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1.
BMJ Open Respir Res ; 9(1)2022 09.
Article in English | MEDLINE | ID: covidwho-2053233

ABSTRACT

BACKGROUND: There is increasing evidence that vitamin D (VD) deficiency may increase individuals' risk of COVID-19 infection and susceptibility. We aimed to determine the relationship between VD deficiency and sufficiency and COVID-19 seropositivity within healthcare workers. METHODS: The study included an observational cohort of healthcare workers who isolated due to COVID-19 symptoms from 12 May to 22 May 2020, from the University Hospitals Birmingham National Health Service Foundation Trust. Data collected included SARS-CoV-2 seroconversion status, serum 25(OH)D3 levels, age, body mass index (BMI), sex, ethnicity, job role and comorbidities. Participants were grouped into four VD categories: (1) Severe VD deficiency (VD<30 nmol/L); (2) VD deficiency (30 nmol/L ≤VD<50 nmol/L); (3) VD insufficiency (50 nmol/L ≤VD<75 nmol/L); (4) VD sufficiency (VD≥75 nmol/L). RESULTS: When VD levels were compared against COVID-19 seropositivity rate, a U-shaped curve was identified. This trend repeated when participants were split into subgroups of age, sex, ethnicity, BMI and comorbidity status. Significant difference was identified in the COVID-19 seropositivity rate between VD groups in the total population and between groups of men and women; black, Asian and minority ethnic (BAME) group; BMI<30 (kg/m2); 0 and +1 comorbidities; the majority of which were differences when the severely VD deficient category were compared with the other groups. A larger proportion of those within the BAME group (vs white ethnicity) were severely VD deficient (p<0.00001). A larger proportion of the 0 comorbidity subgroup were VD deficient in comparison to the 1+ comorbidity subgroup (p=0.046). CONCLUSIONS: Our study has shown a U-shaped relationship for COVID-19 seropositivity in UK healthcare workers. Further investigation is required to determine whether high VD levels can have a detrimental effect on susceptibility to COVID-19 infection. Future randomised clinical trials of VD supplementation could potentially identify 'optimal' VD levels, allowing for targeted therapeutic treatment for those at risk.


Subject(s)
COVID-19 , Vitamin D Deficiency , COVID-19/epidemiology , Female , Health Personnel , Humans , Male , SARS-CoV-2 , State Medicine , United Kingdom/epidemiology , Vitamin D , Vitamin D Deficiency/epidemiology
2.
Cells ; 11(18)2022 09 16.
Article in English | MEDLINE | ID: covidwho-2043594

ABSTRACT

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.


Subject(s)
COVID-19 , Neutrophils , B7-H1 Antigen , COVID-19/immunology , Cell-Free Nucleic Acids , Deoxyribonucleases , Humans , Interleukin-6/pharmacology , Neutrophils/cytology , Phenotype , Phosphatidylinositol 3-Kinases , Reactive Oxygen Species/metabolism , SARS-CoV-2
4.
J Intern Med ; 292(4): 604-626, 2022 10.
Article in English | MEDLINE | ID: covidwho-1922998

ABSTRACT

Vitamin D, when activated to 1,25-dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses to infection. Without supplementation, people living in temperate zones commonly become deficient in the precursor form of vitamin D, 25-hydroxyvitamin D, during winter, as do people who receive less sunlight exposure or those with darker skin pigmentation. Studies performed pre-COVID-19 have shown significant but modest reduction in upper respiratory infections in people receiving regular daily vitamin D supplementation. Vitamin D deficiency, like the risk of severe COVID-19, is linked with darker skin colour and also with obesity. Greater risk from COVID-19 has been associated with reduced ultraviolet exposure. Various studies have examined serum 25-hydroxyvitamin D levels, either historical or current, in patients with COVID-19. The results of these studies have varied but the majority have shown an association between vitamin D deficiency and increased risk of COVID-19 illness or severity. Interventional studies of vitamin D supplementation have so far been inconclusive. Trial protocols commonly allow control groups to receive low-dose supplementation that may be adequate for many. The effects of vitamin D supplementation on disease severity in patients with existing COVID-19 are further complicated by the frequent use of large bolus dose vitamin D to achieve rapid effects, even though this approach has been shown to be ineffective in other settings. As the pandemic passes into its third year, a substantial role of vitamin D deficiency in determining the risk from COVID-19 remains possible but unproven.


Subject(s)
COVID-19 , Vitamin D Deficiency , Dietary Supplements , Hormones , Humans , Sunlight , Vitamin D , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Vitamins/therapeutic use
5.
Lancet Digit Health ; 4(4): e266-e278, 2022 04.
Article in English | MEDLINE | ID: covidwho-1730184

ABSTRACT

BACKGROUND: Uncertainty in patients' COVID-19 status contributes to treatment delays, nosocomial transmission, and operational pressures in hospitals. However, the typical turnaround time for laboratory PCR remains 12-24 h and lateral flow devices (LFDs) have limited sensitivity. Previously, we have shown that artificial intelligence-driven triage (CURIAL-1.0) can provide rapid COVID-19 screening using clinical data routinely available within 1 h of arrival to hospital. Here, we aimed to improve the time from arrival to the emergency department to the availability of a result, do external and prospective validation, and deploy a novel laboratory-free screening tool in a UK emergency department. METHODS: We optimised our previous model, removing less informative predictors to improve generalisability and speed, developing the CURIAL-Lab model with vital signs and readily available blood tests (full blood count [FBC]; urea, creatinine, and electrolytes; liver function tests; and C-reactive protein) and the CURIAL-Rapide model with vital signs and FBC alone. Models were validated externally for emergency admissions to University Hospitals Birmingham, Bedfordshire Hospitals, and Portsmouth Hospitals University National Health Service (NHS) trusts, and prospectively at Oxford University Hospitals, by comparison with PCR testing. Next, we compared model performance directly against LFDs and evaluated a combined pathway that triaged patients who had either a positive CURIAL model result or a positive LFD to a COVID-19-suspected clinical area. Lastly, we deployed CURIAL-Rapide alongside an approved point-of-care FBC analyser to provide laboratory-free COVID-19 screening at the John Radcliffe Hospital (Oxford, UK). Our primary improvement outcome was time-to-result, and our performance measures were sensitivity, specificity, positive and negative predictive values, and area under receiver operating characteristic curve (AUROC). FINDINGS: 72 223 patients met eligibility criteria across the four validating hospital groups, in a total validation period spanning Dec 1, 2019, to March 31, 2021. CURIAL-Lab and CURIAL-Rapide performed consistently across trusts (AUROC range 0·858-0·881, 95% CI 0·838-0·912, for CURIAL-Lab and 0·836-0·854, 0·814-0·889, for CURIAL-Rapide), achieving highest sensitivity at Portsmouth Hospitals (84·1%, Wilson's 95% CI 82·5-85·7, for CURIAL-Lab and 83·5%, 81·8-85·1, for CURIAL-Rapide) at specificities of 71·3% (70·9-71·8) for CURIAL-Lab and 63·6% (63·1-64·1) for CURIAL-Rapide. When combined with LFDs, model predictions improved triage sensitivity from 56·9% (51·7-62·0) for LFDs alone to 85·6% with CURIAL-Lab (81·6-88·9; AUROC 0·925) and 88·2% with CURIAL-Rapide (84·4-91·1; AUROC 0·919), thereby reducing missed COVID-19 cases by 65% with CURIAL-Lab and 72% with CURIAL-Rapide. For the prospective deployment of CURIAL-Rapide, 520 patients were enrolled for point-of-care FBC analysis between Feb 18 and May 10, 2021, of whom 436 received confirmatory PCR testing and ten (2·3%) tested positive. Median time from arrival to a CURIAL-Rapide result was 45 min (IQR 32-64), 16 min (26·3%) sooner than with LFDs (61 min, 37-99; log-rank p<0·0001), and 6 h 52 min (90·2%) sooner than with PCR (7 h 37 min, 6 h 5 min to 15 h 39 min; p<0·0001). Classification performance was high, with sensitivity of 87·5% (95% CI 52·9-97·8), specificity of 85·4% (81·3-88·7), and negative predictive value of 99·7% (98·2-99·9). CURIAL-Rapide correctly excluded infection for 31 (58·5%) of 53 patients who were triaged by a physician to a COVID-19-suspected area but went on to test negative by PCR. INTERPRETATION: Our findings show the generalisability, performance, and real-world operational benefits of artificial intelligence-driven screening for COVID-19 over standard-of-care in emergency departments. CURIAL-Rapide provided rapid, laboratory-free screening when used with near-patient FBC analysis, and was able to reduce the number of patients who tested negative for COVID-19 but were triaged to COVID-19-suspected areas. FUNDING: The Wellcome Trust, University of Oxford Medical and Life Sciences Translational Fund.


Subject(s)
COVID-19 , Triage , Artificial Intelligence , COVID-19/diagnosis , Humans , SARS-CoV-2 , State Medicine
6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316180

ABSTRACT

ARDS is the major cause of mortality in patients with SARS-CoV-2 pneumonia. We report a single-centre study comparing the characteristics of ARDS patients with and without SARS-CoV-2. A greater proportion of SARS-CoV-2 patients were from an Asian ethnic group (p=0.002). SARS-CoV-2 patients had lower circulating leukocytes, neutrophils and monocytes (p<0.0001), but higher CRP (p=0.016) on ICU admission. SARS-CoV-2 patients required a longer duration of mechanical ventilation (p=0.01), but had lower vasopressor requirements (p=0.016). While the clinical syndromes of SARS-CoV-2 and CAP-ARDS are similar, the dysregulated inflammation observed in SARS-CoV-2 may contribute to the increased duration of respiratory failure.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321853

ABSTRACT

Background: - Ethnic minorities account for 34% of critically ill COVID-19 patients despite constituting 14% of the UK population. Internationally, researchers have called for studies to understand deterioration risk factors to inform clinical risk tool development. Methods: - Multi-centre cohort study of hospitalised COVID-19 patients (n=3671) exploring determinants of health, including Index of Multiple Deprivation (IMD) sub-indices, as risk factors for presentation, deterioration and mortality by ethnicity. Receiver operator characteristics were plotted for CURB65 and ISARIC4C by ethnicity and area under the curve (AUC) calculated. Results: - Ethnic minorities were admitted with higher Charlson Comorbidity Scores than age, sex and deprivation matched controls and from the highest IMD sub-indices of at least one deprivation form: Indoor Living Environment(LE), Outdoor LE, Adult Skills and Wider Barriers to Housing and Services. Admission from the highest sub-indices of these deprivation forms was associated with multilobar pneumonia on presentation and ITU admission. AUC did not exceed 0.7 for CURB65 or ISARIC4C among any ethnicity except ISARIC4C among Indian patients 0.83 (0.73-0.93). Ethnic minorities presenting with pneumonia and low CURB65(0-1) had higher mortality than Caucasians (22.6% vs.9.4%;p<0.001);Africans were at highest risk (38.5%;p=0.006), followed by Caribbean (26.7%;p=0.008), Indian (23.1%;p=0.007) and Pakistani (21.2%;p=0.004). Conclusions: - Ethnic minorities exhibit higher multimorbidity despite younger age structures and disproportionate exposure to unscored risk factors: obesity and deprivation. Household overcrowding, air pollution, housing quality and adult skills deprivation are associated with multi-lobar pneumonia on presentation and ITU admission which are mortality risk factors. Risk tools need to reflect risks predominantly affecting ethnic minorities.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-321852

ABSTRACT

Background: Internationally, researchers have called for evidence to support tackling health inequalities during the Severe acute respiratory syndrome coronavirus 2(COVID19) pandemic. UK Office for National Statistics data suggests that patients in regions of most deprived overall, generic Index of Multiple Deprivation Score(IMDS) are twice as likely to die of COVID19 than other causes. The Intensive Care National Audit and Research Centre (ICNARC) report that BAME patients account for 34% of critically ill COVID19 patients nationally despite constituting 14% of the population. This paper is the first to explore the roles of social determinants of health, including specific IMDS sub-indices with indicators for household quality deprivation, household overcrowding deprivation and air pollution deprivation, as modulators of presentation, Intensive Care Unit(ITU) admission and outcomes among COVID19 patients of all ethnicities. Methods: : An in-depth retrospective cohort study of 408 hospitalised COVID19 patients admitted to the Queen Elizabeth Hospital, Birmingham was conducted. Quantitative data analyses including two-step cluster analyses were applied. Results: : Patients admitted from highest living environment(LE) deprivation indices were at increased risk of presenting with multi-lobar pneumonia and, in turn, ITU admission whilst patients admitted from highest Barriers to Housing and Services(BHS) deprivation indices were at increased risk of ITU admission. Admission to ITU significantly increased the risk of death. Black, Asian and Minority Ethnic(BAME) patients were more likely, than white patients, to present with multi-lobar pneumonia, be admitted to ITU and be admitted from highest BHS and LE deprivation indices. Comorbidities and frailty significantly increased the risk of death among COVID19 patients irrespective of deprivation. Conclusions: : Air pollution and housing quality deprivation are potential modulators of presentation with multi-lobar pneumonia. Household overcrowding deprivation and presentation with multi-lobar pneumonia are potential modulators of ITU admission. Patents of BAME ethnicity are more likely to be admitted from regions of highest air pollution, housing quality and household overcrowding deprivation;this is likely to contribute an explanation towards the higher ITU admissions reported among COVID19 BAME patients. These findings have urgent implications for supporting front line clinical decisions, disseminating practical advice around applying social distancing messages at the household level and informing wider pandemic strategy.

9.
Lancet Respir Med ; 10(3): 255-266, 2022 03.
Article in English | MEDLINE | ID: covidwho-1586183

ABSTRACT

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council.


Subject(s)
COVID-19 , Adolescent , Antibodies, Monoclonal, Humanized , Bayes Theorem , COVID-19/drug therapy , Humans , Infliximab/therapeutic use , SARS-CoV-2 , Standard of Care , Treatment Outcome
10.
Ren Fail ; 43(1): 1621-1633, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1562360

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is common among patients with COVID-19. However, AKI incidence may increase when COVID-19 patients develop acute respiratory distress syndrome (ARDS). Thus, this systematic review and meta-analysis aimed to assess the incidence and risk factors of AKI, need for kidney replacement therapy (KRT), and mortality rate among COVID-19 patients with and without ARDS from the first wave of COVID-19. METHODS: The databases MEDLINE and EMBASE were searched using relevant keywords. Only articles available in English published between December 1, 2019, and November 1, 2020, were included. Studies that included AKI in COVID-19 patients with or without ARDS were included. Meta-analyses were conducted using random-effects models. RESULTS: Out of 618 studies identified and screened, 31 studies met the inclusion criteria. A total of 27,500 patients with confirmed COVID-19 were included. The overall incidence of AKI in patients with COVID-19 was 26% (95% CI 19% to 33%). The incidence of AKI was significantly higher among COVID-19 patients with ARDS than COVID-19 patients without ARDS (59% vs. 6%, p < 0.001). Comparing ARDS with non-ARDS COVID-19 cohorts, the need for KRT was also higher in ARDS cohorts (20% vs. 1%). The mortality among COVID-19 patients with AKI was significantly higher (Risk ratio = 4.46; 95% CI 3.31-6; p < 0.00001) than patients without AKI. CONCLUSION: This study shows that ARDS development in COVID-19-patients leads to a higher incidence of AKI and increased mortality rate. Therefore, healthcare providers should be aware of kidney dysfunction, especially among elderly patients with multiple comorbidities. Early kidney function assessment and treatments are vital in COVID-19 patients with ARDS.


Subject(s)
Acute Kidney Injury/epidemiology , COVID-19/complications , Respiratory Distress Syndrome/complications , COVID-19/epidemiology , Humans , Incidence , Respiratory Distress Syndrome/epidemiology , Risk Factors
11.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-296041

ABSTRACT

Background Uncertainty in patients’ COVID-19 status contributes to treatment delays, nosocomial transmission, and operational pressures in hospitals. However, typical turnaround times for batch-processed laboratory PCR tests remain 12-24h. Although rapid antigen lateral flow testing (LFD) has been widely adopted in UK emergency care settings, sensitivity is limited. We recently demonstrated that AI-driven triage (CURIAL-1.0) allows high-throughput COVID-19 screening using clinical data routinely available within 1h of arrival to hospital. Here we aimed to determine operational and safety improvements over standard-care, performing external/prospective evaluation across four NHS trusts with updated algorithms optimised for generalisability and speed, and deploying a novel lab-free screening pathway in a UK emergency department. Methods We rationalised predictors in CURIAL-1.0 to optimise separately for generalisability and speed, developing CURIAL-Lab with vital signs and routine laboratory blood predictors (FBC, U&E, LFT, CRP) and CURIAL-Rapide with vital signs and FBC alone. Models were calibrated during training to 90% sensitivity and validated externally for unscheduled admissions to Portsmouth University Hospitals, University Hospitals Birmingham and Bedfordshire Hospitals NHS trusts, and prospectively during the second-wave of the UK COVID-19 epidemic at Oxford University Hospitals (OUH). Predictions were generated using first-performed blood tests and vital signs and compared against confirmatory viral nucleic acid testing. Next, we retrospectively evaluated a novel clinical pathway triaging patients to COVID-19-suspected clinical areas where either model prediction or LFD results were positive, comparing sensitivity and NPV with LFD results alone. Lastly, we deployed CURIAL-Rapide alongside an approved point-of-care FBC analyser (OLO;SightDiagnostics, Israel) to provide lab-free COVID-19 screening in the John Radcliffe Hospital’s Emergency Department (Oxford, UK), as trust-approved service improvement. Our primary improvement outcome was time-to-result availability;secondary outcomes were sensitivity, specificity, PPV, and NPV assessed against a PCR reference standard. We compared CURIAL-Rapide’s performance with clinician triage and LFD results within standard-care. Results 72,223 patients met eligibility criteria across external and prospective validation sites. Model performance was consistent across trusts (CURIAL-Lab: AUROCs range 0.858-0.881;CURIAL-Rapide 0.836-0.854), with highest sensitivity achieved at Portsmouth University Hospitals (CURIAL-Lab:84.1% [95% Wilson’s score CIs 82.5-85.7];CURIAL-Rapide:83.5% [81.8 - 85.1]) at specificities of 71.3% (95% Wilson’s score CIs: 70.9 - 71.8) and 63.6% (63.1 - 64.1). For 3,207 patients receiving LFD-triage within routine care for OUH admissions between December 23, 2021 and March 6, 2021, a combined clinical pathway increased sensitivity from 56.9% for LFDs alone (95% CI 51.7-62.0) to 88.2% with CURIAL-Rapide (84.4-91.1;AUROC 0.919) and 85.6% with CURIAL-Lab (81.6-88.9;AUROC 0.925). 520 patients were prospectively enrolled for point-of-care FBC analysis between February 18, 2021 and May 10, 2021, of whom 436 received confirmatory PCR testing within routine care and 10 (2.3%) tested positive. Median time from patient arrival to availability of CURIAL-Rapide result was 45:00 min (32-64), 16 minutes (26.3%) sooner than LFD results (61:00 min, 37-99;log-rank p<0.0001), and 6:52 h (90.2%) sooner than PCR results (7:37 h, 6:05-15:39;p<0.0001). Sensitivity and specificity of CURIAL-Rapide were 87.5% (52.9-97.8) and 85.4% (81.3-88.7), therefore achieving high NPV (99.7%, 98.2-99.9). CURIAL-Rapide correctly excluded COVID-19 for 58.5% of negative patients who were triaged by a clinician to ‘COVID-19-suspected’ (amber) areas. Impact CURIAL-Lab & CURIAL-Rapide are generalisable, high-throughput screening tests for COVID-19, rapidly excluding the illness with higher NPV than LFDs. CURIAL-Rapide can be used in comb nation with near-patient FBC analysis for rapid, lab-free screening, and may reduce the number of COVID-19-negative patients triaged to enhanced precautions (‘amber’) clinical areas.

12.
BMJ Open ; 11(11): e050202, 2021 11 11.
Article in English | MEDLINE | ID: covidwho-1515299

ABSTRACT

INTRODUCTION: Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. METHODS AND ANALYSIS: The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBERS: EudraCT2020-001684-89, ISRCTN40580903.


Subject(s)
COVID-19 , Adult , Clinical Trials, Phase II as Topic , Hospitalization , Humans , Multicenter Studies as Topic , Research , SARS-CoV-2
13.
BMJ Open Respir Res ; 8(1)2021 09.
Article in English | MEDLINE | ID: covidwho-1438096

ABSTRACT

INTRODUCTION: The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). METHODS AND ANALYSIS: The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. ETHICS AND DISSEMINATION: All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. CONCLUSION: This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD.


Subject(s)
COVID-19/complications , Lung Diseases, Interstitial , Humans , Longitudinal Studies , Lung Diseases, Interstitial/epidemiology , Observational Studies as Topic , Pandemics , Prospective Studies , United Kingdom/epidemiology
14.
BMJ Open Respir Res ; 7(1)2020 11.
Article in English | MEDLINE | ID: covidwho-1388517

ABSTRACT

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is the major cause of mortality in patients with SARS-CoV-2 pneumonia. It appears that development of 'cytokine storm' in patients with SARS-CoV-2 pneumonia precipitates progression to ARDS. However, severity scores on admission do not predict severity or mortality in patients with SARS-CoV-2 pneumonia. Our objective was to determine whether patients with SARS-CoV-2 ARDS are clinically distinct, therefore requiring alternative management strategies, compared with other patients with ARDS. We report a single-centre retrospective study comparing the characteristics and outcomes of patients with ARDS with and without SARS-CoV-2. METHODS: Two intensive care unit (ICU) cohorts of patients at the Queen Elizabeth Hospital Birmingham were analysed: SARS-CoV-2 patients admitted between 11 March and 21 April 2020 and all patients with community-acquired pneumonia (CAP) from bacterial or viral infection who developed ARDS between 1 January 2017 and 1 November 2019. All data were routinely collected on the hospital's electronic patient records. RESULTS: A greater proportion of SARS-CoV-2 patients were from an Asian ethnic group (p=0.002). SARS-CoV-2 patients had lower circulating leucocytes, neutrophils and monocytes (p<0.0001), but higher CRP (p=0.016) on ICU admission. SARS-CoV-2 patients required a longer duration of mechanical ventilation (p=0.01), but had lower vasopressor requirements (p=0.016). DISCUSSION: The clinical syndromes and respiratory mechanics of SARS-CoV-2 and CAP-ARDS are broadly similar. However, SARS-CoV-2 patients initially have a lower requirement for vasopressor support, fewer circulating leukocytes and require prolonged ventilation support. Further studies are required to determine whether the dysregulated inflammation observed in SARS-CoV-2 ARDS may contribute to the increased duration of respiratory failure.


Subject(s)
COVID-19/complications , Critical Care/methods , Patient Outcome Assessment , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/etiology , C-Reactive Protein/metabolism , Cohort Studies , Female , Humans , Leukocytes/metabolism , Male , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/therapy , Respiratory Mechanics , Retrospective Studies , SARS-CoV-2 , Time , United Kingdom , Vasoconstrictor Agents/therapeutic use
15.
BMJ Open Respir Res ; 8(1)2021 08.
Article in English | MEDLINE | ID: covidwho-1350028

ABSTRACT

BACKGROUND: Ethnic minorities account for 34% of critically ill patients with COVID-19 despite constituting 14% of the UK population. Internationally, researchers have called for studies to understand deterioration risk factors to inform clinical risk tool development. METHODS: Multicentre cohort study of hospitalised patients with COVID-19 (n=3671) exploring determinants of health, including Index of Multiple Deprivation (IMD) subdomains, as risk factors for presentation, deterioration and mortality by ethnicity. Receiver operator characteristics were plotted for CURB65 and ISARIC4C by ethnicity and area under the curve (AUC) calculated. RESULTS: Ethnic minorities were hospitalised with higher Charlson Comorbidity Scores than age, sex and deprivation matched controls and from the most deprived quintile of at least one IMD subdomain: indoor living environment (LE), outdoor LE, adult skills, wider barriers to housing and services. Admission from the most deprived quintile of these deprivation forms was associated with multilobar pneumonia on presentation and ICU admission. AUC did not exceed 0.7 for CURB65 or ISARIC4C among any ethnicity except ISARIC4C among Indian patients (0.83, 95% CI 0.73 to 0.93). Ethnic minorities presenting with pneumonia and low CURB65 (0-1) had higher mortality than White patients (22.6% vs 9.4%; p<0.001); Africans were at highest risk (38.5%; p=0.006), followed by Caribbean (26.7%; p=0.008), Indian (23.1%; p=0.007) and Pakistani (21.2%; p=0.004). CONCLUSIONS: Ethnic minorities exhibit higher multimorbidity despite younger age structures and disproportionate exposure to unscored risk factors including obesity and deprivation. Household overcrowding, air pollution, housing quality and adult skills deprivation are associated with multilobar pneumonia on presentation and ICU admission which are mortality risk factors. Risk tools need to reflect risks predominantly affecting ethnic minorities.


Subject(s)
Air Pollution/analysis , Benchmarking/methods , COVID-19/therapy , Housing/standards , Patient Admission , Risk Assessment/methods , Age Distribution , Age Factors , Aged , COVID-19/ethnology , Comorbidity , Crowding , Female , Follow-Up Studies , Humans , Male , Middle Aged , Multimorbidity , Risk Factors , SARS-CoV-2 , United Kingdom/epidemiology
17.
Clin Med (Lond) ; 21(2): e144-e149, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1089178

ABSTRACT

The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets - the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.


Subject(s)
COVID-19 , Dietary Supplements , Respiratory Tract Infections , Rickets , Vitamin D Deficiency , Vitamin D , Humans , Pandemics , Respiratory Tract Infections/prevention & control , Rickets/prevention & control , SARS-CoV-2 , Vitamin D/therapeutic use , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/epidemiology , Vitamin D Deficiency/prevention & control
18.
R Soc Open Sci ; 7(12): 201912, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1003869

ABSTRACT

Vitamin D is a hormone that acts on many genes expressed by immune cells. Evidence linking vitamin D deficiency with COVID-19 severity is circumstantial but considerable-links with ethnicity, obesity, institutionalization; latitude and ultraviolet exposure; increased lung damage in experimental models; associations with COVID-19 severity in hospitalized patients. Vitamin D deficiency is common but readily preventable by supplementation that is very safe and cheap. A target blood level of at least 50 nmol l-1, as indicated by the US National Academy of Medicine and by the European Food Safety Authority, is supported by evidence. This would require supplementation with 800 IU/day (not 400 IU/day as currently recommended in UK) to bring most people up to target. Randomized placebo-controlled trials of vitamin D in the community are unlikely to complete until spring 2021-although we note the positive results from Spain of a randomized trial of 25-hydroxyvitamin D3 (25(OH)D3 or calcifediol) in hospitalized patients. We urge UK and other governments to recommend vitamin D supplementation at 800-1000 IU/day for all, making it clear that this is to help optimize immune health and not solely for bone and muscle health. This should be mandated for prescription in care homes, prisons and other institutions where people are likely to have been indoors for much of the summer. Adults likely to be deficient should consider taking a higher dose, e.g. 4000 IU/day for the first four weeks before reducing to 800 IU-1000 IU/day. People admitted to the hospital with COVID-19 should have their vitamin D status checked and/or supplemented and consideration should be given to testing high-dose calcifediol in the RECOVERY trial. We feel this should be pursued with great urgency. Vitamin D levels in the UK will be falling from October onwards as we head into winter. There seems nothing to lose and potentially much to gain.

20.
Clin Med (Lond) ; 21(1): e48-e51, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-914784

ABSTRACT

There is growing evidence linking vitamin D deficiency with risk of COVID-19. It is therefore distressing that there is major disagreement about the optimal serum level for 25-hydroxyvitamin D (25(OH)D) and appropriate supplement dose. The UK Scientific Advisory Committee for Nutrition has set the lowest level for defining sufficiency (10 ng/ml or 25 nmol/L) of any national advisory body or scientific society and consequently recommends supplementation with 10 micrograms (400 IU) per day. We have searched for published evidence to support this but not found it. There is considerable evidence to support the higher level for sufficiency (20 ng/ml or 50 nmol/L) recommended by the European Food Safety Authority and the American Institute of Medicine and hence greater supplementation (20 micrograms or 800 IU per day). Serum 25(OH)D concentrations in the UK typically fall by around 50% through winter. We believe that governments should urgently recommend supplementation with 20-25 micrograms (800-1,000 IU) per day.


Subject(s)
COVID-19/epidemiology , Pandemics , Vitamin D Deficiency/prevention & control , Vitamin D/analogs & derivatives , Vitamin D/administration & dosage , Dietary Supplements , Dose-Response Relationship, Drug , Humans , SARS-CoV-2 , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/epidemiology , Vitamins/administration & dosage
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