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Background: Treatment for hypertension improves cardiovascular outcomes. Frailty may be present in older people treated for hypertension, but associates with adverse drug effects, potentially including falls resulting in fractures. We aimed to determine the association between baseline frailty and fractures in patients initiated on antihypertensive treatment. Methods: We conducted a retrospective cohort study using United Kingdom primary care data, including new users of first-line antihypertensives aged 65 years or over. We reported degree of frailty (fit, mild, moderate, severe) at antihypertensive initiation using the Electronic Frailty Index. We examined the association of frailty with fractures using multivariable Poisson regression, and assessed for interaction between antihypertensive class and frailty. Results: Of 113,779 patients aged 65 years or over who initiated on first-line antihypertensives, 49,634 patients (44%) were mildly or more frail. Over 4.1 years mean follow-up, 6567 (5.8%) experienced a fracture, with 3832 (58%) of these fractures occurring in frail people. Among those with severe frailty, doubling of fracture risk was observed after antihypertensive initiation, compared with fit people [adjusted rate ratio 2.26, 95% confidence interval (CI) 1.93–2.65]. Secondary analyses indicate this pattern was replicated for hip and arm fractures, and strongest for spine fractures, and the association between different types of antihypertensives and fractures varied by frailty (p = 0.004), being lower in moderately frail users of renin-angiotensin blockers compared with calcium channel blockers [rate ratio 0.81, 95% CI 0.71–0.94]. Conclusions: Frailty is common among older patients initiating first-line antihypertensive treatment, and was associated with an increased fracture rate. Awareness of this is important to encourage clinicians to consider risk of falls and fractures when treating hypertension.

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.

BackgroundSelf-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 Alzheimer’s Society, and ZOE Limited, UK.Research in contextEvidence before this studyWe 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.

BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population. METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence. FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p

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 (1·47) 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, Alzheimer’s Society, and ZOE Limited.Research in contextEvidence before this studyTo 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.

BACKGROUND: COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.METHODS: This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.FINDINGS: Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50-2·48; pINTERPRETATION: To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.FUNDING: ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.

BackgroundCOVID-19 vaccines show excellent efficacy in clinical trials and real-world data, but some people still contract SARS-CoV-2 despite vaccination. This study sought to identify risk factors associated with SARS-CoV-2 infection post-vaccination and describe characteristics of post-vaccination illness.MethodsAmongst 1,102,192 vaccinated UK adults from the COVID Symptom Study, 2394 (0.2%) cases of post-vaccination SARS-CoV-2 infection were identified between 8th December 2020 and 1st May 2021. Using a control group of vaccinated individuals testing negative, we assessed the associations of age, frailty, comorbidity, area-level deprivation and lifestyle factors with infection. Illness profile post-vaccination was assessed using a second control group of unvaccinated cases.FindingsOlder adults with frailty (OR=2.78, 95% CI=[1.98-3.89], p-valueInterpretationOur findings suggest that older individuals with frailty and those living in most deprived areas are at increased risk of infection post-vaccination. We also showed reduced symptom burden and duration in those infected post-vaccination. Efforts to boost vaccine effectiveness in at-risk populations, and to targeted infection control measures, may still be appropriate to minimise SARS-CoV-2 infection.FundingThis work is supported by UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust and via a grant to ZOE Global; the Wellcome Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z). Investigators also received support from the Chronic Disease Research Foundation, the Medical Research Council (MRC), British Heart Foundation, the UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, the Wellcome Flagship Programme (WT213038/Z/18/Z and Alzheimer’s Society (AS-JF-17-011), and the Massachusetts Consortium on Pathogen Readiness (MassCPR).Research in contextEvidence before this studyTo identify existing evidence for risk factors and characteristics of SARS-CoV-2 infection post-vaccination, we searched PubMed for peer-reviewed articles published between December 1, 2020 and May 18, 2021 using keywords (“COVID-19” OR “SARS-CoV-2”) AND (“Vaccine” OR “vaccination”) AND (“infection”) AND (“risk factor*” OR “characteristic*”). We did not restrict our search by language or type of publication. Of 202 articles identified, we found no original studies on individual risk and protective factors for COVID-19 infection following vaccination nor on nature and duration of symptoms in vaccinated, community-based individuals. Previous studies in unvaccinated populations have shown that social and occupational factors influence risk of SARS-CoV-2infection, and that personal factors (age, male sex, multiple morbidities and frailty) increased risk for adverse outcomes in COVID-19. Phase III clinical trials have demonstrated good efficacy of BNT162b2 and ChAdOx1 vaccines against SARS-CoV-2 infection, confirmed in published real-world data, which additionally showed reduced risk of adverse outcomes including hospitalisation and death.Added value of this studyThis is the first observational study investigating characteristics of and factors associated with SARS-CoV-2 infection after COVID-19 vaccination. We found that vaccinated individuals with frailty had higher rates of infection after vaccination than those without. Adverse determinants of health such as increased social deprivation, obesity, or a less healthy diet were associated with higher likelihood of infection after vaccination. In comparison with unvaccinated individuals, those with post-vaccination infection had fewer symptoms of COVID-19, and more were entirely asymptomatic. Fewer vaccinated individuals experienced five or more symptoms, required hospitalisation, and, in the older adult group, fewer had prolonged illness duration (symptoms lasting longer than 28 days).Implications of all the available evidenceSome individuals still contract COVID-19 after vaccination and our data suggest that frail older adults and those living in more deprived areas are at higher risk. However, in most individuals illness appears less severe, with reduced need for hospitalisation and lower risk of prolonged illness duration. Our results are relevant for health policy post-vaccination and highlight the need to prioritise those most at risk, whilst also emphasising the balance between the importance of personal protective measures versus adverse effects from ongoing social restrictions. Strategies such as timely prioritisation of booster vaccination and optimised infection control could be considered for at-risk groups. Research is also needed on how to enhance the immune response to vaccination in those at higher risk.