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1.
LANCET DIGITAL HEALTH ; 4(4), 2022.
Article in English | Web of Science | ID: covidwho-1935260

ABSTRACT

Background Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings Between June 17, 2020, and April 14, 2021, 47 795 (75.2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86.6%] of 12 909 vs 36 415 [72.4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0.79 [95% CI 0.70-0.89], p=0.0001, for 70-79 years;0.52 [0.46-0.58], p<0.0001, for >80 years), independent of patient demographics and illness severity. 84 (54.2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27.5% in the week before June 16, 2020, to 75-80% in January, 2021. Interpretation Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

2.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-335588

ABSTRACT

Background Remdesivir has been evaluated in clinical trial populations, but there is a sparsity of evidence evaluating effectiveness in general populations. Methods Adults eligible to be treated with remdesivir, requiring oxygen but not ventilated, were identified from UK patients hospitalised with COVID-19. Patients treated with remdesivir within 24h of hospitalisation were compared with propensity-score matched controls;estimates of effectiveness were calculated for short-term outcomes (14-day mortality, 28-day mortality, time-to-recovery among others) using multivariable modelling. Results 9,278 out of 39,330 patients satisfied eligibility criteria. 1,549 patients were identified as 'treated' and matched with 4,964 controls. Patients were 62% male, mean (SD) age 63.1 (15.6) years, 80% 'White' ethnicity, and symptomatic for a median of 6 days prior to baseline. There was no statistically significant benefit of remdesivir at 14 days in terms of mortality or clinical status;there were signals of effectiveness in time-to-recovery after day 9, and a reduction in 28-day mortality. Conclusion In a real-world setting, initiation of remdesivir within 24h of hospitalisation in conjunction with standard of care was not associated with a benefit at 14 days but supports clinical trial evidence of a potential reduction in 28-day mortality.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330329

ABSTRACT

Introduction Shared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection. Methods The UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam. Results A total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days;interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05;1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00;1.56) and severe admission (RR 1.27 95%CrI 1.07;1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants. Conclusion These interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.

4.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-330206

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients;(ii) 167 genes located in COVID-19 GWAS risk loci;or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com .

6.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326637

ABSTRACT

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

8.
American Journal of Human Genetics ; 108(7):1350-1355, 2021.
Article in English | Web of Science | ID: covidwho-1312879

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

9.
Annals of Oncology ; 31:S992, 2020.
Article in English | EMBASE | ID: covidwho-805759

ABSTRACT

Background: The SARS-CoV-2 pandemic in the UK triggered a national characterisation protocol and information on co-morbidities including malignant neoplasm is recorded. A lack of prospective data regarding cancer patients with COVID-19 hampers the development of an evidence based approach in this population. The Clinical Characterisation Protocol-CANCER-UK is a UK multi-disciplinary project aimed at characterising the presentation and course of COVID-19 in cancer patients with the aim of informing practice. Methods: The international Severe Acute Respiratory and emerging Infections Consortium (ISARIC)-4C COVID-19 Clinical Information Network (CO-CIN) collects data on hospital inpatients with proven/high likelihood of COVID-19. Data was collected in 166 UK sites using a questionnaire adopted by the WHO. Data on patients with malignant neoplasm was extracted from the main dataset. We chose a priori to restrict any analysis of outcome to patients who were admitted more than 14 days before data extraction (13th May 2020). Results: As of 13th May 2020 1797 of 16160 participants had malignant neoplasm (8.6% of all cases). Age<50 62 (3.5%), 50-60 378 (21%), 70-79 558 (31%), 80+ 1002 (42%). Male 1147 (64%);Female 645 (36%). Commonest comorbidities chromic pulmonary disease (22%), chronic kidney disease (21%), uncomplicated diabetes (19%) and dementia (14%). Outcomes 35% discharged alive, 30% care ongoing & 35% died. Admiited to ICU: 150 cases (25% discharged alive,31% care ongoing & 45% died). Receiving invasive ventiation: 67 cases (18% discharged alive, 25% care ongoing:25% & 57% died). HR mortality for malignancy (adjusted for age, sex, other comorbidity): 1.13 (1.02-1.24, p=0.017). Data on presentation will be presented. Conclusions: Europe’s largest prospective COVID-19 dataset demonstrates that cancer is independently associated with mortality in patients admitted with COVID-19. Data collection is on-going and updated data will be presented including a comparison of cancer vs. non-cancer cohort with regard to presentation, comorbidity and otucomes. Clinical trial identification: ISRCTN66726260. Legal entity responsible for the study: and international Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Coronavirus Clinical Characterisation Consortium (ISARIC4C). Funding: UK Research and Innovation, Medical Research Council and Department for Health and Social Care. Disclosure: All authors have declared no conflicts of interest.

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