Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma.

Institute for Lung Health, Glenfield Hospital, Leicester LE3 9QP, UK.
Thorax (Impact Factor: 8.56). 01/2008; 62(12):1043-9. DOI: 10.1136/thx.2006.073429
Source: PubMed

ABSTRACT Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo-controlled studies examining the effect of inhaled corticosteroids.
Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non-eosinophilic asthma and 10 healthy controls. The patients with non-eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double-blind, placebo-controlled crossover study in which the effects of inhaled mometasone 400 microg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated.
Patients with non-eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm(2) vs 23 cells/mm(2) in eosinophilic asthma and 0 cells/mm(2) in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 microm vs 10.3 microm in eosinophilic asthma and 5.1 microm in controls, p = 0.002). Non-eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm(2), p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC(20) (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008).
Non-eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short-term response to treatment with inhaled corticosteroids.

Download full-text


Available from: Dominick Shaw, Jan 29, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of the present study was to rate the level of spread of asthma-induced bronchial morphological changes on chest X-ray (CXR), using the modified Shwachman–Kulczycki (S–K) rating scale as predicted by the dynamic of blood cell count (CBC). A sample of 40 asthma patients’ records was classified into 4 groups based on their clinical presentations and frequency of their visits to the hospital; Group-1 ⩽2 visits per week with reversible symptoms, Group-2 ⩾2 visits per week with irreversible symptoms, Group-3: ⩾3–4 visits per week with irreversible symptoms; Group-4: patients with severe shortness of breath in whom SaO2 was threatening, hence were admitted as inpatients. Patients’ CXR were scored based on the modified Shwachman–Kulczycki (S–K) scale rating. Blood analysis showed that RBC and their indices (HCT, HGB, MCH, RDW) were highest in group-2. White blood cells and their derivatives (NEU, EOS and LYM) were highest in group 4. CXR for group-2 showed bilateral increased bronchovascular markings but normal both lung fields and ruled out for costo-phrenic angles type of fever. Chest X-ray for group-3 showed hyperinflation, perihilar marking associated with bronchial thickening and unfolding aorta. In patients in group-4 development of broncho-pneumonic infiltration type of SOB and some evidence of bronchial edema with significant (p < 0.05) elevation in WBC were observed. The regression of S–K score on the dynamic of some CBC parameters was significant (p < 0.05). The best subsets that describe the model were:
    02/2015; 354(2). DOI:10.1016/j.ejcdt.2014.11.012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intérêt de la mesure de l'inflammation en clinique dans l'asthme F. Schleich, R. Louis L'évaluation de la composante inflammatoire chez le patient asthmatique par l'analyse de l'expectoration induite, la mesure du monoxyde d'azote dans l'air exhalé (FE NO) ou des condensats d'air exhalé est une étape importante de la caractérisation phénotypique de la maladie. La mesure de l'inflammation éosinophilique des voies aériennes de l'asthmatique a un intérêt clinique majeur car elle permet de prédire une réponse favorable aux corticostéroïdes inhalés et peut ainsi guider le traitement. Dans cette synthèse, nous présenterons les différentes techniques d'objectivation d'une inflammation corticosensible, leurs méthodologies, l'interprétation à donner à leurs résultats et leurs intérêts en pratique clinique.
    Edited by Encyclopédie Médico-chirurgicale EMC Pneumologie, 07/2012;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is a chronic disease characterised by variable airflow obstruction, bronchial hyperresponsiveness and airways inflammation. At an immunological level Th2 inflammation and the presence of activated eosinophils and mast cells are key features of asthma. ST2, the receptor for the novel cytokine IL-33, is expressed upon Th2 lymphocytes and mast cells but its role in clinical and experimental asthma remains unclear. IL-33 has been shown to induce local and systemic eosinophilia when administered to the peritoneum of mice. In this thesis I have set out to test the hypothesis that the activation of mast cells by IL-33 acting on cell surface ST2 plays a critical role in allergic airways inflammation. I began by studying the function of ST2 on mast cells in vitro. I found that ST2 was expressed at an early stage of development, and correlated closely with the expression of the stem cell factor receptor (c-kit), a marker present on mast cells from a progenitor stage. Despite this mast cells generated form ST2 gene deleted mice proliferated and matured normally. When mast cells were activated by IL-33, acting in an ST2-dependent manner, pro-inflammatory cytokines and chemokines were released that have potential roles in asthma, specifically IL-6, IL-13, MIP-1α and MCP-1. To extend these findings I looked at the role of ST2 in allergic airways inflammation. I first optimised and validated an ovalbumin and adjuvant based ‘short’ twelve day model of murine asthma and demonstrated that ST2 gene deletion results in attenuated eosinophilic inflammation. In addition to being ST2 dependent it is possible that this adjuvant based short model is mast cell dependent, unlike longer adjuvant based models which are mast cell and ST2 independent. Therefore I went on to study an adjuvant-free model of asthma which has been demonstrated to be mast cell dependent. In this adjuvant-free model of asthma the airway inflammation was attenuated in ST2 gene deficient mice compared with wild type mice, while AHR was unaffected. There was an associated reduction in IgE production and thoracic lymph node recall Th2 cytokine responses. I then examined the effect of ST2 activation in the lungs. When IL-33 was administered directly to the airways of naïve mice it induced the features of experimental asthma. There was extensive eosinophilic inflammation within the lung tissue and airspaces. The Th2 cytokines IL-5 and IL-13, and the eosinophil chemoattractant chemokines eotaxin-1 and eotaxin-2 were detected at increased concentrations. Significant airways hyperresponsiveness was also generated. Using ST2 gene deleted mice I demonstrated that these effects were ST2 specific. Although I have shown that mast cells are activated by IL-33 in vitro, I used mast cell deficient mice to demonstrate that the eosinophilic inflammation generated by IL-33 is unaffected by the absence of mast cells. These data show that IL-33 can induce in the lungs the cardinal pathological characteristics of asthma, and that it appears to act upstream of other important mediators such as IL-13 and the eotaxins. Furthermore the IL-33 receptor ST2 is required in an adjuvant free model of asthma, which is more akin to human disease. Placing these findings in the context of recent evidence that IL-33 is released by structural cells in response to damage or injury suggests that IL-33 may play a key role in initiating the immunological features of clinical asthma. As a consequence of this position in the hierarchy of inflammation IL-33 offers a promising direct target for novel biological therapies in asthma.