Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (TFH) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that TFH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of TFH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that TFH cells support stromal cell responses to vaccines.

Reference-based comparison of adaptive immune receptor repertoires.

B and T cell receptor (immune) repertoires can represent an individual's immune history. While current repertoire analysis methods aim to discriminate between health and disease states, they are typically based on only a limited number of parameters. Here, we introduce immuneREF: a quantitative multidimensional measure of adaptive immune repertoire (and transcriptome) similarity that allows interpretation of immune repertoire variation by relying on both repertoire features and cross-referencing of simulated and experimental datasets. To quantify immune repertoire similarity landscapes across health and disease, we applied immuneREF to >2,400 datasets from individuals with varying immune states (healthy, [autoimmune] disease, and infection). We discovered, in contrast to the current paradigm, that blood-derived immune repertoires of healthy and diseased individuals are highly similar for certain immune states, suggesting that repertoire changes to immune perturbations are less pronounced than previously thought. In conclusion, immuneREF enables the population-wide study of adaptive immune response similarity across immune states.

Pathogenesis, immunology, and immune-targeted management of the multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Toward real-world automated antibody design with combinatorial Bayesian optimization.

Antibodies are multimeric proteins capable of highly specific molecular recognition. The complementarity determining region 3 of the antibody variable heavy chain (CDRH3) often dominates antigen-binding specificity. Hence, it is a priority to design optimal antigen-specific CDRH3 to develop therapeutic antibodies. The combinatorial structure of CDRH3 sequences makes it impossible to query binding-affinity oracles exhaustively. Moreover, antibodies are expected to have high target specificity and developability. Here, we present AntBO, a combinatorial Bayesian optimization framework utilizing a CDRH3 trust region for an in silico design of antibodies with favorable developability scores. The in silico experiments on 159 antigens demonstrate that AntBO is a step toward practically viable in vitro antibody design. In under 200 calls to the oracle, AntBO suggests antibodies outperforming the best binding sequence from 6.9 million experimentally obtained CDRH3s. Additionally, AntBO finds very-high-affinity CDRH3 in only 38 protein designs while requiring no domain knowledge.

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 beta [IL-1beta] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. Copyright © 2021, The Author(s), under exclusive licence to Springer Nature B.V.

Platelet activation and COVID-19 mortality: Insights from coagulopathy, antiplatelet therapy and inflammation

Background: Severe coronavirus disease 2019 (COVID-19) is associated with inflammatory cytokine burst and coagulopathy. Platelets may contribute to microthrombosis development and be a target in COVID-19 therapy. Aim(s): To determine the significance of platelet activation and antiplatelet agents (APAs) treatment in COVID-19 pathophysiology and mortality in two cohorts of patients with COVID-19. Method(s): We explored two cohorts of COVID-19 patients: Cohort A (NCT04624997) included 208 ambulatory and hospitalized patients of different clinical severity with evaluation of soluble CD40 ligand (sCD40L) and P-selectin (sP-sel) plasma levels of within the first 48 hours following admission. Cohort B included 2878 patients initially admitted in medical ward with collection of clinical characteristics and outcomes (NCT04344327). In both cohorts, the primary outcome was in-hospital mortality. Result(s): In cohort A, circulating median levels of sCD40L and sP-sel were significantly increased solely in critical patients with COVID-19 (sP-sel: 40059 pg/ml, IQR 26876-54678;sCD40L: 1914 pg/ml IQR 1410-2367;p < 0.001 for both), signaling platelet hyper-activation. However, pre-hospitalization APAs did not significantly modified sCD40L and sP-sel levels. Admission sP-sel levels were predictive in-hospital mortality (Kaplan-Meier log-rank p = 0.004), even after adjustment on CRP, while adjustment on D-dimer abolished this relationship, suggesting that platelet activation is highly interrelated with coagulopathy. We confirmed this finding in a Cox model adjusted for age, sex, CRP and D-dimer levels (Odds ratio 1.78, 95% CI 0.63-4.50). We confirmed in cohort B (2878 patients) that, among patients receiving APA before hospitalization, there was no significant difference in the proportion of death in a Cox model (Hazard ratio 1.0, IQR0.77-1.30) adjusted for demographic comorbidities. Conclusion(s): Our findings highlight the critical role of coagulopathy, in contrast to platelet activation, in discriminating COVID-19 severity and increased risk of in-hospital mortality. We also confirm that APAs before hospitalization do not influence neither mortality nor platelet activation. (Table Presented).

Prognostic value of troponin elevation at admission and during monitoring in COVID-19 patients

Background: Troponin seems to be a biological marker of interest in the risk-stratification of COVID 19 at admission, but few studies focus on exploring its prognostic abilities during hospitalization. Aim(s): To assess the ability of troponin levels at admission and during follow-up to predict in-hospital mortality in COVID-19 patients. Method(s): Troponin was measured at admission and throughout hospitalization amongst COVID-19 patients. We explored the prognostic ability of baseline troponin and kinetics on COVID-19 patients outcomes using logistic regression and Cox model. Result(s): Amongst 399 patients enrolled with confirmed COVID-19, 247 had at least 2 troponin measurements during hospitalization and 319 (80%) survived, while 80 (20%) died during hospitalization. Elevated troponin upon arrival was significantly associated with mortality (Odds Ratio (OR) 5.65 (95% CI 3.24 -9.88);p < 0.01). Patients with an elevated troponin level and underlying cardiovascular diseases were more likely to experience death than those without elevated troponin nor cardiovascular history (Hazard Ratio 4.62 (1.96-10.91);p < 0.001). There seems to be a level-dependent association between troponin level and in-hospital mortality (p < 0.01). To assess the ability of troponin monitoring during the first 10 days of hospitalization to predict in-hospital mortality we analyzed the ratio of troponin (ROT) between the highest level of troponin and the baseline troponin measurement. An increase over 75% of the ROT was not significantly associated with in hospital mortality (OR 1.02 (95% CI 1.01-1.04);p = 0.12). During follow-up, there was no significant differences of in-mortality between patients with constant elevated troponin throughout hospitalization and those who went from a normal to an elevated troponin (p = 0.15). Conclusion(s): For COVID-19 patients, troponin seems to be a relevant factor for in-hospital mortality and risk-stratification at admission but its monitoring during follow-up does not appear to be valuable in predicting disease progression.

Allergic diseases and immunodeficiencies in children, lessons learnt from COVID-19 pandemic by 2022: A statement from the EAACI-section on pediatrics.

By the April 12, 2022, the COVID-19 pandemic had resulted in over half a billion people being infected worldwide. There have been 6.1 million deaths directly due to the infection, but the pandemic has had many more short- and long-term pervasive effects on the physical and mental health of the population. Allergic diseases are among the most prevalent noncommunicable chronic diseases in the pediatric population, and health-care professionals and researchers were seeking answers since the beginning of pandemic. Children are at lower risk of developing severe COVID-19 or dying from infection. Allergic diseases are not associated with a higher COVID-19 severity and mortality, apart from severe/poorly controlled asthma. The pandemic disrupted routine health care, but many mitigation strategies, including but not limited to telemedicine, were successfully implemented to continue delivery of high-standard care. Although children faced a multitude of pandemic-related issues, allergic conditions were effectively treated remotely while reduction in air pollution and lack of contact with outdoor allergens resulted in improvement, particularly respiratory allergies. There is no evidence to recommend substantial changes to usual management modalities of allergic conditions in children, including allergen immunotherapy and use of biologicals. Allergic children are not at greater risk of multisystem inflammatory syndrome development, but some associations with Long COVID were reported, although the data are limited, and further research is needed. This statement of the EAACI Section on Pediatrics provides recommendations based on the lessons learnt from the pandemic, as available evidence.

Allergic diseases and immunodeficiencies in children, lessons learnt from COVID‐19 pandemic by 2022: A statement from the EAACI‐section on pediatrics

By the April 12, 2022, the COVID‐19 pandemic had resulted in over half a billion people being infected worldwide. There have been 6.1 million deaths directly due to the infection, but the pandemic has had many more short‐ and long‐term pervasive effects on the physical and mental health of the population. Allergic diseases are among the most prevalent noncommunicable chronic diseases in the pediatric population, and health‐care professionals and researchers were seeking answers since the beginning of pandemic. Children are at lower risk of developing severe COVID‐19 or dying from infection. Allergic diseases are not associated with a higher COVID‐19 severity and mortality, apart from severe/poorly controlled asthma. The pandemic disrupted routine health care, but many mitigation strategies, including but not limited to telemedicine, were successfully implemented to continue delivery of high‐standard care. Although children faced a multitude of pandemic‐related issues, allergic conditions were effectively treated remotely while reduction in air pollution and lack of contact with outdoor allergens resulted in improvement, particularly respiratory allergies. There is no evidence to recommend substantial changes to usual management modalities of allergic conditions in children, including allergen immunotherapy and use of biologicals. Allergic children are not at greater risk of multisystem inflammatory syndrome development, but some associations with Long COVID were reported, although the data are limited, and further research is needed. This statement of the EAACI Section on Pediatrics provides recommendations based on the lessons learnt from the pandemic, as available evidence.

Early SARS-CoV-2 dynamics and immune responses in unvaccinated participants of an intensely sampled longitudinal surveillance study

Background A comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure. Methods An ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally. Nine study participants who developed COVID-19 between November, 2020 and March, 2021 were monitored at high temporal resolution for three months in terms of viral loads as well as associated inflammatory biomarker and antibody responses. CD8 + T cells targeting SARS-CoV-2 in blood samples from study participants were evaluated. Results Here we show that the resulting datasets, supported by Bayesian modeling, allowed the underlying kinetic processes to be described, yielding a number of unexpected findings. Early viral replication is rapid (median doubling time, 3.1 h), providing a narrow window between exposure and viral shedding, while the clearance phase is slow and heterogeneous. Host immune responses different widely across participants. Conclusions Results from our small study give a rare insight into the life-cycle of COVID-19 infection and hold a number of important biological, clinical, and public health implications. Plain language summary Managing the response to the COVID-19 pandemic requires information about how quickly the virus reproduces and the effect on the immune system of the person who is infected. We measured the speed at which SARS-CoV-2 reproduces in unvaccinated individuals at various timepoints between when they first became infected, and there was no longer any detectable virus present in their bodies. We also measured changes in their immune response. Our findings can be used to develop guidelines for the clinical management of COVID-19 patients and optimize testing procedures to determine whether people are infected with SARS-CoV-2. Gunawardana et al. monitor the viral load, inflammatory biomarkers and antibody response long-term in people who developed COVID-19. Early viral replication is rapid, providing a narrow window between exposure and viral shedding.

The Effects of Adding Pictorial Depth Cues to the Poggendorff Illusion.

We tested if the misapplication of perceptual constancy mechanisms might explain the perceived misalignment of the oblique lines in the Poggendorff illusion. Specifically, whether these mechanisms might treat the rectangle in the middle portion of the Poggendorff stimulus as an occluder in front of one long line appearing on either side, causing an apparent decrease in the rectangle's width and an apparent increase in the misalignment of the oblique lines. The study aimed to examine these possibilities by examining the effects of adding pictorial depth cues. In experiments 1 and 2, we presented a central rectangle composed of either large or small bricks to determine if this manipulation would change the perceived alignment of the oblique lines and the perceived width of the central rectangle, respectively. The experiments demonstrated no changes that would support a misapplication of perceptual constancy in driving the illusion, despite some evidence of perceptual size rescaling of the central rectangle. In experiment 3, we presented Poggendorff stimuli in front and at the back of a corridor background rich in texture and linear perspective depth cues to determine if adding these cues would affect the Poggendorff illusion. The central rectangle was physically large and small when presented in front and at the back of the corridor, respectively. The strength of the Poggendorff illusion varied as a function of the physical size of the central rectangle, and, contrary to our predictions, the addition of pictorial depth cues in both the central rectangle and the background decreased rather than increased the strength of the illusion. The implications of these results with regards to different theories are discussed. It could be the case that the illusion depends on both low-level and cognitive mechanisms and that deleterious effects occur on the former when the latter ascribes more certainty to the oblique lines being the same line receding into the distance.

The cannabinoid receptor-1 gene interacts with stressful life events to increase the risk for problematic alcohol use.

Problematic alcohol use is a major contributor to the global burden of death and disabilities, and it represents a public health concern that has grown substantially following the COVID-19 pandemic. The available treatment options remain limited and to develop better pharmacotherapies for alcohol misuse we need to identify suitable biological targets. Previous research has implicated the brain's endocannabinoid system (ECS) in psychiatric and stress-related outcomes, including substance use and habituation to repeated stress. Moreover, genetic variants in the cannabinoid-1 receptor gene (CNR1; CB1R) have been associated with personality traits, which are in turn predictors of substance use disorders. To date, however, no human genome-wide association study has provided evidence for an involvement of the ECS in substance use outcomes. One reason for this ECS-related "missing heritability" may be unexamined gene-environment interactions. To explore this possibility, we conducted cross-sectional analyses using DNA samples and stress-exposure data from a longitudinal Swedish population-based study (N = 2,915). Specifically, we genotyped rs2023239, a functional C/T single nucleotide polymorphism in CNR1, previously reported to be associated with CNR1 binding in the brain, subjective reward following alcohol intake, and alcohol cue-elicited brain activation. Our two outcomes of interest were (i) problematic alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), and (ii) personality trait scores based on the Five Factor Model. We found no baseline association between rs2023239 and problematic alcohol use or personality traits. However, there was a clear trend for interaction between rs2023239's risk allele (C) and stressful life events (SLEs) in both childhood and adulthood, which predicted problematic alcohol use. Although not significant, there was also some indication that the risk allele interacted with child SLEs to increase scores on neuroticism. Our study supports the notion that the ECS can affect alcohol intake behaviors by interacting with life adversities and is-to the best of our knowledge-the first to focus on the interaction between CNR1 and stressors in both childhood and adulthood in humans. Further studies are warranted to confirm these findings.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

Lupus anticoagulant positivity is not associated with venous thromboembolism or in-hospital mortality in COVID-19

Background : Antiphospholipid antibodies (APA) clinical relevance in COVID-19 is controversial. Aims : We aimed to investigate the prevalence and prognostic value of conventional and non-conventional APA in COVID-19 patients. Methods : This study was a multi-centric, prospective observational French cohort of patients hospitalized for COVID-19 suspicion. Results : 249 patients were hospitalized for suspected COVID-19, including 154 (61.8%) with confirmed COVID-19 and 95 (38.2%) not confirmed. We found a significant increase in lupus anticoagulant (LA) positivity among COVID-19 positive patients (60.9% versus 23.7% in non-COVID19 patients, P < 0.001), while prevalence of conventional (LA, IgG, IgM and IgA isotypes) and non-conventional APA (anti-phosphatidylserine/prothrombin IgG and IgM) were low in both groups. COVID-19 patients with LA positivity had higher levels of fibrinogen (6.0 g/L, IQR 5.0-7.0 versus 5.3 IQR 4.3-6.4, P = 0.028) and C-reactive protein (CRP, 115.5 IQR 66.0-204.8 versus 91.8 mg/L, IQR 27.0-155.1, P = 0.019). Univariate analysis did not show any association between LA positivity and higher risk of venous thromboembolism (VTE, OR 1.02, 95% CI 0.44-2.43, P = 0.95) or inhospital mortality (OR 1.80, 95% CI 0.70-5.05, P = 0.24). Unadjusted and adjusted (to CRP, age and sex) Kaplan-Meier survival curves according to LA positivity confirmed the absence of association with VTE or in-hospital mortality (unadjusted: P = 0.64 and P = 0.26, respectively;adjusted: hazard ratio = 1.13 95% CI 0.48-2.60 and 1.80 95% CI 0.67-5.01). Conclusions : COVID-19 patients have an increased prevalence of LA positivity associated with biological inflammation markers. However, positive LA at admission is not associated with VTE risk and/or inhospital mortality.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

Diabetes, Drug Treatment, and Mortality in COVID-19: A Multinational Retrospective Cohort Study.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57-0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54-0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52-0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35-0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74-0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28-0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

BACKGROUND: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.

Impact à long terme du COVID-19 chez les patients dialysés

Déclaration de liens d’intérêts: Les auteurs déclarent ne pas avoir de liens d’intérêts.

Protective Effects of Astodrimer Sodium 1% Nasal Spray Formulation against SARS-CoV-2 Nasal Challenge in K18-hACE2 Mice.

Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1ß, TNFα and TGFß and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents.

There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HtAEC) and human small airway epithelial cells (HsAEC) grown at the air-liquid interface (ALI). These cultures were infected at the apical side with one of two different SARS-CoV-2 isolates. Each virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35 °C than 37 °C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. Remdesivir, GS-441524 (the parent nucleoside of remdesivir), EIDD-1931 (the parent nucleoside of molnupiravir) and IFN (ß1 and λ1) all resulted in dose-dependent inhibition of viral RNA and infectious virus titers collected at the apical side. However, AT-511 (the free base form of AT-527 currently in clinical testing) failed to inhibit viral replication in these in vitro primary cell models. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.