There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of ...disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity.
A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection.
Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 Relative Risk (RR) = 0.42 (95%CI: 0.34–0.52), P < 0.001, WHO outcome score >5 RR = 0.33 (95%CI: 0.21–0.50), P < 0.001, and to have had a LOS > 3 days RR = 0.84 (95%CI: 0.76–0.92), P < 0.001. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity.
We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease.
AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.
Hospitalisations relating to acute respiratory deteriorations (ARD) in Interstitial Lung Disease (ILD) have poor outcomes. Factors predicting adverse outcomes are not fully understood and data ...addressing the use of illness severity scores in prognostication are limited.
To investigate the use of CURB-65 and NEWS-2 severity scores in the prediction of mortality following ARD-ILD hospitalisation, using prospective methodology and to validate previously determined cut-offs, derived from a retrospective study cohort.
A dual-centre prospective observational cohort study of all adults (≥18y) hospitalised with ARD-ILD in Bristol, UK (n = 179). Gender-Age-Physiology (GAP), CURB-65 and NEWS-2 scores were calculated for each eligible admission.
Receiver operating characteristics (ROC) curve analysis was used to quantify the strength of discrimination for NEWS-2 and CURB-65 scores. Univariable and multivariable logistic regression analyses were performed to explore the relationship between baseline severity scores and mortality.
GAP showed some merit at predicting 30-day mortality (AUC = 0.64, P = 0.015); whereas CURB-65 showed modest predictive value for in-hospital (AUC = 0.72, P < 0.001) and 90-day mortality (AUC = 0.67, P < 0.001). NEWS-2 showed higher predictive value for in-hospital (AUC = 0.80, P < 0.001) and 90-day mortality (AUC = 0.75, P < 0.001), with an optimal derived cut-off ≥6.5 found to be sensitive and specific for predicting in-hospital (83% and 63%) and 90-day (73% and 72%) mortality. In exploratory analyses, GAP score addition improved the predictive ability of NEWS-2 against 30-day mortality and CURB-65 across all time-periods.
NEWS-2 has good discriminatory value for predicting in-hospital mortality and moderate discriminatory value for predicting 90-day mortality. The optimal NEWS-2 cut-off value determined was the same as in a previous retrospective cohort, confirming the NEWS-2 score shows promise in predicting mortality following ARD-ILD hospitalisation.
•ARD-ILD is associated with high in-hospital, 30- and 90- day mortality, irrespective of cause.•NEWS-2 has high sensitivity and specificity in predicting 90d & in-hospital mortality in ARD-ILD.•CURB-65 showed high sensitivity for predicting mortality but low specificity.•CURB-65 did not add value to the NEWS-2 predictive ability.•Simple illness severity scores may support refinement of ARD-ILD management pathways.
Whilst other studies have reported the effectiveness of mRNA vaccination against hospitalisation, including emergency department or intensive care admission, few have assessed effectiveness against ...other more clinically robust indices of COVID-19 severity.
A prospective single-centre test-negative design case–control study of adults hospitalised with COVID-19 disease or other acute respiratory disease between 1 June 2021 and 20 July 2022. We assessed VE (vaccine effectiveness) against hospitalisation, length of stay LOS >3 days, WHO COVID Score >5 and supplementary oxygen FiO2 (fraction inspired oxygen) >28%, conducting regression analyses controlling for age, gender, index of multiple deprivation, Charlson comorbidity index, time, and community infection prevalence.
935 controls and 546 cases were hospitalised during the Delta period, with 721 controls and 372 cases hospitalised during the Omicron study period. Two-dose BNT162b2 was associated with VE 82.5% 95% confidence interval 76.2%–87.2% against hospitalisation following Delta infection, 63.3% 26.9–81.8%, 58.5% 24.8–77.3%, and 51.5% 16.7–72.1% against LOS >3 days, WHO COVID Score >5, and requirement for FiO2 >28% respectively. Three-dose BNT162b2 protection against hospitalisation with Omicron infection was 30.9% 5.9–49.3%, with sensitivity analyses ranging from 28.8–72.6%. Protection against LOS >3 days, WHO COVID Score >5 and requirement for FiO2 >28% was 56.1% 20.6–76.5%, 58.8% 31.2–75.8%, and 41.5% −0.4–66.3%, respectively. In the UK, BNT162b2 was prioritised for high-risk individuals and those aged >75 years. In the latter group we found a higher estimate of VE against hospitalisation of 47.2% 16.8–66.6%.
BNT162b2 vaccination results in risk reductions for hospitalisation and multiple patient outcomes following Delta and Omicron COVID-19 infection, particularly in older adults. BNT162b2 remains effective against severe SARS-CoV-2 disease.
AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.
Background: Whilst other studies have reported the effectiveness of mRNA vaccination against hospitalisation, including emergency department or intensive care admission, few have assessed ...effectiveness against other more clinically robust indices of COVID-19 severity. Methods: A prospective single-centre test-negative design case–control study of adults hospitalised with COVID-19 disease or other acute respiratory disease between 1 June 2021 and 20 July 2022. We assessed VE (vaccine effectiveness) against hospitalisation, length of stay LOS >3 days, WHO COVID Score >5 and supplementary oxygen FiO2 (fraction inspired oxygen) >28%, conducting regression analyses controlling for age, gender, index of multiple deprivation, Charlson comorbidity index, time, and community infection prevalence. Findings: 935 controls and 546 cases were hospitalised during the Delta period, with 721 controls and 372 cases hospitalised during the Omicron study period. Two-dose BNT162b2 was associated with VE 82.5% 95% confidence interval 76.2%–87.2% against hospitalisation following Delta infection, 63.3% 26.9–81.8%, 58.5% 24.8–77.3%, and 51.5% 16.7–72.1% against LOS >3 days, WHO COVID Score >5, and requirement for FiO2 >28% respectively. Three-dose BNT162b2 protection against hospitalisation with Omicron infection was 30.9% 5.9–49.3%, with sensitivity analyses ranging from 28.8–72.6%. Protection against LOS >3 days, WHO COVID Score >5 and requirement for FiO2 >28% was 56.1% 20.6–76.5%, 58.8% 31.2–75.8%, and 41.5% −0.4–66.3%, respectively. In the UK, BNT162b2 was prioritised for high-risk individuals and those aged >75 years. In the latter group we found a higher estimate of VE against hospitalisation of 47.2% 16.8–66.6%. Interpretation: BNT162b2 vaccination results in risk reductions for hospitalisation and multiple patient outcomes following Delta and Omicron COVID-19 infection, particularly in older adults. BNT162b2 remains effective against severe SARS-CoV-2 disease. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.
Background: There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing ...severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. Methods: A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. Findings: Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 Relative Risk (RR) = 0.42 (95%CI: 0.34–0.52), P < 0.001, WHO outcome score >5 RR = 0.33 (95%CI: 0.21–0.50), P < 0.001, and to have had a LOS > 3 days RR = 0.84 (95%CI: 0.76–0.92), P < 0.001. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Interpretation: We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.
The relationships between the nervous and the immune systems raise the question of whether neurotrophic factors, in addition to the regulation of neural cell ontogeny, may influence lymphocyte ...development. We report in this work that the pattern of neurotrophin receptor expression depends on the developmental stage of T cells. The presence of nerve growth factor receptor trkA could not be detected in any of the thymocyte subsets, whereas brain-derived neurotrophic factor (BDNF) receptor trkB was expressed in all thymocyte subpopulations. Interestingly, both trkB mRNA and protein expression inversely correlated with the maturation stage and the differentiation potential of thymocytes, being more expressed in CD4-8- immature thymocytes and progressively declining in CD8+ and CD4+ single-positive and CD4+8+ more mature thymocytes. The developmentally regulated expression of trkB is further shown by the inhibition or enhancement of trkB expression induced by signals that either trigger or impair the transition from immature to more differentiated stages of the thymocyte developmental pathway. Signals generated following the interaction of BDNF with trkB receptor resulted in the stimulation of trkB autophosphorylation and in the up-regulation of the expression of the c-fos gene in CD4-8- cells and enhanced thymocyte survival. Finally, BDNF is expressed in thymic stroma and is further up-regulated by signals generated by the thymocyte/stromal cell interaction. These data suggest that BDNF may be a novel survival factor for thymocyte precursors and support the presence of developmentally regulated feedback mechanisms based on autocrine/paracrine neurotrophin/receptor interactions that may be involved in the thymocyte differentiation process.
Retinoic acid (RA) controls the differentiation of a variety of cell types, although its role in influencing T cell development and the mechanisms potentially involved have not been thoroughly ...investigated. To study the ability of RA to modulate T cell development, we established a thymic stromal cell line (TC-1S) that supports the phenotypic maturation of CD4-8- double negative (DN) or CD3-4-8- triple negative (TN) thymocyte precursors. Cocultures of either DN or TN thymocytes on a monolayer of TC-1S cells resulted in the appearance of thymocytes with a more mature phenotype (CD4+8+ double positive, CD4+ or CD8+ single positive, and CD3(low) cells). Double negative T cell contact with TC-1S cells also increased the production of fibronectin (FN) by the thymic stroma and the expression of the VLA-4 FN receptor on the DN cells. Ab-mediated inhibition of the interaction between FN and its receptors significantly reduced the level of induced T cell maturation. Addition of RA either to TC-1S cells alone or to the coculture with DN cells decreased stromal cell FN expression, antagonized DN cell-induced increase in stromal cell FN production and significantly inhibited in vitro thymocyte maturation. The effects of RA were likely mediated by RA acid receptors alpha and gamma expressed both in DN thymocytes and TC-1S cells. Together these data suggest that FN/VLA-4 interaction may be an important component of stromal cell-dependent thymocyte phenotypic differentiation and that this interaction can be one of the targets for the influence of RA in T cell development.
A number of behavioural and cellular studies have suggested that activity-dependent synaptic plasticity associated with learning and memory may lead to the expression of various genes whose protein ...products can play a critical role in memory acquisition and consolidation. Long-term potentiation (LTP) and long-term depression (LTD) represent two forms of synaptic plasticity which have been widely studied by electrophysiological techniques. However, the molecular mechanisms at target gene involved in the generation of long term depression remain to be determined. To elucidate the molecular mechanism underlying activity dependent synaptic remodeling in striatal long term depression, we used the mRNA differential display technology to isolate genes that are induced or modulated by high frequency stimulation of the corticostriatal pathway in a rat brain slice preparation. We have differentially displayed, by means of reverse transcriptase-polymerase chain reaction, mRNA species isolated from striatal slices in which long term depression was induced by tetanic stimuli as well as from slices stimulated at low frequency. We then compared radio-labeled RT-PCR banding patterns to isolate cDNAs that are differentially expressed. Three independent cDNAs were isolated and identified whose mRNA level were enhanced by tetanic stimulation inducing long term depression. We provide evidence that two of these genes encode proteins involved in synaptic vesicle trafficking (dynamin I and amphiphysin II). Moreover, expression of tissue plasminogen activator (t-PA) gene was also increased following striatal long term depression. Our data suggest that a complex pattern of genes acting at presynaptic level and extracellularly may be involved in LTD-associated synaptic remodeling.
We have examined the expression of a panel of cytokines in thymic epithelial cells and CD4-CD8- (DN) thymocytes following cell to cell lymphostromal interaction, in an experimental model which ...enhances in vitro thymocyte maturation. Since retinoic acid (RA) has been previously shown to be an inhibitor of thymocyte maturation process in this model, we wanted to analyse cytokine expression in DN thymocytes and thymic epithelial cells following the RA-induced impairment of in vitro thymocyte maturation. Cell to cell lymphostromal interaction results in increased IL2 and decreased IL7 expression in thymocytes while the expression of IL1 beta and IL7 increased and decreased, respectively, in thymic epithelial cells. Addition of RA to lympho-stromal cell co-culture results in the enhancement of IL4 and IL7 expression in thymocytes while in thymic epithelial cells IL1 alpha decreased and IL6 and IL7 increased. These data indicate that discrete patterns of cytokine expression are present in thymocyte precursors and in thymic epithelial cells during in vitro T-cell development. They furthermore suggest that specific cytokine modulation might contribute to the RA-induced impairment of thymocyte differentiation.
