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Lord Byron can be classified as the prototype of contemporary celebrities endorsing pseudo-scientific views and opposing vaccination policies based on his public statements, while privately he appears to have had double standards since he had his page inoculated against smallpox. Through a review of the biomedical and historical literature this paper examines the role of the example given by celebrities during vaccination campaigns,focusing on the historical figure of Lord Byron. A reassessment of his writings on the topic of vaccination (cowpox inoculation)is then performed and put in the greater context of celebrities, past and present, commenting in favour or against immunisation policies. Byron's case demonstrates how health institutions should not underestimate the influence of 'VIPs' on the success of vaccinations, and should seek their help and positive example when trying to persuade the general population of the importance of vaccinations.
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Introduction Elevated soluble urokinase Plasminogen Activator Receptor (suPAR) is a biomarker associated with adverse outcomes. We aimed to investigate the associations among plasma suPAR levels (testing the cut-offs <=4 and >=6 ng/mL that supports patient discharge/hospitalisation, respectively) with other biomarkers such as PCR, PCT, IL-6 and with sex, age, discharge/death and WHO disease severity in patients tested positive for SARS-CoV-2. Methods We performed an observational cohort study of 99 patients (37 females, 62 males) presenting with COVID-19 symptoms at Department of Infectous and Critical Care of our Hospital in April 2020. Plasma suPAR was measured using suPARnostic kit (Virogates, Denmark), an immunoturbidimetric method on Abbott Alinity i platform. Patients were followed for development of mechanical ventilation, mortality or discharged. Statistical analysis was performed using Principal Component Analysis (PCA) that can be applied to datasets to obtain a simplified model for stratifying patients by reducing the number of variables. PCA weights the variables according to their relative importance. This method, in our case, can aid in determining key variables in management of patients affected by SARS-CoV-2. Results The mean age was 58 years;women had a higher concentration average of suPAR (8.9 vs 8.3 ng/mL) but the subdivision by sex did not determine any clustering. All variables showed a positive correlation with disease severity, better with IL-6 and suPAR (IL-6=25.3%, suPAR=24%, age=16.4%, PCT=15.4%, PCR=17.2%), allowing a subdivision of 3 groups (severe/ critic: IL-6=227.65 pg/mL, suPAR=9.26 ng/mL;moderate: IL-6=48.1 pg/mL, suPAR=7.35 ng/mL, paucisymptomatic: IL-6=3.7 pg/mL, suPAR=2.78 ng/mL). Combining the variables and discharge/death outcome showed positive correlation although this did not result any clear clustering (n.78 discharged: IL-6=214 pg/mL, suPAR=8.23 ng/mL;n.14 dead: IL-6=286 pg/mL, suPAR=11.31 ng/mL). Discussion Our data show that suPAR levels increase as the disease worsens. Statistical analyses demonstrated that suPAR levels are positively correlated with age and IL-6 levels. Therefore, further evaluation of suPAR plasma levels in different symptoms of COVID-19 patients could still provide important indications for early admission and treatment.
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COVID-19 is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The persistent and excessive inflammatory response can build up a clinical picture that is difficult to manage and potentially fatal. Potent activators of inflammatory phenomena are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). HMGB1 is an intranuclear protein that is either passively released during hypoxia-related necrosis or actively released by macrophages. Heme oxygenase (HO-1) has an anti-inflammatory effect by inhibiting HMGB1, which could be a therapeutic target to reduce COVID-19 inflammation. In our study, we evaluated CD3, CD4, CD8, HMGB1 and HO-1 in the COVID-19 lung and correlated it to clinical data.
Subject(s)
COVID-19 , HMGB1 Protein , Respiratory Distress Syndrome , Humans , COVID-19/complications , SARS-CoV-2/metabolism , Heme Oxygenase-1/metabolismABSTRACT
Background: Treatment guidelines recommend the use of tocilizumab in patients with a current CRP >7.5 mg/dl. Recent data showed that survival benefit might be greater in those with higher CRP levels. We aimed to estimate the causal effect of intensification with tocilizumab on mortality overall and after stratification for PaO2/FiO2 ratio, CRP levels. Methods: Observational cohort study of patients with severe COVID-19 pneumonia. Primary endpoint was day-28 mortality. Survival analysis was conducted to estimate the conditional and average causal effect of tocilizumab intensification vs. glucocorticoids alone using Kaplan-Meier curves and Cox regression models with a time-varying variable for the intervention. Analysis was controlled for age, ethnicity, duration of symptoms, at hospital admission (baseline, BL) PaO2/FiO2 ratio, CRP (BL and current), Charlson comorbidity index and post-BL use of remdesivir and invasive mechanical ventilation. The hypothesis of the existence of effect measure modification by CRP and PaO2/FiO2 ratio was tested by including an interaction term in the model. Results: 992 patients median age 69 years, 72.9% males, 597 (60.2%) treated with monotherapy and 395 (31.8%), adding tocilizumab upon respiratory deterioration were included. At BL, median CRP was 6.0 mg/dl (IQR 3.0-15.0) and median PaO2/FiO2 ratio was 261 mmHg (200-303). The two groups differed for median values of: CRP (6 vs 7 mg/dL;p<.001)), IL-6, (27.6 vs 175.0 mg/L;p<.001) LDH (525 vs 622 U/L;p<.001), lymphocytes (939 vs 835/mm3;p<.001) and PaO2/FiO2 ratio (276 vs 235 mmHg;p<.001) at BL. In the unadjusted analysis there was no statistically significant difference in mortality between the two groups, but there was strong evidence for an effect of the intensification after controlling for key BL and post-BL confounders, consistent with the estimate in trials (adjusted hazard ratio (aHR)=0.59, 95% CI:0.38-0.90). Although the study was not powered to detect interactions (p>0.57) there was a signal for intensification to have a larger effect in subsets, especially participants with high levels of CRP at intensification (Figure). Conclusion: Our data suggest that intensification with tocilizumab confers reduced survival benefit in those intensifying with a CRP of 0-7.5 mg/dl. It also provides substantial benefit even in patients who are intensified with a CRP>15 mg/dl. Large randomised studies are needed to establish an exact cut-off for clinical use.
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Background: A large global effort is ongoing to develop vaccines against SARS-CoV-2, the causative agent of COVID-19. While there is accumulating information on the antibody response against SARS-CoV-2, less is known about the SARS-CoV-2 antigens that are targeted by CD8 T cells. Such knowledge will be of high value to gain fundamental insights into the antigenic landscape of SARS-CoV-2 recognized by CD8 T cells, to develop tool allowing focused analysis of the SARS-CoV-2 specific T cell responses directly ex vivo, and to understand whether current vaccine designs are covering the CD8 T cell recognized antigens. Methods: To address this issue, we have analyzed samples from 18 COVID-19 patients for CD8 T cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 common HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predicted binding affinity and likelihood of successful proteasomal processing. To probe for CD8 T cell recognition of the selected epitope-HLA complexes, we made use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated to fluorescent dyes. Results: In addition to previous studies showing CD8 T cell reactivity towards epitopes derived from the spike protein of SARS-CoV-2, we have identified several CD8 T cell recognized epitopes derived from the ORF1ab, including one epitope displaying clear immunodominant properties across patients positive for HLA-A*01:01. Investigation of the functional status of part of the identified responses (including 4 responses specific for the immunodominant epitope) revealed that the T cell responses were highly dysfunctional. In addition the SARS-CoV-2 specific CD8 T cell responses displayed an increased expression of NKG2A in comparison with bulk CD8 T cells, which may explain their dysfunctional state. Conclusions: Our data suggest that part of the ORF1ab encodes multiple CD8 T cell antigens including one immunodominant epitope. Noteworthy these epitopes were derived from a part of the viral genome that is not included in the majority of vaccine candidates in development, and this may potentially influence their clinical activity and safety profile. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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Background: The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit. Methods: The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching. Results: Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in non-treated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission. Conclusions: Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation.
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While there is accumulating evidence on the antibody response against SARS-CoV-2, we are only beginning toacquire knowledge regarding the SARS-CoV-2 specific CD8 T-cell response. Therefore, it is an urgent matter to gaina deeper insight into the virus specific CD8 T-cell response to both assist vaccine design and provide tools toevaluate the vaccine-induced T-cell responses. To address this issue, we have analyzed samples from 20 COVID-19 patients for CD8 T-cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 of the mostcommon HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predictedbinding affinity and likelihood of successful proteasomal processing. In addition, SARS-CoV-2 epitope predictionsshared by the science community were considered. To probe for CD8 T-cell recognition of the selected epitopes, wemade use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated tofluorescent dyes. Our data demonstrated that CD8 T-cell reactivity against SARS-CoV-2 was common. Remarkably, a substantial fraction of the observed CD8 T-cell responses were directed towards the ORF1ab polyprotein 1ab.These CD8 T-cell responses were frequently of a profound magnitude. In particular, a CD8 T-cell response towardsa potentially immunodominant epitope (TTDPSFLGRY) restricted to the HLA-A∗01:01 allele was found in all patientspositive for this allele. Interestingly, the fraction of SARS-CoV-2 specific CD8 T cells expressing the inhibitoryreceptor NKG2A was higher as compared to bulk CD8 T cells. In conclusion, the fact that a major part of theidentified SARS-CoV-2 specific CD8 T-cell response is directed against a part of the viral genome that is notincluded in the majority of vaccine candidates currently in development may potentially influence their clinical activityand toxicity profile.