Metabolomic and gut microbiome profiles across the spectrum of community-based COVID and non-COVID disease: A COVID-19 Biobank study.

Whilst many with SARS-CoV-2 infection have mild disease, managed in the community, individuals with cardiovascular risk factors experienced often more severe acute disease, requiring hospitalisation. Increasing concern has also developed over long symptom duration in many individuals, including the majority who managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. We examine post-illness metabolomic and gut-microbiome profiles, in community-dwelling participants with SARS-CoV-2, ranging from asymptomatic illness to Post-COVID Syndrome, and participants with prolonged non-COVID-19 illnesses. We also assess a pre-established metabolomic biomarker score for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, and greater biomarker scores, associated with longer illness, both in individuals with and without SARS-CoV-2 infection. We found no association between illness duration and gut microbiome in convalescence. Findings highlight the potential role of cardiometabolic dysfunction to the experience of long illness duration, including after COVID-19.

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.

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors

SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. From cross-sectional antibody testing of 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies (jointly in April-May 2021, and TwinsUK only in November 2021-January 2022), we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables. Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months, compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK "Shielded Patient List" had consistently greater odds (2 to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies. Lay summaryIn this study, we analysed blood samples from 9,361 participants from two studies in the UK: an adult twin registry, TwinsUK (4,739 individuals); and the Avon Longitudinal Study of Parents and Children, ALSPAC (4,622 individuals). We did this work as part of the UK Government National Core Studies initiative researching COVID-19. We measured blood antibodies which are specific to SARS-CoV-2 (which causes COVID-19). Having a third COVID-19 vaccination boosted antibody levels. More than 90% of people from TwinsUK had levels after third vaccination that were greater than the average level after second vaccination. Importantly, this was the case even in individuals on the UK "Shielded Patient List". We found that people with lower antibody levels after first vaccination were more likely to report having COVID-19 later on, compared to people with higher antibody levels. People on the UK "Shielded Patient List", and individuals who reported that they had poorer general health, were more likely to have lower antibody levels after vaccination. In contrast, people who had had a previous COVID-19 infection were more likely to have higher antibody levels following vaccination compared to people without infection. People receiving the Oxford/AstraZeneca rather than the Pfizer BioNTech vaccine had lower antibody levels after one or two vaccinations. However, after a third vaccination, there was no difference in antibody levels between those who had Oxford/AstraZeneca and Pfizer BioNTech vaccines for their first two doses. These findings support having a third COVID-19 vaccination to boost antibodies.

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.

Concordance of B and T cell responses to SARS-CoV-2 infection, irrespective of symptoms suggestive of COVID-19.

ObjectivesTo assess T cell responses in individuals with and without a positive antibody response to SARS-CoV-2, in symptomatic and asymptomatic individuals during the COVID-19 pandemic. MethodsParticipants were drawn from the TwinsUK cohort, selected according to a) presence or absence of COVID-associated symptoms (S+, S-), logged prospectively through the COVID Symptom Study app, and b) Anti-IgG Spike and anti-IgG Nucleocapsid antibodies measured by ELISA (Ab+, Ab-), during the first wave of the UK pandemic. T cell helper and regulatory responses after stimulation with SARS-CoV-2 peptides were assessed. Results32 participants were included in final analysis. 14 of 15 with IgG Spike antibodies had a T cell response to SARS-CoV-2-specific peptides; none of 17 participants without IgG Spike antibodies had a T cell response (Chi-squared 28.2, p<0.001). Quantitative T cell responses correlated strongly with fold-change in IgG Spike antibody titre (rho=0.79, p<0.0001) but not to symptom score (rho=0.17, p=0.35). ConclusionsHumoral and cellular immune responses to SARS-CoV-2 are highly correlated, with no evidence that cellular immunity differs from antibody status four months after acute illness.

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.

Disentangling post-vaccination symptoms from early COVID-19

BackgroundIdentifying and testing individuals likely to have SARS-CoV-2 is critical for infection control, including post-vaccination. Vaccination is a major public health strategy to reduce SARS-CoV-2 infection globally. Some individuals experience systemic symptoms post-vaccination, which overlap with COVID-19 symptoms. This study compared early post-vaccination symptoms in individuals who subsequently tested positive or negative for SARS-CoV-2, using data from the COVID Symptom Study (CSS) app. DesignWe conducted a prospective observational study in UK CSS participants who were asymptomatic when vaccinated with Pfizer-BioNTech mRNA vaccine (BNT162b2) or Oxford-AstraZeneca adenovirus-vectored vaccine (ChAdOx1 nCoV-19) between 8 December 2020 and 17 May 2021, who subsequently reported symptoms within seven days (other than local symptoms at injection site) and were tested for SARS-CoV-2, aiming to differentiate vaccination side-effects per se from superimposed SARS-CoV-2 infection. The post-vaccination symptoms and SARS-CoV-2 test results were contemporaneously logged by participants. Demographic and clinical information (including comorbidities) were also recorded. Symptom profiles in individuals testing positive were compared with a 1:1 matched population testing negative, including using machine learning and multiple models including UK testing criteria. FindingsDifferentiating post-vaccination side-effects alone from early COVID-19 was challenging, with a sensitivity in identification of individuals testing positive of 0.6 at best. A majority of these individuals did not have fever, persistent cough, or anosmia/dysosmia, requisite symptoms for accessing UK testing; and many only had systemic symptoms commonly seen post-vaccination in individuals negative for SARS-CoV-2 (headache, myalgia, and fatigue). InterpretationPost-vaccination side-effects per se cannot be differentiated from COVID-19 with clinical robustness, either using symptom profiles or machine-derived models. Individuals presenting with systemic symptoms post-vaccination should be tested for SARS-CoV-2, to prevent community spread. FundingZoe Limited, UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK National Institute for Health Research, UK Medical Research Council and British Heart Foundation, Alzheimers Society, Chronic Disease Research Foundation, Massachusetts Consortium on Pathogen Readiness (MassCPR). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere are now multiple surveillance platforms internationally interrogating COVID-19 and/or post-vaccination side-effects. We designed a study to examine for differences between vaccination side-effects and early symptoms of COVID-19. We searched PubMed for peer-reviewed articles published between 1 January 2020 and 21 June 2021, using keywords: "COVID-19" AND "Vaccination" AND ("mobile application" OR "web tool" OR "digital survey" OR "early detection" OR "Self-reported symptoms" OR "side-effects"). Of 185 results, 25 studies attempted to differentiate symptoms of COVID-19 vs. post-vaccination side-effects; however, none used artificial intelligence (AI) technologies ("machine learning") coupled with real-time data collection that also included comprehensive and systematic symptom assessment. Additionally, none of these studies attempt to discriminate the early signs of infection from side-effects of vaccination (specifically here: Pfizer-BioNTech mRNA vaccine (BNT162b2) and Oxford-AstraZeneca adenovirus-vectored vaccine (ChAdOx1 nCoV-19)). Further, none of these studies sought to provide comparisons with current testing criteria used by healthcare services. Added value of this studyThis study, in a uniquely large community-based cohort, uses prospective data capture in a novel effort to identify individuals with COVID-19 in the immediate post-vaccination period. Our results show that early symptoms of SARS-CoV-2 cannot be differentiated from vaccination side-effects robustly. Thus, post-vaccination systemic symptoms should not be ignored, and testing should be considered to prevent COVID-19 dissemination by vaccinated individuals. Implications of all the available evidenceOur study demonstrates the critical importance of testing symptomatic individuals - even if vaccinated - to ensure early detection of SARS-CoV-2 infection, helping to prevent future pandemic waves in the UK and elsewhere.

Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app

BackgroundMental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (e.g., obesity, comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study. MethodsWe assessed anxiety and depression symptoms using two validated questionnaires in 413,148 individuals between February and April 2021; 26,998 had tested positive for SARS-CoV-2. We adjusted for physical and mental pre-pandemic comorbidities, BMI, age, and sex. FindingsOverall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2 positive (30.4%) vs. negative (26.1%) individuals. This association was small compared to the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants ([≤]40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) vs. more distant (>120 days) infection, suggesting a short-term effect. InterpretationA small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than pre-pandemic. FundingZoe Limited, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, Medical Research Council UK

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.