Interplay between Inhaled Ibuprofenate, SARS-CoV-2, Vasoplegic Pulmonary Vascular Dysfunction, Pneumonia and CARDS

In this manuscript, we will describe the possible mechanisms of action of inhaled sodium ibuprofenate in hypertonic saline formulation-NaIHS, focusing primarily on vasoplegic pulmonary vascular dysfunction leading to severe pneumonia and Coronavirus Disease 2019-associated acute respiratory distress syndrome. We will address the anti-inflammatory, immunomodulatory and antiangiogenic therapeutic effects of NaIHS, which together would exert their action through the negative modulation of local inflammatory mediators, pro-inflammatory cytokines and inflammatory pathways. In such a manner, NaIHS may reverse pulmonary vasoplegia and may thereby restore hypoxic pulmonary vasoconstriction, correcting the uncoupling of the ventilation-perfusion ratio and vasoplegic intrapulmonary shunting and, above all, it may reverse severe hypoxaemia. We will also describe the potential virucidal effects of NaIHS on Severe Acute Respiratory Syndrome-Coronavirus 2. Likewise, we will mention the evidence obtained from the potential adjuvant treatment with NaIHS in two observational cohort studies done in Argentina, the most recent of them with 5146 patients, concluding that NaIHS reduces mortality by 48.7%, although randomised clinical trials are still needed to confirm these data

Repurposing Inhaled Ibuprofenate, a Non Steroidal Anti‐Inflammatory Drug, as a Potential Adjuvant Treatment for Pneumonia, CARDS and its Aetiological Agent SARS‐CoV‐2

Abstract In this manuscript, we will describe and highlight the most important potential underlying mechanisms of action of the inhaled sodium ibuprofenate in hypertonic saline formulation‐NaIHS aerosolisable, as a probable adjuvant treatment for moderate and severe pneumonia and coronavirus disease 2019 (COVID‐19)‐associated acute respiratory distress syndrome in COVID‐19. In both pathological entities, we will refer exclusively to the pulmonary vasoplegic type and we will describe the following therapeutic effects of NaIHS: anti‐inflammatory, immunomodulatory and antiangiogenic. The synergistic action of these therapeutic effects anti‐inflammatory and immunomodulatory together may exert their action at the pulmonary level through the possible reversal of pulmonary vasoplegia and may thereby restore hypoxic pulmonary vasoconstriction, correcting the uncoupling of the ventilation/perfusion ratio and vasoplegic intrapulmonary shunting and, above all, it may reverse severe hypoxaemia and acute respiratory failure. We will also mention the potential virucidal effects of NaIHS on severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). There are available three retrospective observational studies in moderate and severe COVID‐19 pneumonia, carried out in Argentina, with all three studies concluding that there was a significant reduction in mortality. The most important of these was conducted with the approval of the Institutional Review Board of the National Bureau of Economic Research of Harvard and Columbia Universities, which analysed data from 5146 patients and concluded that NaIHS reduced mortality by 48.7%, although randomized clinical trials are still needed to confirm these emerging data and enable the rise of NaIHS as a new adjuvant treatment. Conclusively, we deem essential to reuse known drugs, such as ibuprofen, in COVID‐19, due to the constant emergence of variants and subvariants of concern secondary to mutations and immune escape mechanisms of (SARS‐CoV‐2), since effective medical treatments are currently scarce and many of them are controversial or not available worldwide

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 μg (RSV subgroups A and B, 60 μg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).publishedVersionPeer reviewe

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile