Fenotipos y endotipos de asma grave: mecanismos moleculares implicados en la patogénesis y en la desensibilización a aspirina

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 19-09-201

Current and Future Asthma Treatments: Phenotypical Approach on the Path to Personalized Medicine in Asthma

Despite widely available and effective treatments, achieving asthma control is still an unmet need for many patients. One of the explanations resides perhaps in the heterogeneity of the disease. Asthma is in fact, as we understand it today, a complex syndrome made up of numerous disease variants or asthma phenotypes; when the different underlying mechanisms are identified, the more ambitious term “endotype” is used, with consequent therapeutic implications. Remarkable efforts have been made to identify the features of difficult-to-control (usually severe) asthma, which are different from those described for mild-to-moderate asthma, setting the stage for the development of new and even individualized therapies. As different drugs target different pathways, it is necessary to determine the individual profile of pathophysiological abnormalities for each patient. The most fascinating options of the new asthma treatments are the monoclonal antibodies targeted against key inflammatory cytokines, and the most proximately available treatments within the next years are discussed here. Also, current evidence and understanding of somehow older therapeutic options, such as anticholinergics, thermoplasty, or omalizumab, are reviewed from a phenotypical approach

Bradykinin-Mediated Angioedema Across the History

The origins of the discovery of the “Complement System” date from the second half of the nineteenth century. The official paternity of the Complement System is attributed to Jules Bordet. The complement system can be activated through three major pathways. The classical pathway, the alternative pathway, and the lectin pathway converge in a common final lytic pathway. Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) was first described by Robert Graves in his clinical lectures. The autosomal dominant pattern of HAE was recognized by Sir William Osler. The pathophysiologic basis of C1-INH-HAE as a deficiency of a plasma inhibitor was discovered in the early 1960s. In 1986, the C1NH gene was identified, which encodes the C1-INH protein. Although the possible relationship between angioedema and estrogens in women was described as early as 1986, it was not until the first decade of the twenty-first century when several series of patients with HAE were described with normal levels of the fractions of the complement system. In the last decade, several drugs have been approved and marketed in Europe, in the United States, and in other countries, contributing to the improved management of C1-INH-HAE and patient’s quality of life

How reliably can algorithms identify eosinophilic asthma phenotypes using non-invasive biomarkers?

Asthma is a heterogeneous respiratory disease that encompasses different inflammatory and functional endophenotypes. Many non-invasive biomarkers has been investigated to its pathobiology. Heany et al proposed a clinical algorithm that classifies severe asthmatic patients into likely-eosinophilic phenotypes, based on accessible biomarkers: PBE, current treatment, FeNO, presence of nasal polyps (NP) and age of onset.We assessed the concordance between the algorithm proposed by Heany et al. with sputum examination, the gold standard, in 145 asthmatic patients of the MEGA cohort with varying grades of severity.No correlation was found between both classifications 0.025 (CI = 0.013-0.037). Moreover, no relationship was found between sputum eosinophilia and peripheral blood eosinophilia count in the total studied population.In conclusion, our results suggest that grouping the biomarkers proposed by Heany et al. are insufficient to diagnose eosinophilic phenotypes in asthmatic patients. Sputum analysis remains the gold standard to assess airway inflammation.© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity