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

Asthma-COPD Overlap Syndrome (ACOS): Current Understanding and Future Perspectives

This chapter resumes our current understanding of asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), pretending to offer a comprehensive approach for the practicing physician, and provides some future perspectives on this entity

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

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

Sensitization profiles to purified plant food allergens among pediatric patients with allergy to banana.

Banana fruit allergy is well known, but neither immunoglobulin E recognition patterns to purified plant food allergens nor true prevalences of putative banana allergens have been established. This study aimed to characterize β-1,3-glucanase and thaumatin-like protein (TLP) as banana allergens, testing them, together with other plant food allergens, in 51 children with allergic reactions after banana ingestion and both positive specific IgE and skin prick test (SPT) to banana. Banana β-1,3-glucanase and TLP were isolated and characterized. Both banana allergens, together with kiwifruit TLP Act d 2, avocado class I chitinase Pers a 1, palm pollen profilin Pho d 2 and peach fruit lipid transfer protein (LTP) Pru p 3, were tested by in vitro and in vivo assays. Banana β-1,3-glucanase (Mus a 5) was glycosylated, whereas banana TLP (Mus a 4) was not, in contrast with its homologous kiwi allergen Act d 2. Specific IgE to both banana allergens, as well as to peach Pru p 3, was found in over 70% of sera from banana-allergic children, and Mus a 4 and Pru p 3 provoked positive SPT responses in 6 of the 12 tested patients, whereas Mus a 5 in only one of them. Both peptidic epitopes and cross-reactive carbohydrate determinants were involved in the IgE-binding to Mus a 5, whereas cross-reactivity between Mus a 4 and Act d 2 was only based on common IgE protein epitopes. Profilin Pho d 2 elicited a relevant proportion of positive responses on in vitro (41%) and in vivo (58%) tests. Therefore, Mus a 4 and LTP behave as major banana allergens in the study population, and profilin seems to be also a relevant allergen. Mus a 5 is an equivocal allergenic protein, showing high IgE-binding to its attached complex glycan, and low in vivo potency

Asthma, obesity and diet

El asma y la obesidad son dos trastornos de gran impacto en la salud pública que han aumentado su prevalencia en los últimos años. Numerosos estudios han relacionado ambas entidades. La mayoría de los estudios prospectivos demuestran que la obesidad es un factor de riesgo para el diagnóstico “de novo” de asma. Además, los resultados de diversos estudios sugieren que así como la ganancia de peso aumenta el riesgo de asma, la pérdida mejora su evolución. En general, los estudios prospectivos encuentran una asociación positiva entre el índice de masa corporal (IMC) basal y el posterior desarrollo de asma, lo que sugiere que es el exceso de peso el que podría favorecer el desarrollo de asma, aunque estos resultados no son tan concluyentes cuando se estudia la asociación entre hiperreactividad bronquial con el IMC. Existen distintos factores que podrían explicar esta asociación. La obesidad es capaz de reducir la compliance pulmonar, los volúmenes pulmonares y el diámetro de de las vías respiratorias periféricas, así como alterar los volúmenes sanguíneos pulmonares y la relación ventilación- perfusión. Además, el aumento del funcionamiento normal del tejido adiposo en sujetos obesos conduce a un estado proinflamatorio sistémico, que produce un aumento de las concentraciones séricas de numerosas citoquinas, fracciones solubles de sus receptores y quimiocinas. Muchos de estos mediadores son sintetizados y secretados por células del tejido adiposo y reciben el nombre genérico de adipocinas, entre las que se incluyen IL-6, IL-10, eotaxina, TNF- , TGF- 1, PCR, leptina y adiponectina. Por último, se han identificado regiones específicas del genoma humano que están relacionadas tanto con el asma como con la obesidad. La mayoría de los estudios apuntan a que la obesidad es capaz de aumentar la prevalencia y la incidencia de asma, aunque este efecto parece ser moderado. El tratamiento de los asmáticos obesos debe incluir un programa de control de peso.Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous studies have linked both disorders. Most prospective studies show that obesity is a risk factor for asthma and have found a positive correlation between baseline body mass index (BMI) and the subsequent development of asthma, although these results are not conclusive when studying the association between airway hyperresponsiveness with BMI. Furthermore, several studies suggest that whereas weight gain increases the risk of asthma, weight loss improves the course of the illness. Different factors could explain this association. Obesity is capable of reducing pulmonary compliance, lung volumes and the diameter of peripheral respiratory airways as well as affecting the volume of blood in the lungs and the ventilation-perfusion relationship. Furthermore, the increase in the normal functioning of adipose tissue in obese subjects leads to a systemic proinflammatory state, which produces a rise in the serum concentrations of several cytokines, the soluble fractions of their receptors and chemokines. Many of these mediators are synthesized and secreted by cells from adipose tissue and receive the generic name of adipokines, including IL-6, IL-10, eotaxin, TNF- , TGF- 1, PCR, leptin y adiponectin. Finally, specific regions of the human genome which are related to both asthma and obesity have been identified. Most studies point out that obesity is capable of increasing the prevalence and incidence of asthma, although this effect appears to be modest. The treatment of obese asthmatics must include a weight control progra

Differences in Inflammatory Cytokine Profile in Obesity-Associated Asthma: Effects of Weight Loss

Obesity and asthma are associated with systemic inflammation maintained by mediators released by adipose tissue and lung. This study investigated the inflammatory serum mediator profile in obese subjects (O) (n = 35), non-obese asthma (NOA) patients (n = 14), obese asthmatics (OA) (n = 21) and healthy controls (HC) (n = 33). The effect of weight loss after bariatric surgery (BS) was examined in 10 OA and 31 O subjects. We analyzed serum markers including leptin, adiponectin, TGF-?1, TNFR2, MCP-1, ezrin, YKL-40, ST2, IL-5, IL-9, and IL-18. Compared with HC subjects, the O group showed increased levels of leptin, TGF-?1, TNFR2, MCP-1, ezrin, YKL-40, and ST2; the OA group presented increased levels of MCP-1, ezrin, YKL-40, and IL-18, and the NOA group had increased levels of ezrin, YKL-40, IL-5, and IL-18. The higher adiponectin/leptin ratio in NOA with respect to OA subjects was the only significant difference between the two groups. IL-9 was the only cytokine with significantly higher levels in OA with respect to O subjects. TNFR2, ezrin, MCP-1, and IL-18 concentrations significantly decreased in O subjects after BS. O, OA, and NOA showed distinct patterns of systemic inflammation. Leptin and adiponectin are regulated in asthma by obesity-dependent and-independent mechanisms. Combination of asthma and obesity does not result in significant additive effects on circulating cytokine levels. © 2022 by the authors. Licensee MDPI, Basel, Switzerland