Can self-testing be enhanced to hasten safe return of healthcare workers in pandemics? Random order, open label trial using two manufacturers' SARS-CoV-2 lateral flow devices concurrently (preprint)

ObjectivesTo inform management of competing risks from Covid-19 and key-worker absence, we evaluated whether using two manufacturers lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection and was acceptable to hospital staff. In a nested study, to understand the risks of return to work after a fixed number of days of isolation or quarantine, we examined virus culture at Days 5-7 after positive test or significant exposure. Methods and Analysis1419 fully-vaccinated Liverpool (UK) University Hospitals staff participated in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV2 detection, and whether dual swabbing was acceptable to users. Main outcome was self-reported LFT result. Staff enrolled via routine testing sites for symptomatic staff and close contacts. Recruitment took place between 7th February and 8th May 2022. Participants employed nose-throat swab Innova and nose-only swab Orient Gene LFTs for 10 days, with daily LFTs taken in random order. A swab for polymerase chain reaction (PCR) analysis was taken at Day-5 and, if positive, Day-10. A questionnaire on acceptability was administered on exit. Selected participants gave swabs for viral culture on Days 5-7; swabs were delivered and returned by courier. Cultures were considered positive if cytopathic effect was apparent or the SARs-COV2 N gene sub-genomic RNA was detected by sequencing. Results226 individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49, P=0.03) to be positive. Orient Gene positive Innova negative result-pairs became more frequent over time (P<0.001). If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (P=0.005); swabbing first with Innova made no significant difference (P=0.85). Of 311 individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual c.f. single test results (median 9 cf. 8 on 10-point scale, P<0.001). Viral cultures from swabs taken at Days 5-7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious. ConclusionsDual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work [~]5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics. Trial registrationhttps://www.isrctn.com/ISRCTN47058442 (IRAS Project ID:311842) Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIOmicron BA.1 and BA.2 waves caused large-scale healthcare worker absence in late 2021 - early 2022, risking patient safety from both Covid-19 and reduced care capacity C_LIO_LILateral flow tests (LFTs) reliably detected SARS-CoV-2 antigen, more so with Omicron than prior variants, identifying the most infectious individuals C_LIO_LISelf-testing with LFT SARS-CoV-2 rapid antigen tests reduced Covid-19 transmission, mitigating risks of return to work, including healthcare settings C_LI What this study addsO_LIDual c.f. single brand LFT testing increased SARS-CoV-2 antigen detection marginally, but more than can be explained by extending swabbing from nose-only to nose-throat C_LIO_LINHS deployment of nose-only LFTs in response to compound pressures from Omicron, winter and pandemic burnout was safe and acceptable to most participating hospital staff C_LIO_LICulturable virus was detected confidently in a fifth (and potentially in a further third) of LFT-positive hospital workers 5-7 days after their self-referral for testing, indicating substantial protracted infectiousness C_LI How this study might affect research, practice or policyO_LIThis study shows international Covid-19 policies for return to work after fixed periods (e.g. 5 days after positive test) were flawed: too little emphasis was placed on variation in infectivity between individuals C_LIO_LIFuture pandemic preparedness needs to plan testing quality assurance unified across healthcare and community self-testing contexts, including continuous study of serial daily antigen, nucleic acid and culturable virus test results C_LI

One year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study (preprint)

BackgroundIn patients with COVID-19 requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) one year after discharge. MethodsAdults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. FindingsIn 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI: -0.026 to 0.034, p = 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change -0.12 (0.22) vs -0.11 (0.22), p = 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. InterpretationSystemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL one year after hospital discharge. Treatments to address this are urgently needed. Take home messageSystemic corticosteroids given for acute COVID-19 do not affect health-related quality of life or other patient reported outcomes, physical and mental health outcomes, and organ function one year after hospital discharge

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Cohort Profile: Post-hospitalisation COVID-19 study (PHOSP-COVID) (preprint)

Abstract [bullet] PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged. [bullet] PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials. [bullet] Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs). [bullet] Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites. [bullet] All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research. [bullet] In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022. [bullet] Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.

Evaluation of S/F94 as a proxy for COVID-19 severity (preprint)

Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the SaO2/FIO2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of SaO2. Using synthetic and real data, we found that the correlation of S/F with a gold standard (PaO2/FIO2, P/F ratio) improved substantially when measurements with SaO2 > 0.94 are excluded(Spearman r, synthetic data: S/F: 0.31; S/F94: 0.85). We refer to this measure as S/F94. In order to test the underlying assumptions and validity of S/F94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F94 is predictive of mortality in COVID-19. We then compared the sample sizes required for trials using different outcome measures (S/F94, the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest sample size was needed when S/F94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify realworld power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C https://isaric4c.net/endpoints. We demonstrated that S/F94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.

Nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination. (preprint)

Background Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods Plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months. Nasal and plasma anti-S IgG remained elevated for at least 12 months with high plasma neutralising titres against all variants. Of 180 with complete data, 160 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal. Samples 12 months after admission showed no association between nasal IgA and plasma IgG responses, indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.

Outcome of COVID-19 in hospitalised immunocompromised patients: an analysis of the WHO ISARIC CCP-UK prospective cohort study. (preprint)

Background Immunocompromised patients may be at higher risk of mortality if hospitalised with COVID-19 compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death, and how this risk changed over the pandemic. Methods We included patients >=19yrs with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK. We defined immunocompromise as: immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination and co-morbidities. We used Bayesian logistic regression to explore mortality over time. Findings Between 17/01/2020 and 28/02/2022 we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. 29% (n=6,499) of immunocompromised and 21% (n=28,608) of immunocompetent patients died in hospital. The odds of inhospital mortality were elevated for immunocompromised patients (adjOR 1.44, 95% CI 1.39-1.50, p<0.001). As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50-69yrs was 88% for men and 83% for women, and for those >80yrs was 99% for men, and 98% for women. Conclusions Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses and monoclonal antibodies should be considered for this group.

Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol

Background Acute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population. Methods and findings All individuals recruited using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) and admitted to 1,609 hospitals in 54 countries with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection from February 15, 2020 to February 1, 2021 were included in the study. Data were collected and analysed for the duration of a patient’s admission. Incidence, staging, and timing of AKI were evaluated using a traditional and eKDIGO definition, which incorporated a commensurate decrease in sCr. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristics and outcomes—intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital death—were compared for all 3 groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. A total of 75,670 patients were included in the final analysis cohort. Median length of admission was 12 days (interquartile range [IQR] 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7% versus 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% versus 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% versus 23%) invasive ventilation (45% versus 15%), and increased mortality (38% versus 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted odds ratio: 1.78, 95% confidence interval: 1.71 to 1.80, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% versus 50% death and 35% versus 70% ICU admission) but significantly higher when compared to patients with no AKI (25% versus 19% death and 35% versus 23% ICU admission) (all p-values <5 × 10−5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis. Conclusions An extended KDIGO definition of AKI resulted in a significantly higher detection rate in this population. These additional cases of AKI occurred early in the hospital admission and were associated with worse outcomes compared to patients without AKI.

Changing patterns of SARS-CoV-2 infection through Delta and Omicron waves by vaccination status, previous infection and neighbourhood deprivation: A cohort analysis of 2.7M people. (preprint)

Objective: To examine if SARS-CoV-2 infections vary by vaccination status, if an individual had previously tested positive and by neighbourhood socioeconomic deprivation across the Delta and Omicron epidemic waves of SARS-CoV-2. Design: Cohort study using electronic health records Setting: Cheshire and Merseyside, England (3rd June 2021 to 1st March 2022) Participants: 2.7M residents Main Outcome measure: Registered positive test for SARS-CoV-2 Results: Social inequalities in registered positive tests were dynamic during the study. Originally higher SARS-CoV-2 rates in the most socioeconomically deprived neighbourhoods changed to being higher in the least deprived neighbourhoods from the 1st September 2021. While the introduction of Omicron initially reset inequalities, they continued to be dynamic and inconsistent. Individuals who were fully vaccinated (two doses) were associated with fewer registered positive tests (e.g., between 1st September and 27th November 2021: (i) individuals engaged in testing - Hazards Ratio (HR) = 0.48, 95% Confidence Intervals (CIs) = 0.47-0.50; (ii) individuals engaged with healthcare - HR = 0.34, 95% CIs = 0.33-0.34). Individuals with a previous registered positive test were also less likely to have a registered positive test (e.g., between 1st September and 27th November 2021: (i) individuals engaged in testing - HR = 0.16, 95% CIs = 0.15-0.18; (ii) individuals engaged with healthcare - HR = 0.14, 95% CIs = 0.13-0.16). However, Omicron is disrupting these associations due to immune escape resulting in smaller effect sizes for both measures. Conclusions: Changing patterns of SARS-CoV-2 infections during the Delta and Omicron waves reveals a dynamic pandemic that continues to affect diverse communities in sometimes unexpected ways.

Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study of the ISARIC cohort (preprint)

BackgroundAcute kidney injury (AKI) is one of the most common and significant problems in patients with COVID-19. However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional KDIGO definition can fail to identify patients for whom hospitalization coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesized that an extended KDIGO definition, adapted from the International Society of Nephrology 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI with similarly poor outcomes as previously reported in this population. Methods and FindingsAll individuals in the ISARIC cohort admitted to hospital with SARS-CoV-2 infection from February 15th, 2020, to February 1st, 2021, were included in the study. Data was collected and analysed for the duration of a patients admission. Incidence, staging and timing of AKI were evaluated using a traditional and extended KDIGO (eKDIGO) definition which incorporated a commensurate decrease in serum creatinine. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristic and outcomes - intensive care unit (ICU) admission, invasive mechanical ventilation and in-hospital death - were compared for all three groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. 75,670 patients from 54 countries were included in the final analysis cohort. Median length of admission was 12 days (IQR 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7 vs 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% vs 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% vs 23%) invasive ventilation (45% vs 15%) and increased mortality (38% vs 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted OR: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% vs 50% death and 35% vs 70% ICU admission) but significantly higher when compared to patients with no AKI (25% vs 19% death and 35% vs 23% ICU admission) (all p values < 5x10-5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis. ConclusionsThe use of an extended KDIGO definition to diagnose AKI in this population resulted in a significantly higher incidence rate compared to traditional KDIGO criteria. These additional cases of AKI appear to be occurring in the community or early in the hospital admission and are associated with worse outcomes than those without AKI. Author SummaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPrevious studies have shown that acute kidney injury (AKI) is a common problem among hospitalized patients with COVID-19. C_LIO_LIThe current biochemical criteria used to diagnose AKI may be insufficient to capture AKI that develops in the community and is recovering by the time a patient presents to hospital. C_LIO_LIThe use of an extended definition, that can identify AKI both during its development and recovery phase, may allow us to identify more patients with AKI. These patients may benefit from early management strategies to improve long term outcomes. C_LI What did the researchers do and find?O_LIIn this study, we examined AKI incidence, severity and outcomes among a large international cohort of patients with COVID-19 using both a traditional and extended definition of AKI. C_LIO_LIWe found that using the extended definition identified almost twice as many cases of AKI than the traditional definition (31.7 vs 16.8%). C_LIO_LIThese additional cases of AKI were generally less severe and occurred earlier in the hospital admission. Nevertheless, they were associated with worse outcomes, including ICU admission and in-hospital death (adjusted odds ratio: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001) than those with no AKI. C_LI What do these findings mean?O_LIThe current definition of AKI fails to identify a large group of patients with AKI that appears to develop in the community or early in the hospital admission. C_LIO_LIGiven the finding that these cases of AKI are associated with worse admission outcomes than those without AKI, identifying and managing them in a timely manner is enormously important. C_LI

Rapid selection of P323L in the SARS-CoV-2 polymerase (NSP12) in humans and non-human primate models and confers a large plaque phenotype (preprint)

The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study (preprint)

Background There are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. Methods PHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35.6% were female, mean age 58.7 (SD 12.5) years, and 27.8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/165 (25.6%) and one year 232/804 (28.9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0.68 (95% CI 0.46-0.99), obesity OR 0.50 (95%CI 0.34-0.74) and IMV OR 0.42 (95%CI 0.23-0.76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0.88 (0.74-1.00), five months 0.74 (0.60-0.88) to one year: 0.74 (0.59-0.88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19 (preprint)

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Recovery from Covid-19 critical illness: a secondary analysis of the ISARIC4C CCP-UK cohort study and the RECOVER trial (preprint)

Background We aimed to compare the prevalence and severity of fatigue in survivors of Covid-19 versus non-Covid-19 critical illness, and to explore potential associations between baseline characteristics and worse recovery. Methods We conducted a secondary analysis of two prospectively collected datasets. The population included was 92 patients who received invasive mechanical ventilation (IMV) with Covid-19, and 240 patients who received IMV with non-Covid-19 illness before the pandemic. Follow-up data was collected post-hospital discharge using self-reported questionnaires. The main outcome measures were self-reported fatigue severity and the prevalence of severe fatigue (severity >7/10) 3 and 12-months post-hospital discharge. Results Covid-19 IMV-patients were significantly younger with less prior comorbidity, and more males, than pre-pandemic IMV-patients. At 3-months, the prevalence (38.9% [7/18] vs. 27.1% [51/188]) and severity (median 5.5/10 vs. 5.0/10) of fatigue was similar between the Covid-19 and pre-pandemic populations respectively. At 6-months, the prevalence (10.3% [3/29] vs. 32.5% [54/166]) and severity (median 2.0/10 vs. 5.7/10) of fatigue was less in the Covid-19 cohort. In the Covid-19 population, women under 50 experienced more severe fatigue, breathlessness, and worse overall health state compared to other Covid-19 IMV-patients. There were no significant sex differences in long-term outcomes in the pre-pandemic population. In the total sample of IMV-patients included (i.e. all Covid-19 and pre-pandemic patients), having Covid-19 was significantly associated with less severe fatigue (severity <7/10) after adjusting for age, sex, and prior comorbidity (adjusted OR 0.35 (95%CI 0.15-0.76, p=0.01). Conclusion. Fatigue may be less severe after Covid-19 than after other critical illness.

Occupational inequalities in the prevalence of COVID-19: A longitudinal observational study of England, August 2020 to January 2021 (preprint)

BackgroundThe COVID-19 pandemic has reinforced, amplified and created new health inequalities. There is less evidence on how COVID-19 prevalence varies by measures of work and occupation which represent a key social determinant of health. The aim of the study is to evaluate how occupational inequalities in the prevalence of COVID-19 varies across England and their possible explanatory factors. MethodsWe used data for 363,651 individuals (2,178,835 observations) aged 18 years and over between 1st May 2020 and 31st January 2021 from the ONS Covid Infection Survey, a representative longitudinal survey of individuals in England. We focus on two measures of work; employment status for all adults, and work sector of individuals currently working. Multi-level binomial regression models were used to estimate the likelihood of testing positive of COVID-19, adjusting for known explanatory covariates. Results0.9% of participants tested positive for COVID-19 over the study period. COVID-19 prevalence was higher among adults who were students or furloughed (i.e., temporarily not working). Among adults currently working, COVID-19 prevalence was highest in adults employed in the hospitality sector, with higher prevalence for individuals employed in transport, social care, retail, health care and educational sectors. Inequalities by work were not consistent over time. ConclusionsWe find an unequal distribution of infections relating to COVID-19 by work and employment status. Our findings demonstrate the need for greater workplace interventions to protect employees, but also that a large proportion of SARS-CoV-2 transmission occurs outside of work. In particular, populations who experienced social and economic harms through being furloughed were also more likely to experience a double burden of increased likelihood of COVID-19.

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity (preprint)

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses (preprint)

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.

Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study (preprint)

BackgroundThe long-term sequelae of coronavirus disease 2019 (Covid-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with Covid-19 and associated risk factors. MethodsThis is a prospective cohort study of children ([≤]18 years old) admitted with confirmed Covid-19 to Z.A. Bashlyaeva Childrens Municipal Clinical Hospital in Moscow, Russia. Children admitted to the hospital during the first wave of the pandemic, between April 2, 2020 and August 26, 2020, were included. Telephone interview using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Covid-19 Health and Wellbeing paediatric follow up survey. Persistent symptoms (>5 months) were further categorised by system(s) involved. FindingsOverall, 518 of 853 (61%) of eligible children were available for the follow-up assessment and included in the study. Median age was 10.4 years (IQR, 3-15.2) and 270 (52.1%) were girls; median follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%,) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: age "6-11 years" (odds ratio 2.74 (95% confidence interval 1.37 to 5.75) and "12-18 years" (2.68, 1.41 to 5.4), and a history of allergic diseases (1.67, 1.04 to 2.67). InterpretationA quarter of children experienced persistent symptoms months after hospitalization with acute covid-19 infection, with almost one in ten experiencing multi-system involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up. Our findings highlight the need for replication and further investigation of potential mechanisms as well as clinical support to improve long term outcomes in children. FundingNone. O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that Covid-19 may result in short- and long-term consequences to health. Studies in children and adolescents are limited and available evidence is scarce. We searched Embase for publications from inception to April, 25, 2021, using the following phrases or combinations of phrases "post-covid condition" or "post-covid syndrome" or "covid sequalae" or "post-acute covid" or "long covid" or "long hauler" with "pediatric*" or "paediatric*" or "child*" or "infant*" or "newborn*" or "toddler*" or "neonate*" or "neonatal" or "adolescent*" or "teen*". We found small case series and small cohort studies looking at Covid-19 consequences in children. No large cohort studies of previously hospitalised children, assessing symptom duration, categorisation or attempting multivariable analyses to identify independent risk factors for long Covid development were identified. Added value of this studyTo our knowledge, this is the largest cohort study with the longest follow-up since hospital discharge of previously hospitalised children. We found that even months after discharge from the hospital, approximately a quarter of children experience persistent symptoms with one in ten having multi-system involvement. Older age and allergic diseases are associated with Covid-19 consequences. Parents of some children report emotional and behavioural changes in their children after Covid-19. Implications of all the available evidenceOur findings highlight the need for continued global research of Covid-19 consequences in the paediatric population. Older children admitted to the hospital should be carefully monitored upon discharge. Large, controlled studies aiming to identify risk groups and potential intervention strategies are required to fill knowledge gaps. C_TEXTBOX

Sequence analysis of SARS-CoV-2 in nasopharyngeal samples from patients with COVID-19 illustrates population variation and diverse phenotypes, placing the in vitro growth properties of B.1.1.7 and B.1.351 lineage viruses in context. (preprint)

New variants of SARS-CoV-2 are continuing to emerge and dominate the regional and global sequence landscapes. Several variants have been labelled as Variants of Concern (VOCs) because of perceptions or evidence that these may have a transmission advantage, increased risk of morbidly and/or mortality or immune evasion in the context of prior infection or vaccination. Placing the VOCs in context and also the underlying variability of SARS-CoV-2 is essential in understanding virus evolution and selection pressures. Sequences of SARS-CoV-2 in nasopharyngeal swabs from hospitalised patients in the UK were determined and virus isolated. The data indicated the virus existed as a population with a consensus level and non-synonymous changes at a minor variant. For example, viruses containing the nsp12 P323L variation from the Wuhan reference sequence, contained minor variants at the position including P and F and other amino acids. These populations were generally preserved when isolates were amplified in cell culture. In order to place VOCs B.1.1.7 (the UK Kent variant) and B.1.351 (the South African variant) in context their growth was compared to a spread of other clinical isolates. The data indicated that the growth in cell culture of the B.1.1.7 VOC was no different from other variants, suggesting that its apparent transmission advantage was not down to replicating more quickly. Growth of B.1.351 was towards the higher end of the variants. Overall, the study suggested that studying the biology of SARS-CoV-2 is complicated by population dynamics and that these need to be considered with new variants.

Physical, cognitive and mental health impacts of COVID-19 following hospitalisation: a multi-centre prospective cohort study (preprint)

Background The impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood. Methods PHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function. Findings We report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity. Interpretation We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services. Funding: UKRI and NIHR