Evidence That Severe Asthma Can Be Divided Pathologically into Two Inflammatory Subtypes with Distinct Physiologic and Clinical Characteristics

Abstract

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.

Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

“…ASM hyperplasia is one of the irreversible structural changes that occur in the airways of asthmatic patients (56). Thickening of the airway wall, partially from ASM hyperplasia, has a potential contribution toward irreversible airway obstruction in patients with severe asthma (57). In the present study, we demonstrated that activin A increased the number and DNA synthesis of HASMC.…”

Improving the diagnosis of eosinophilic asthma

“…Several methods are being used to identify airway eosinophilia in the airways including bronchial biopsies, induced sputum, blood, and exhaled breath. Traditionally, airway biopsies or bronchoalveolar lavage is considered as the gold standard for assessing airway inflammation [15] but this method is too invasive for routine clinical use. Therefore, there has been great interest in methods to assess airway inflammation noninvasively and in a convenient and inexpensive way.…”

“…Wenzel and colleagues first described this 'eosinophil high' severe asthma phenotype when performing bronchial biopsies and showed that it was associated with airway remodeling and risk of near-fatal asthma attacks [15]. Others showed that severe eosinophilic asthma is characterized by frequent exacerbations and often requires systemic corticosteroid treatment for control of the disease [14,16,17].…”

Allergen-dependent solubilization of IL-13 receptor α2 reveals a novel mechanism to regulate allergy

“…32,33 Normal controls had normal pulmonary function, if able to perform pulmonary function tests, and had no history of any respiratory illness. Normal patients were recruited from National Jewish and from Cincinnati Children's Hospital Medical Center bronchoalveolar lavage (BAL) specimen bank.…”

“…Normal patients were recruited from National Jewish and from Cincinnati Children's Hospital Medical Center bronchoalveolar lavage (BAL) specimen bank. Cell free lavage fluid was obtained as previously described 32,33 and stored at −70°C until analysis. BAL fluid was analyzed for human IL-13Rα2 by using the DuoSet kit from R&D Systems (Minneapolis, Minn) according to the manufacturer's instructions.…”