Comparison of Asthma Phenotypes in Severe Asthma Cohorts (SARP, U-BIOPRED, ProAR and COREA) From 4 Continents.

PURPOSE: Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively. METHODS: The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma. RESULTS: The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts. CONCLUSIONS: The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Alcohol and its metabolites dysregulate cellular bioenergetics and induce oxidative and endoplasmic reticulum stress in primary human bronchial epithelial cells.

BACKGROUND: Chronic alcohol consumption/misuse is a significant risk factor for pneumonia and lung infection leading to the development of chronic pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and lung fibrosis. In this study, we sought to delineate the mechanism of alcohol-associated lung disease. We did so by measuring in vitro mitochondrial, endoplasmic reticulum (ER) oxidative stress in human bronchial epithelial cells (hBECs) treated with ethanol and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters or FAEEs) metabolites. METHODS: Primary hBECs from a normal subject were treated with relevant concentrations of ethanol and its metabolites and incubated at 37°C for 24 h. Viability and cytotoxicity were determined using cell viability and lactate dehydrogenase (LDH) assay kits, respectively. Oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured by colorimetric reaction, and 4-hydroxynenonal (4HNE) by immunohistochemistry. Endoplasmic reticulum stress and dysregulated cellular bioenergetics were determined by western blot analysis. Mitochondrial stress and real-time ATP production rates were determined using a Seahorse Extracellular Flux analyzer. Amelioration of ethanol-induced oxidative/ER stress and mitochondrial energetics was determined using an AMPKα agonist. RESULTS: Human bronchial epithelial cells treated with ethanol, acetaldehyde, and FAEEs showed a concentration-dependent increase in the secretion of LDH, oxidative/ER stress, deactivation of AMPKα phosphorylation and mitochondrial stress (decreased spare respiratory capacity) with concomitant decreases in mitochondrial and glycolytic ATP production rates. FAEEs caused greater cytotoxicity, ER stress, and dysregulated cellular bioenergetics than those ethanol and its oxidative metabolite. AMPKα agonist-pretreated cells significantly ameliorated ethanol-induced oxidative/ER stress, deactivation of AMPKα, and dysregulated cellular bioenergetics. CONCLUSIONS: Findings of this study suggest that ethanol and its metabolites contribute to cytotoxicity, oxidative/ER stress, and dysregulation of cellular bioenergetics in hBECs. The attenuation of ethanol-induced ER/oxidative stress and mitochondrial respiration by an AMPKα agonist may reflect a potential for it to be developed as a therapeutic agent for chronic alcohol-associated lung disease.

Producción de interferón-gamma e interleuquina 4 por células mononucleadas de sangre periférica infectadas con virus respiratorio sincicial y adenovirus / Interferon-gamma and interleukin-4 production by respiratory synctytial virus and adenovirus infected peripheral blood mononuclear cells

Las infecciones respiratorias por virus respiratorio sincicial (VRS) y adenovirus (Ad) son la principal causa de morbimortalidad entre las infecciones respiratorias agudas bajas (RAB) de la infancia. Ambos virus pueden dejas secuelas, al VRS se le ha atribuido desencadenar obstrucción bronquial persistente y al Ad, especialmente el Ad7h, bronquectasias, fibrosis y daño pulmonar crónico. Los mecanismos por los que estos virus pueden producir estas secuelas no se conocen, pero hay evidencias que sugieren que ésta sea causada por un mecanismo inmunológico, dependiente del tipo de virus y de la respuesta del huésped. El objetivo de este trabajo fue determinar el tipo de respuesta inmune frente a la infección por VRS y Ad mediante la cuantificación de interferón-gamma (IFN-gamma) e interleuquina-4 (IL-4), citoquinas marcadas de respuesta inmune celular y humoral respectivamente. Las ILs fueron cuantificadas en el sobrenadante de cultivo de células mononucleadas de sangre periférica infectadas o no infectadas in vitro con VRS, Ad3, Ad7h y control con mitógeno (PHA) y de células mononucleadas de lactantes con infección natural por VRS y grupo control estimuladas o no con mitógenos (PHA y PWN). Los lactantes con IRAB por VRS presentaron una disminución significativa en la producción de IFN-gamma e IL-4 por células mononucleadas no estimuladas y estimuladas con PHA. Esta disminución fue mayor para el IFN-gamma que para la IL-4, por lo que la relación IFN eta/IL-4 fue menor en estos lactantes. La producción de IL-4 pero no la de IFN-eta de los lactantes infectados con VRS que tenían antecedentes de atopia (p< 0,02). Las células mononucleadas de niños sanos infectadas in vitro con Ad estimulan la producción de IFN-gamma pero no la de IL-4 y con Ad7h, responden con una producción de IFN-gamma en este modelo in vitro. Estos resultados sugieren que la respuesta del sistema inmune frente a la infección viral dependerá del tipo de virus infectante y de la variabilidad genética del individuo. Esto demuestra la importancia de estudiar la respuesta inmune de cada virus en los diferentes individuos ya que el resultado de protección o daño dependerá de la interrelación huésped-virus