader set of symptoms, not just fever with respiratory symptoms. In parallel, multiple large-scale citizen science digital surveillance platforms launched to complement knowledge from laboratory and somewhat smaller clinical studies. Symptoms such as loss of sense of smell have been identified as strongly predictive of COVID-19 infection in both clinical and syndromic surveillance analyses, and have therefore been used to inform these testing policy changes and access expansion. Added value of this studyThis study identifies symptoms that are or are not consistently associated with SARS-CoV-2 test positivity over time and across three country-based COVID-19 surveillance platforms in the United States, United Kingdom and Israel. These platforms are website and smartphone based, as well as cross-sectional and longitudinal. The study period of 4 months covers fluctuating COVID-19 prevalence during the fall of the first wave and, in some areas, rise of the second wave. In addition, the study period overlaps expansion of test access and test seeking. Importantly, these analyses track and highlight the value of individual symptoms to predict SARS-CoV-2 test positivity under a range of conditions. Implications of all the available evidenceDespite differences in surveillance methodology, access to SARS-CoV-2 testing and disease prevalence, loss of sense of smell or taste was consistently the strongest predictor of COVID-19 infection across all platforms over time. As access to testing broadened, the relevance of COVID-like symptoms and consistency of their predictive ability became apparent. However, confidence bounds generally widened with a fall in COVID-19 incidence. Therefore, for the most robust symptom-based COVID-19 prediction models should consider surveillance data during periods of higher incidence and improved test access, and effect estimates that replicate across different epidemiologic conditions and platforms.

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App

Reports of "Long-COVID", are rising but little is known about prevalence, risk factors, or whether it is possible to predict a protracted course early in the disease. We analysed data from 4182 incident cases of COVID-19 who logged their symptoms prospectively in the COVID Symptom Study app. 558 (13.3%) had symptoms lasting >=28 days, 189 (4.5%) for >=8 weeks and 95 (2.3%) for >=12 weeks. Long-COVID was characterised by symptoms of fatigue, headache, dyspnoea and anosmia and was more likely with increasing age, BMI and female sex. Experiencing more than five symptoms during the first week of illness was associated with Long-COVID, OR=3.53 [2.76;4.50]. A simple model to distinguish between short and long-COVID at 7 days, which gained a ROC-AUC of 76%, was replicated in an independent sample of 2472 antibody positive individuals. This model could be used to identify individuals for clinical trials to reduce long-term symptoms and target education and rehabilitation services.

Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study

BackgroundMen and older women have been shown to be at higher risk of adverse COVID-19 outcomes. Animal model studies of SARS-CoV and MERS suggest that the age and sex difference in COVID-19 symptom severity may be due to a protective effect of the female sex hormone estrogen. Females have shown an ability to mount a stronger immune response to a variety of viral infections because of more robust humoral and cellular immune responses. ObjectivesWe sought to determine whether COVID-19 positivity increases in women entering menopause. We also aimed to identify whether premenopausal women taking exogenous hormones in the form of the combined oral contraceptive pill (COCP) and post-menopausal women taking hormone replacement therapy (HRT) have lower predicted rates of COVID-19, using our published symptom-based model. DesignThe COVID Symptom Study developed by Kings College London and Zoe Global Limited was launched in the UK on 24th March 2020. It captured self-reported information related to COVID-19 symptoms. Data used for this study included records collected between 7th May - 15th June 2020. Main outcome measuresWe investigated links between COVID-19 rates and 1) menopausal status, 2) COCP use and 3) HRT use, using symptom-based predicted COVID-19, tested COVID-19, and disease severity based on requirement for hospital attendance or respiratory support. ParticipantsFemale users of the COVID Symptom Tracker Application in the UK, including 152,637 women for menopause status, 295,689 for COCP use, and 151,193 for HRT use. Analyses were adjusted for age, smoking and BMI. ResultsPost-menopausal women aged 40-60 years had a higher rate of predicted COVID (P=0.003) and a corresponding range of symptoms, with consistent, but not significant trends observed for tested COVID-19 and disease severity. Women aged 18-45 years taking COCP had a significantly lower predicted COVID-19 (P=8.03E-05), with a reduction in hospital attendance (P=0.023). Post-menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P=2.22E-05) for HRT users alone. ConclusionsOur findings support a protective effect of estrogen on COVID-19, based on positive association between predicted COVID-19 and menopausal status, and a negative association with COCP use. HRT use was positively associated with COVID-19 symptoms; however, the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential comorbidities. Trial registrationThe App Ethics has been approved by KCL ethics Committee REMAS ID 18210, review reference LRs-19/20-18210

Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app

As no one symptom can predict disease severity or the need for dedicated medical support in COVID-19, we asked if documenting symptom time series over the first few days informs outcome. Unsupervised time series clustering over symptom presentation was performed on data collected from a training dataset of completed cases enlisted early from the COVID Symptom Study Smartphone application, yielding six distinct symptom presentations. Clustering was validated on an independent replication dataset between May 1-May 28th, 2020. Using the first 5 days of symptom logging, the ROC-AUC of need for respiratory support was 78.8%, substantially outperforming personal characteristics alone (ROC-AUC 69.5%). Such an approach could be used to monitor at-risk patients and predict medical resource requirements days before they are required. One sentence summaryLongitudinal clustering of symptoms can predict the need for respiratory support in severe COVID-19.

Key predictors of attending hospital with COVID19: An association study from the COVID Symptom Tracker App in 2,618,948 individuals

ObjectivesWe aimed to identify key demographic risk factors for hospital attendance with COVID-19 infection. DesignCommunity survey SettingThe COVID Symptom Tracker mobile application co-developed by physicians and scientists at Kings College London, Massachusetts General Hospital, Boston and Zoe Global Limited was launched in the UK and US on 24th and 29th March 2020 respectively. It captured self-reported information related to COVID-19 symptoms and testing. Participants2,618,948 users of the COVID Symptom Tracker App. UK (95.7%) and US (4.3%) population. Data cut-off for this analysis was 21st April 2020. Main outcome measuresVisit to hospital and for those who attended hospital, the need for respiratory support in three subgroups (i) self-reported COVID-19 infection with classical symptoms (SR-COVID-19), (ii) selfreported positive COVID-19 test results (T-COVID-19), and (iii) imputed/predicted COVID-19 infection based on symptomatology (I-COVID-19). Multivariate logistic regressions for each outcome and each subgroup were adjusted for age and gender, with sensitivity analyses adjusted for comorbidities. Classical symptoms were defined as high fever and persistent cough for several days. ResultsOlder age and all comorbidities tested were found to be associated with increased odds of requiring hospital care for COVID-19. Obesity (BMI >30) predicted hospital care in all models, with odds ratios (OR) varying from 1.20 [1.11; 1.31] to 1.40 [1.23; 1.60] across population groups. Pre-existing lung disease and diabetes were consistently found to be associated with hospital visit with a maximum OR of 1.79 [1.64,1.95] and 1.72 [1.27; 2.31]) respectively. Findings were similar when assessing the need for respiratory support, for which age and male gender played an additional role. ConclusionsBeing older, obese, diabetic or suffering from pre-existing lung, heart or renal disease placed participants at increased risk of visiting hospital with COVID-19. It is of utmost importance for governments and the scientific and medical communities to work together to find evidence-based means of protecting those deemed most vulnerable from COVID-19. Trial registrationThe App Ethics have been approved by KCL ethics Committee REMAS ID 18210, review reference LRS-19/20-18210