Severe Asthma: An Expanding and Mounting Clinical Challenge

Abstract

Although all patients with asthma have variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness, some have disease that is severe in many aspects: persistent airflow obstruction, ongoing symptoms, increased frequency of exacerbations and most importantly, a diminished response to medications. A number of definitions have emerged to characterize the clinical features of severe asthma, but a central feature of this phenotype is the need for high doses of medications, especially corticosteroids, in attempts to achieve disease control. The prevalence of severe asthma is also undergoing reevaluation from the usual estimate of 10% to larger numbers based on medication needs and the lack of disease control achieved. At present, the underlying mechanisms of severe asthma are not established but likely reflect a heterogeneous pattern, rather than a single unifying process. Guideline-directed treatment for severe asthma has limits with usual approaches centered on high doses of inhaled corticosteroids, long-acting beta-agonists, and trials with omalizumab, the monoclonal antibody to IgE. With the development of approaches to recognize asthma phenotypes with distinct pathogenesis and hence unique therapeutic targets, it is hoped that a personalized strategy in treatment directed toward disease-specific features will improve outcomes for this high risk, severely affected population of patients.

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma

“…Even in low concentrations, BAL RANTES incites eosinophil attraction and has been shown to correlate with the proportion of BAL eosinophils (46). Our data demonstrate a reduction in both TGF-b 1 and RANTES in BAL fluid in the weeks after BT applied to a single lobe, which in turn correlated with a decrease in BAL eosinophil proportion throughout the time period of BT treatment. It is interesting in this context that eotaxin, another cytokine expressed by epithelial cells that can elicit eosinophil recruitment into airways, did not change significantly in the three measurements.…”

“…Asthma continues to be one of the most prevalent health conditions, affecting 25 million individuals in the United States and more than 200 million worldwide (1). Although only 10% of patients have severe, uncontrolled, persistent asthma, these patients account for an estimated 80% of the economic burden of healthcare costs attributed to this disease (2,3).…”

Allergy in severe asthma

“…A fundamental feature of severe asthma in both adults and children is its heterogeneity, with multiple clinical phenotypes (6,(45)(46)(47)(48)(49)(50). When unsupervised cluster analyses are performed, whether in adults or children, several common clinical features provide phenotypic distinctions, including the age of onset of disease, presence of comorbidities, differences in lung function and the degree of atopic sensitization (50)(51)(52).…”

Polyunsaturated Lysophosphatidic Acid As a Potential Asthma Biomarker

“…The biological effector functions of LPA are attributed to at least six G-protein coupled LPA receptors (LPA [1][2][3][4][5][6] ) with overlapping specificities and varying tissue distribution [22]. LPA receptors are expressed by lung epithelial and endothelial cells as well as infiltrating inflammatory cells including eosinophils, macrophages, neutrophils, T cells, mast cells and dendritic cells (DCs) [23][24][25][26][27].…”

“…Despite recent advances in understanding the molecular and pathophysiological basis of asthma, there is no cure for this disease; however availability of inhaled corticosteroids, short and long-acting β-agonists, and to some extent leukotriene C4 antagonists, has proven to be effective in managing the disorder [3,4]. Progress in developing new therapies against asthma has been slow due to heterogeneity of the disease and the existence of multiple phenotypes resulting from complex geneenvironment interactions [5].…”