Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

OBJECTIVE: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. DESIGN/PATIENTS: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). MEASUREMENTS: Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). RESULTS: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. CONCLUSIONS: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundLow-dose corticosteroids have been shown to reduce mortality for hypoxic COVID-19 patients requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (i.e. receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality. On 11 May 2022, the independent Data Monitoring Committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only to this comparison due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support continues. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 25 May 2021 and 12 May 2022, 1272 COVID-19 patients with hypoxia and receiving no oxygen (1%) or simple oxygen only (99%) were randomly allocated to receive usual care plus higher dose corticosteroids versus usual care alone (of whom 87% received low dose corticosteroids during the follow-up period). Of those randomised, 745 (59%) were in Asia, 512 (40%) in the UK and 15 (1%) in Africa. 248 (19%) had diabetes mellitus. Overall, 121 (18%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio [RR] 1{middle dot}56; 95% CI 1{middle dot}18-2{middle dot}06; p=0{middle dot}0020). There was also an excess of pneumonia reported to be due to non-COVID infection (10% vs. 6%; absolute difference 3.7%; 95% CI 0.7-6.6) and an increase in hyperglycaemia requiring increased insulin dose (22% vs. 14%; absolute difference 7.4%; 95% CI 3.2-11.5). InterpretationIn patients hospitalised for COVID-19 with clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Apixaban following discharge in hospitalised adults with COVID-19: Preliminary results from a multicentre, open-label, randomised controlled platform clinical trial.

BackgroundThe role of thromboprophylaxis in the post-acute phase of COVID-19 is uncertain due to conflicting results from randomised controlled trials and observational studies. We aimed to determine the effectiveness of post-hospital apixaban in reducing the rate of death and hospital readmission of hospitalised adults with COVID-19. MethodsHEAL COVID is an adaptive randomised open label multicentre platform trial recruiting participants from National Health Service Hospitals in the United Kingdom. Here we report the preliminary results of apixaban comparison of HEAL-COVID. Participants with a hospital admission related to confirmed COVID-19 and an expected date of discharge in the subsequent five days were randomised to either apixaban 2.5 mg twice daily or standard care (no anticoagulation) for 14 days. The primary outcome was hospital free survival at 12 months obtained through routine data sources. The trial was prospectively registered with ISRCTN (15851697) and Clincialtrials.gov (NCT04801940). FindingsBetween 19 May 2021 and 21 November 2022, 402 participants from 109 sites were randomised to apixaban and 399 to standard care. Seven participants withdrew from the apixaban group and one from the standard care group. Analysis was undertaken on an intention-to-treat basis. The apixaban arm was stopped on the recommendation of the oversight committees following an interim analysis due to no indication of benefit. Of the 402 participants randomised to apixaban, 117 experienced death or rehospitalisation during a median follow-up of 344{middle dot}5 days (IQR 125 to 365), and 123 participants receiving standard care experienced death or rehospitalisation during a median follow-up of 349 days (IQR 124 to 365). There was no statistical difference in the rate of death and rehospitalisation (HR: 0{middle dot}96 99%CI 0{middle dot}69-1{middle dot}34; p=0{middle dot}75). Three participants in the apixaban arm experienced clinically significant bleeding during treatment. InterpretationFourteen days of post-hospital anticoagulation with the direct oral anticoagulant apixaban did not reduce the rate of death or rehospitalisation of adults hospitalised with COVID-19. These data do not support the use of prophylactic post-hospital anticoagulation in adults with COVID-19. FundingHEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [BRC-1215-20014*].

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundDimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19 MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified. InterpretationIn adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

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

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 real-world 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.

BackgroundMost 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. MethodsPlasma 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. FindingsStrong 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. InterpretationThe 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. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSWhile systemic immunity to SARS-CoV-2 is important in preventing severe disease, mucosal immunity prevents viral replication at the point of entry and reduces onward transmission. We searched PubMed with search terms "mucosal", "nasal", "antibody", "IgA", "COVID-19", "SARS-CoV-2", "convalescent" and "vaccination" for studies published in English before 20th July 2022, identifying three previous studies examining the durability of nasal responses that generally show nasal antibody to persist for 3 to 9 months. However, these studies were small or included individuals with mild COVID-19. One study of 107 care-home residents demonstrated increased salivary IgG (but not IgA) after two doses of mRNA vaccine, and another examined nasal antibody responses after infection and subsequent vaccination in 20 cases, demonstrating rises in both nasal IgA and IgG 7 to 10 days after vaccination. Added value of this studyStudying 446 people hospitalised for COVID-19, we show durable nasal and plasma IgG responses to ancestral (B.1 lineage) SARS-CoV-2, Delta and Omicron (BA.1) variants up to 12 months after infection. Nasal antibody induced by infection with pre-Omicron variants, bind Omicron virus in vitro better than plasma antibody. Although nasal and plasma IgG responses were enhanced by vaccination, Omicron binding responses did not reach levels equivalent to responses for ancestral SARS-CoV-2. Using paired plasma and nasal samples collected approximately 12 months after infection, we show that nasal IgA declines and shows a minimal response to vaccination whilst plasma antibody responses to S antigen are well maintained and boosted by vaccination. Implications of all the available evidenceAfter COVID-19 and subsequent vaccination, Omicron binding plasma and nasal antibody responses are only moderately enhanced, supporting the need for booster vaccinations to maintain immunity against SARS-CoV-2 variants. Notably, there is distinct compartmentalisation between nasal IgA and plasma IgA and IgG responses after vaccination. These findings highlight the need for vaccines that induce robust and durable mucosal immunity.

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

BackgroundImmunocompromised 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. MethodsWe 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. FindingsBetween 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 in-hospital 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. ConclusionsImmunocompromised 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. FundingNational Institute for Health Research; Medical Research Council; Chief Scientist Office, Scotland.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

IntroductionSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. MethodsWe performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. ResultsIn the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. ConclusionsIL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients

BackgroundWhilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. MethodsHere, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. ResultsOur analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61 - 0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. ConclusionsAlthough clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. Author SummaryCOVID-19 clinical outcomes vary immensely, but a patients genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isnt clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.

GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19.

Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.

Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis

BackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0{middle dot}87; 95% CI 0{middle dot}77-0{middle dot}98; p=0{middle dot}026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Systematic comparison of ranking aggregation methods for gene lists in experimental results

A common experimental output in biomedical science is a list of genes implicated in a given biological process or disease. The results of a group of studies answering the same, or similar, questions can be combined by meta-analysis to find a consensus or a more reliable answer. Ranking aggregation methods can be used to combine gene lists from various sources in meta-analyses. Evaluating a ranking aggregation method on a specific type of dataset before using it is required to support the reliability of the result since the property of a dataset can influence the performance of an algorithm. Evaluation of aggregation methods is usually based on a simulated database especially for the algorithms designed for gene lists because of the lack of a known truth for real data. However, simulated datasets tend to be too small compared to experimental data and neglect key features, including heterogeneity of quality, relevance and the inclusion of unranked lists. In this study, a group of existing methods and their variations which are suitable for meta-analysis of gene lists are compared using simulated and real data. Simulated data was used to explore the performance of the aggregation methods as a function of emulating the common scenarios of real genomics data, with various heterogeneity of quality, noise level, and a mix of unranked and ranked data using 20000 possible entities. In addition to the evaluation with simulated data, a comparison using real genomic data on the SARS-CoV-2 virus, cancer (NSCLC), and bacteria (macrophage apoptosis) was performed. We summarise our evaluation results in terms of a simple flowchart to select a ranking aggregation method for genomics data.

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

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.

Receptor binding and escape from Beta antibody responses drive Omicron-B.1.1.529 evolution

On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate spreading rapidly in Southern Africa was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.

Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves: prospective multicentre observational cohort study

BackgroundChildren and young people (CYP) were less affected than adults in the first wave of SARS-CoV-2 in the UK. We test the hypothesis that clinical characteristics of hospitalized CYP with SARS-CoV-2 in the UK second wave would differ from the first due to the combined impact of the alpha variant, school reopening and relaxation of shielding. MethodsPatients <19 years hospitalised in the UK with clinician-reported SARS-CoV-2 were enrolled in a prospective multicentre observational cohort study between 17th January 2020 and 31st January 2021. Minimum follow up time was two weeks. Clinical characteristics were compared between the first (W1) and second wave (W2) of infections. Findings2044 CYP aged <19 years were reported from 187 hospitals. 427/2044 (20.6%) had asymptomatic/incidental SARS-CoV-2 infection and were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). Patients in W2 were significantly older (median age 6.5 years, IQR 0.3-14.9) than W1 (4.0 (0.4-13.6, p 0.015). Fever was more common in W1, otherwise presenting symptoms and comorbidities were similar across waves. After excluding CYP with MIS-C, patients in W2 had lower PEWS at presentation, lower antibiotic use and less respiratory and cardiovascular support compared to W1. There was no change in the proportion of CYP admitted to critical care between W1 and W2. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year old), had lower Paediatric Early Warning Scores (PEWS) at presentation, shorter length of hospital stay and received less respiratory support. MIS-C was responsible for a large proportion of critical care admissions, invasive and non-invasive ventilatory support, inotrope and intravenous corticosteroid use in CYP without comorbidities. InterpretationSevere disease in CYP admitted with symptomatic SARS-CoV-2 in the UK remains rare. One in five CYP in this cohort had asymptomatic/incidental SARS-CoV-2 infection. We found no evidence of increased disease severity in W2 compared with W1. FundingShort form: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation. Long form: This work is supported by grants from the National Institute for Health Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135). Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust, or PHE.

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive individuals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

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

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 recruits critically-ill cases and compares their genomes 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.

An adaptive randomized controlled trial of non-invasive respiratory strategies in acute respiratory failure patients with COVID-19

BackgroundBoth continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety. MethodsIn the Recovery-Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days. ResultsOver 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). ConclusionsCPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO. (Funded by the UK National Institute for Health Research; ISRCTN 16912075).

Pandemic, epidemic, endemic: B cell repertoire analysis reveals unique anti-viral responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus

Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of IGHV4-39 in both EBOV and COVID-19 infection cohorts. We also show unique characteristics absent in RSV infection or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risks off-target effects.