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

Immune modulation mediated by preformed antigen-antibody complexes : its application to human immediate hypersensitivity diseases

Delving through the literature on antigen-antibody complexes, one cannot help being astonished by the steadily increasing number of papers written on this subject over the last thirty years. Although this no doubt reflects the fundamental scientific interest if the subject matter, it may also be indicative of its intrinsic complexity. A great variety of antigen-antibody complexes have been studied through the years and they have been found to exert widely disparate – or even contradictory – effects on the immune system. Complexes have been used both to enhance or suppress an immune response, and so it was recognized early on that they could represent a powerful means of influencing the immune system. The interplay of numerous parameters determines the ultimate outcome on the immune system; the antigen to antibody ratio, the isotype of the antibody, the capacity to activate complement and the source of antibody – be it isologous or heterolous – are but a few of the factors capable of influencing profoundly the handling of complexes by the host. Several reviews have appeared in this subject, but there are so many variables involved that they tend other to focus on narrow aspects of the subjects (e.g., introduction of rheumatoid factor) or to remain at a general theoretical level. None of these reviews deal, event in a pragmatic fashion, with the practical application of antigen-antibody complexes, i.e., the potential of using complexes for therapeutic purposes. I venture to hope that this thesis may go some way to fill this void. During the last few years we have studied the use of antigen-antibody complexes for the treatment of human diseases that are characterized by an “inappropriate” production of antibodies. In this context, I mean by inappropriate the production of antibodies that is deemed to have a direct detrimental effect on the organism that produces them. For reasons which will be gone into a fully later, the first system my coworkers and I decided to investigate is that of the IgE antibody immune response of atopic individuals towards antigens present in an airborne form in the environment, and so most f this thesis will deal with the use of antigen-antibody complexes in the treatment of human immediate hypersensitivity to allergens. I will focus on the results and experience gathered in our laboratory, first on the analysis of the immune response to allergens and then on the actual utilization of performed antigen-antibody complexes in immediate hypersensitivity. The experimental work that led us to clinical application will be outlined followed by the description of the clinical experience gained so far in human immediate hypersensitivityThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199

Suppression de la réponse immunitaire IgE à l'aide d'anticorps spécifiques

Complexes formed by antibodies and antigens have a considerable potential in terms of influencing immune response. Applied to allergy, these complexes have been used to reduce the production of specific IgE antibodies to certain allergens. Thus approximately 400 patients with either asthma or atopic dermatitis have been treated up to now by the injection of such complexes formed using their own antibodies. Such treatment has proved to be free of any adverse reactions and effective in the treatment of both these types of disorder, with a significant reduction in their inflammatory component. Biologically, the injection of these complexes results in a selective reduction in the production of antibodies specific to the allergen concerned, both IgG and IgE, and an increase in the production of corresponding anti-idiotype antibodies. The recently demonstrated efficacy of complexes formed of F (ab')2 antibody fragments has opened up the possibility of treatment in which antibodies are prepared from a pool of donors. The reduction of specific antibodies justifies envisaging the application of the same treatment concept to certain auto-immune diseases, e.g. myasthenia gravis

MHC Class II-Restricted Epitopes Containing an Oxidoreductase Activity Prompt CD4(+) T Cells with Apoptosis-Inducing Properties.

Abrogating an unwanted immune response toward a specific antigen without compromising the entire immune system is a hoped-for goal in immunotherapy. Instead of manipulating dendritic cells and suppressive regulatory T cells, depleting effector T cells or blocking their co-stimulatory pathways, we describe a method to specifically inhibit the presentation of an antigen eliciting an unwanted immune reaction. Inclusion of an oxidoreductase motif within the flanking residues of MHC class II epitopes polarizes CD4(+) T cells to cytolytic cells capable of inducing apoptosis in antigen presenting cells (APCs) displaying cognate peptides through MHC class II molecules. This novel function results from an increased synapse formation between both cells. Moreover, these cells eliminate by apoptosis bystander CD4(+) T cells activated at the surface of the APC. We hypothesize that they would thereby block the recruitment of cells of alternative specificity for the same autoantigen or cells specific for another antigen associated with the pathology, providing a system by which response against multiple antigens linked with the same disease can be suppressed. These findings open the way toward a novel form of antigen-specific immunosuppression