Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

SARS-CoV-2 infection rapidly elicits anti-Spike antibodies whose quantity in plasma gradually declines upon resolution of symptoms. This decline is part of the evolution of an immune response leading to B cell differentiation into short-lived antibody-secreting cells or resting memory B cells. At the same time, the ongoing class switch and antibody maturation processes occurring in germinal centers lead to the selection of B cell clones secreting antibodies with higher affinity for their cognate antigen, thereby improving their functional activity. To determine whether the decline in SARS-CoV-2 antibodies is paralleled with an increase in avidity of the anti-viral antibodies produced, we developed a simple assay to measure the avidity of anti-receptor binding domain (RBD) IgG elicited by SARS-CoV-2 infection. We longitudinally followed a cohort of 29 convalescent donors with blood samples collected between 6- and 32-weeks post-symptoms onset. We observed that, while the level of antibodies declines over time, the anti-RBD avidity progressively increases and correlates with the B cell class switch. Additionally, we observed that anti-RBD avidity increased similarly after SARS-CoV-2 mRNA vaccination and after SARS-CoV-2 infection. Our results suggest that anti-RBD IgG avidity determination could be a surrogate assay for antibody affinity maturation and, thus, suitable for studying humoral responses elicited by natural infection and/or vaccination

Humoral Responses Elicited after a Fifth Dose of SARS-CoV-2 mRNA Bivalent Vaccine

While an important part of the world’s population is vaccinated against SARS-CoV-2, new variants continue to emerge. We observe that even after a fifth dose of the mRNA bivalent vaccine, most vaccinated individuals have antibodies that poorly neutralize several Omicron subvariants, including BQ.1.1, XBB, XBB.1.5, FD.1.1, and CH.1.1. However, Fc-effector functions remain strong and stable over time against new variants, which may partially explain why vaccines continue to be effective. We also observe that donors who have been recently infected have stronger antibody functional activities, including neutralization and Fc-effector functions, supporting the observations that hybrid immunity leads to better humoral responses

Presence of the Fungus B. dendrobatidis, but not B. salamandrivorans, in Wild Pyrenean Brook Newts (Calotriton asper) in Spain and France

International audienceIn the last 20 years, the emergence of chytridiomycosis due to the chytrid fungi Batrachochytrium dendrobatidis (Bd), and the more recently described Batrachochytrium salamandrivorans (Bsal), has caused severe amphibian population regressions across the planet (Bosch et al. 2001; Spitzen-van der Sluijs et al. 2016; Scheele et al. 2019). This has generated an increase in scientific interest to decipher the complex interaction between the environment, the fungus and amphibian hosts, and increased surveillance efforts in many localities (Canessa et al. 2020). Batrachochytrium spp. affect the vital function of the amphibian skin, leading to lethargy or skin discoloration, hyperkeratosis, erosions (even ulcerations in Bsal) of the epidermis, and eventually death (Berger et al. 1998; Weldon et al. 2004; Stuart et al. 2004; Wake and Vredenburg 2010; Martel et al. 2013). Bd is currently found on all continents where amphibians are present (Skerratt et al. 2007), affecting more than 700 species within the three orders of amphibians and has been considered a major threat to amphibian biodiversity worldwide (Crawford et al. 2010; Fisher et al. 2012; Olson et al. 2013; Olson and Ronnenberg 2014)

Presence of the Fungus Batrachochytrium dendrobatidis, but not Batrachochytrium salamandrivorans, in Wild Pyrenean Brook Newts (Calotriton asper) in Spain and France

Este artículo contiene 6 páginas, 12 tabla, 2 figuras.This work was supported by the French Laboratory of Excellence project TULIP (ANR-10-LABX-41; ANR-11-IDEX-0002-02) by the INTERREG POCTEFA ECTOPYR (no. EFA031/15) and by the LIFE+ LIMNOPIRINEUS (LIFE13 NAT/ ES1210) projects.Peer reviewe

Presence of the Fungus B. dendrobatidis, but not B. salamandrivorans, in Wild Pyrenean Brook Newts (Calotriton asper) in Spain and France

International audienceIn the last 20 years, the emergence of chytridiomycosis due to the chytrid fungi Batrachochytrium dendrobatidis (Bd), and the more recently described Batrachochytrium salamandrivorans (Bsal), has caused severe amphibian population regressions across the planet (Bosch et al. 2001; Spitzen-van der Sluijs et al. 2016; Scheele et al. 2019). This has generated an increase in scientific interest to decipher the complex interaction between the environment, the fungus and amphibian hosts, and increased surveillance efforts in many localities (Canessa et al. 2020). Batrachochytrium spp. affect the vital function of the amphibian skin, leading to lethargy or skin discoloration, hyperkeratosis, erosions (even ulcerations in Bsal) of the epidermis, and eventually death (Berger et al. 1998; Weldon et al. 2004; Stuart et al. 2004; Wake and Vredenburg 2010; Martel et al. 2013). Bd is currently found on all continents where amphibians are present (Skerratt et al. 2007), affecting more than 700 species within the three orders of amphibians and has been considered a major threat to amphibian biodiversity worldwide (Crawford et al. 2010; Fisher et al. 2012; Olson et al. 2013; Olson and Ronnenberg 2014)