Hereditary angioedema classification: Expanding knowledge by genotyping and endotyping.

Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym "H4AE" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification.

Exploring the impact of inflammatory endotypes on olfactory function and quality of life in chronic rhinosinusitis patients.

OBJECTIVES: The aim of this observational cross-sectional study was to determine the endotypic inflammatory pattern of a sample of patients with CRS in Brazil, correlate it with olfactory function, and evaluate the clinical severity of the disease. METHODS: In this cross-sectional study, 73 CRS patients were recruited. Patients were classified into type 2 and non-type 2 endotypic patterns based on IgE and eosinophilia levels. All subjects performed the University of Pennsylvania Smell Identification Test (UPSIT®) and responded to the Sino-Nasal Outcome Test (SNOT-22). RESULTS: The majority of patients had type 2 CRS (n=57, 78.1%). Patients with type 2 CRS compared to non-type 2 CRS had a higher prevalence of nasal polyps (93% vs. 12.5%), asthma (40.3% vs. 12.5%), and non-steroidal anti-inflammatory drug exacerbated respiratory disease (NERD, 17.5% vs. 0%). Type 2 patients also had significantly lower UPSIT® and higher SNOT-22, Lund-Kennedy, and Lund-Mackay scores. CONCLUSION: Our study provides evidence that type 2 CRS is associated with a higher prevalence of nasal polyps, asthma, and NERD, as well as decreased olfactory function and worse quality of life scores. These data will contribute to the body of knowledge on CRS and the development of treatments for this disease in Brazil.

Exploring the impact of inflammatory endotypes on olfactory function and quality of life in chronic rhinosinusitis patients

Abstract Objectives The aim of this observational cross-sectional study was to determine the endotypic inflammatory pattern of a sample of patients with CRS in Brazil, correlate it with olfactory function, and evaluate the clinical severity of the disease. Methods In this cross-sectional study, 73 CRS patients were recruited. Patients were classified into type 2 and non-type 2 endotypic patterns based on IgE and eosinophilia levels. All subjects performed the University of Pennsylvania Smell Identification Test (UPSIT®) and responded to the Sino-Nasal Outcome Test (SNOT-22). Results The majority of patients had type 2 CRS (n = 57, 78.1%). Patients with type 2 CRS compared to non-type 2 CRS had a higher prevalence of nasal polyps (93% vs. 12.5%), asthma (40.3% vs. 12.5%), and non-steroidal anti-inflammatory drug exacerbated respiratory disease (NERD, 17.5% vs. 0%). Type 2 patients also had significantly lower UPSIT® and higher SNOT-22, Lund-Kennedy, and Lund-Mackay scores. Conclusion Our study provides evidence that type 2 CRS is associated with a higher prevalence of nasal polyps, asthma, and NERD, as well as decreased olfactory function and worse quality of life scores. These data will contribute to the body of knowledge on CRS and the development of treatments for this disease in Brazil. Level of evidence: 3.

Beyond the Clinic: The Activation of Diverse Cellular and Humoral Factors Shapes the Immunological Status of Patients with Active Tuberculosis.

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), has killed nearly one billion people in the last two centuries. Nowadays, TB remains a major global health problem, ranking among the thirteen leading causes of death worldwide. Human TB infection spans different levels of stages: incipient, subclinical, latent and active TB, all of them with varying symptoms, microbiological characteristics, immune responses and pathologies profiles. After infection, Mtb interacts with diverse cells of both innate and adaptive immune compartments, playing a crucial role in the modulation and development of the pathology. Underlying TB clinical manifestations, individual immunological profiles can be identified in patients with active TB according to the strength of their immune responses to Mtb infection, defining diverse endotypes. Those different endotypes are regulated by a complex interaction of the patient's cellular metabolism, genetic background, epigenetics, and gene transcriptional regulation. Here, we review immunological categorizations of TB patients based on the activation of different cellular populations (both myeloid and lymphocytic subsets) and humoral mediators (such as cytokines and lipid mediators). The analysis of the participating factors that operate during active Mtb infection shaping the immunological status or immune endotypes of TB patients could contribute to the development of Host Directed Therapy.

[Phenotypes and endotypes of food allergy]. / Fenotipos y endotipos en alergia alimentaria.

Food allergy is a common event, especially in the pediatric population, affecting between 3-6% of children. There are various challenges in the care of patients with food allergy, but certainly the diversity of symptoms and the outcome of the disease are important aspects in the treatment of patients, in the development of care guidelines and in the knowledge of the Natural history of disease. The classification into phenotypes allows a better understanding of the evolution of food allergy. The endotype is a subtype of a phenotype defined by its pathophysiological characteristic. Genetic, epigenetic, and environmental characteristics interfere with the construction of the phenotype and its possible endotypes. Understanding the phenotypes and endotypes of food allergies brings with it two fundamental aspects: 1) the need to understand that the analysis of phenotypes and endotypes in food allergies will allow establishing prognoses and helping in intervention with specific therapies, and 2) the importance of understanding The characterization of local endotypes and phenotypes, and the dietary diversity of the different countries that make up Latin America brings with it a varied menu of foods that may pose a risk of allergy that needs to be studied.

La alergia alimentaria es un evento frecuente, especialmente en la población pediátrica, que afecta entre el 3-6% de los niños. Existen diversos desafíos en el cuidado de los pacientes con alergia alimentaria, pero ciertamente la diversidad de los síntomas y el desenlace de la enfermedad son aspectos importantes en el tratamiento de los pacientes, en la elaboración de las pautas de cuidado y en el conocimiento de la historia natural de la enfermedad. La clasificación en fenotipos permite una mejor comprensión de la evolución de la alergia alimentaria. El endotipo es un subtipo de un fenotipo definido por su característica fisiopatológica. Las características genéticas, epigenéticas y ambientales interfieren en la construcción del fenotipo y sus posibles endotipos. Entender los fenotipos y endotipos de las alergias alimentarias trae consigo dos aspectos fundamentales: 1) la necesidad de entender que el análisis de fenotipos y endotipos en alergia alimentaria permitirá establecer pronósticos y ayudar en la intervención con terapias específicas, y 2) la importancia de comprender la caracterización de los endotipos y fenotipos locales, y la diversidad alimentaria de los diferentes países que conforman América Latina trae consigo un variado menú de alimentos que puede suponer un riesgo de alergia que es necesario estudiar.

Valoración de la calidad de vida en pacientes con asma severa posterior al tratamiento con biológicos en el marco de la medicina personalizada

RESUMEN El asma severa incluye un pequeño porcentaje de pacientes que varía de acuerdo a los diferentes países, aun así, los pacientes con asma grave no controlada tienen una morbilidad desproporcionadamente alta junto a una utilización de la asistencia sanitaria. Objetivos: Evaluar la respuesta al tratamiento con biológicos en pacientes asmáticos severos y la importancia de realizar la clasificación de fenotipo y endotipo, en una muestra de pacientes asmáticos severos entre 18 y 60 años de ambos sexos que concurrieron al servicio de Alergia e Inmunología del Hospital Nuevo San Roque, Córdoba, Argentina en el periodo marzo 2016 y marzo 2019. Material y métodos: Se realizó análisis de historia clínica, determinación de IgE, eosinófilos, clasificación de asma según GINA, espirometría, pruebas cutáneas, Test de control de Asma (Asthma control Test) (ACT) y respuesta según Evaluación Global Efectividad Tratamiento por el médico (Global evaluation of treatment effectiveness) (GETE). Resultados: Un total de 12 pacientes asmáticos severos, con test cutáneos positivos (Prick test), valores de IgE y eosinófilos elevados. En los valores espirometricos de pos BD, se observaron diferencias en las tres etapas de seguimiento, los valores iniciales fueron de 50,1 ± 4,4, aumentando a 83,5 ± 4,4 a los 6 meses, y con resultados medios de 88,5 ± 4,15 a los 12 meses. Los valores de ACT fueron al inicio 10,17 ± 1,44, a los 6 meses 22,33 ± 0,68 y al año de 24,67 ± 0,14. Puntaje GETE a los 6 meses, la mayoría de los pacientes refirió tener GETE control completo del asma (42%) o mejor control del asma (33%), mientras que el profesional que los asistió no refirió haber observado ningún paciente con nivel excelente mientras que el 75% fueron clasificados como mejor control del asma. Conclusión: La evaluación inicial correcta del paciente asmático y el tratamiento de precisión adecuado son las herramientas que deben aplicarse para obtener no solamente la remisión de las manifestaciones clínicas si no también una amplia mejoría en su calidad de vida.

ABSTRACT BACKGROUND Severe asthma includes a small percentage of patients that varies across different countries, yet patients with uncontrolled severe asthma have disproportionately high morbidity and healthcare utilization. Objectives: To assess the response to treatment with biologics in severe asthmatic patients and the importance of performing the phenotype and endotype classification in a sample of severe asthmatic patients between 18 and 60 years of age of both sexes who attended the Allergy and Immunology service of the Nuevo Hospital San Roque, Córdoba, Argentina from March 2016 to March 2019. Material and methods :Analysis of: medical history, measurement of laboratory parameters: IgE, eosinophils, asthma classification according to GINA, spirometry, skin tests, Asthma control Test (ACT) and response according to Global evaluation of treatment effectiveness (Global Evaluation Effectiveness Treatment by the doctor). Results: A total of 12 severe asthmatic patients, with positive Prick tests, elevated IgE and eosinophil values. Regarding spirometry: in the post BD values, differences were observed in the three stages of follow-up: the initial spirometry values were 50.1 ± 4.4, increasing to 83.5 ± 4.4 at 6 months, and with mean results of 88.5 ± 4.15 at 12 months. The ACT values were at baseline 10.17 ± 1.44, at 6 months 22.33 ± 0.68 and at one year: 24.67 ± 0.14. GETE score At 6 months, most of the GETE patients reported having complete asthma control (42%) or better asthma control (33%), while the professional who assisted them did not report having observed any patient with an excellent level; and 75% were classified as better asthma control. Conclusion: The correct initial evaluation of the asthmatic patient and the appropriate precision treatment are the tools that must be applied to obtain not only the remission of the clinical manifestations but also a broad improvement in their quality of life.

[Asthma: endotypes and phenotypes at a pediatric age]. / Asma: endotipos y fenotipos en la edad pediátrica.

The concepts of endotype and phenotype have been introduced in the past few years with the purpose of identifying the different variants of asthma in children and adults by the interaction of epigenetic factors, such as genotype, environmental factors, and not inherited factors. All these factors participate in the onset and progression of asthma, as well as environmental allergens, which are the cause of asthma in most children and teenagers. The latest onset may be induced by the characteristics of the environment, as happens in most adults (occupational asthma). In a review of a hundred medical records of children with and without a family history, and of a group of patients in whom high IgE levels were not detected, clear differences were observed in terms of the age of onset and other characteristics, although the sensitization to allergens was very similar in those three groups (Dermatophagoides mites).

Los términos endotipo y fenotipo se han introducido en los últimos años con la finalidad de identificar las diferentes variantes del asma, tanto en los niños como en los adultos, por la interacción de los factores epigenéticos, como el genotipo, los factores ambientales y los no heredados. Todos estos factores participan en el inicio y progresión del asma, así como los alérgenos ambientales, causantes del asma en la mayoría de los niños y adolescentes. El inicio más tardío de la enfermedad puede estar inducido por las características del ambiente, como ocurre en la mayoría de los adultos (asma ocupacional). En una revisión de un centenar de historias clínicas de niños, unos con antecedentes familiares, otros sin ellos y un grupo más pequeño de 10 pacientes en el que no se detectaron cifras de IgE elevadas, se observaron diferencias evidentes en cuanto a la edad de inicio y otras características, aunque la sensibilización a alérgenos fue muy similar en los tres grupos (a Dermatophagoides).

Reslizumab in the treatment of inadequately controlled asthma in adults and adolescents with elevated blood eosinophils: clinical trial evidence and future prospects.

Eosinophils have long been implicated as playing a central role in the pathophysiology of asthma in many patients, and eosinophilic asthma is now recognized as an important asthma endotype. Eosinophil differentiation, maturation, migration, and survival are primarily under the control of interleukin-5 (IL-5). Reslizumab is a humanized monoclonal (immunoglobulin G4/κ) antibody that binds with high affinity to circulating human IL-5 and downregulates the IL-5 signaling pathway, potentially disrupting the maturation and survival of eosinophils. In 2016, an intravenous formulation of reslizumab was approved in the USA, Canada, and Europe as add-on maintenance treatment for patients aged ⩾18 years with severe asthma and with an eosinophilic phenotype. The efficacy of reslizumab as add-on intravenous therapy has been reported in several phase III studies in patients with inadequately controlled moderate-to-severe asthma and elevated blood eosinophil counts (⩾400 cells/µl). Compared with placebo, reslizumab was associated with significant improvements in clinical exacerbation rate, forced expiratory volume in 1 s, asthma symptoms and quality of life, and significant reductions in blood eosinophil counts. Reslizumab also demonstrated a favorable tolerability profile similar to that of placebo, with reported adverse events being mostly mild to moderate in severity. Ongoing studies are focusing on the evaluation of a subcutaneous formulation of reslizumab in patients with asthma and elevated eosinophil levels. This review discusses the preclinical and clinical trial data available on reslizumab, potential opportunities for predicting an early response to reslizumab, and future directions in the field of anti-IL-5 antibody therapy.

Impact of cigarette smoking on the middle meatus microbiome in health and chronic rhinosinusitis.

BACKGROUND: Although cigarette smoking aggravates chronic rhinosinusitis (CRS), a detailed examination of the sinus microbiota in CRS and its clinical subtypes has yet to be performed in relation to history of smoking. Consequently, we examined associations between smoking history and sinonasal microbiome alterations in both CRS and non-CRS populations. METHODS: Middle meatus swabs collected during endoscopic sinus surgery were analyzed by analysis of 16S ribosomal RNA (rRNA) sequences. Multiple analysis of variance tests were performed to determine whether microbiome composition varied with smoking history and other clinical/demographic covariates associated with CRS subtypes. RESULTS: A total 70 CRS patients and 31 control subjects were analyzed. In a univariate analysis, smoking (p = 0.04), preoperative antibiotics (p = 0.03), and purulence (p = 0.0002) were significantly associated with the genus-level composition of the middle meatus microbiota. When included in a multivariable model, smoking was found to have significant interactions with CRS (p = 0.02), polyposis (p = 0.03), purulence (p = 0.0004), and use of saline rinses (p = 0.05). Diverse bacterial taxa differed significantly in abundance between never-smokers and current/former smokers, as well as between different CRS subtypes. CONCLUSION: Substantial changes in sinus bacterial colonization were observed in smokers and nonsmokers. Although the microbiota of both CRS and non-CRS subjects were altered with smoking history, different bacterial taxa were affected by smoking in the 2 patient groups. Thus, the effects of smoking on the sinus microbiota are likely to be modified by physiological and immunological functions of the underlying sinus mucosa.