Skip to main content
Article thumbnail
Location of Repository

The Clinical Implications of Eosinophilic Inflammation in Asthma

By Pranabashis Haldar


Asthma is a complex and heterogeneous disorder, comprising domains of pathology (airway inflammation), physiology (disordered airway function) and clinical expression (symptoms and exacerbations) that are variably related. Within this network, the role of eosinophils remains uncertain. This thesis explores further the relationship between eosinophilic inflammation and clinical asthma by: 1. using multivariate statistical techniques to characterise and classify relationships between individual domains in the asthma population; 2. investigating clinical outcomes with mepolizumab (anti-IL 5) in a randomised placebo controlled trial for 12 months, in subjects with refractory eosinophilic asthma. In the first study I have used factor analysis techniques to formulate statistically independent domains of the clinical phenotype. These have been entered into a cluster analysis algorithm to identify subgroups that define a classification model based on expression patterns and composite relationships across the asthma domains. By applying this independently to populations of Primary and Secondary Care asthma, I have identified two secondary care predominant clusters, characterised by discordance between asthma symptoms and eosinophilic airway inflammation. I have shown that discordant clusters derive greatest clinical benefit with a management strategy directed at maintaining a normal sputum eosinophil count, supporting its implementation in secondary care. More specifically, I report a 10-fold reduction in severe exacerbations with inflammation guided therapy in discordant eosinophil-predominant asthma, supporting a specific role for eosinophils in these events. In the second study, I report a significant reduction in severe exacerbations with mepolizumab therapy, but no effect on other clinical outcome measures. These findings support a specific effector role for eosinophils in the pathogenesis of severe exacerbations; and dissociation of this endpoint and other clinical outcome measures. Finally, I report a 12 month washout analysis of mepolizumab treated subjects in which a significant increase in severe exacerbation frequency is observed that is temporally preceded by rising sputum eosinophils

Publisher: University of Leicester
Year: 2011
OAI identifier:

Suggested articles


  1. (1961). [Chronic nonspecific respiratory diseases.]. Ned Tijdschr Geneeskd
  2. (1953). A clinical and pathological study of fatal cases of status asthmaticus. Thorax
  3. (1967). A clustering technique for summarising multivariate data. Behavioural Science
  4. (1992). A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial.
  5. (1953). A factor in lungs of anaphylactically shocked guinea pigs which can induce eosinophilia in normal animals. Blood
  6. (1991). A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell
  7. (2008). A new perspective on concepts of asthma severity and control. Eur Respir J
  8. (2006). A plea to abandon asthma as a disease concept. Lancet
  9. (2001). A randomized controlled study evaluating medical treatment versus surgical treatment in addition to medical treatment of nasal polyposis.
  10. (2007). A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med
  11. (2004). Acute asthma in adults: a review. Chest
  12. (2009). Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy
  13. (2006). Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases.
  14. (2000). Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis. Eur Respir J
  15. (2002). Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax
  16. (2003). Airway structural alterations selectively associated with severe asthma.
  17. (1995). Allergen-induced changes in bone marrow progenitors and airway responsiveness in dogs. Int Arch Allergy Immunol
  18. (1992). Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis
  19. (1997). An interleukin 5 mutant distinguishes between two functional responses in human eosinophils.
  20. (2009). An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med
  21. (2005). An ongoing Confidential Enquiry into asthma deaths
  22. (2002). Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax
  23. (1973). Annual Review of Biophysics and Bioengineering
  24. (2009). Anti-IL-5 (mepolizumab) therapy does not alter IL-5 receptor alpha levels in patients with eosinophilic esophagitis.
  25. (2008). Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.
  26. (2003). Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics.
  27. (2003). Anti-IL5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.
  28. (1962). Antihistamine activity in extracts of horse eosinophils.
  29. (2006). AntiIL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol
  30. (2005). Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.
  31. (2010). Antiinterleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut
  32. (2008). Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergeninduced Eosinophilic Responses. Am J Respir Crit Care Med
  33. (1998). Apoptosis, proliferation, and expression of Bcl-2, Fas, and Fas ligand in bronchial biopsies from asthmatics.
  34. (2007). Apoptotic eosinophils in sputum from asthmatic patients correlate negatively with levels of IL-5 and eotaxin. Respir Med
  35. (1998). Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am J Respir Crit Care Med
  36. (2006). Asthma exacerbations . 4: Prevention. Thorax
  37. (2002). Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet
  38. (2000). Asthma Workshop Committee. Proceedings of the ATS workshop on refractory asthma. Current understanding, recommendations and unanswered questions. Am J Respir Crit Care Med
  39. (2006). Asthma: defining of the persistent adult phenotypes. Lancet
  40. (1994). B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10.
  41. Beiträge zur Theorie und Praxis der histologischen Färbung. Test (Hrsg.), I. Teil: Die chemische Auffassung der Färbung. II. Teil: Die Anilinfarben in chemischer, technologischer und histologischer Beziehung.
  42. (1998). Brittle asthma. Thorax
  43. (1958). Bronchial asthma and chronic bronchitis treated with hydrocortisone acetate inhalations. Br Med J
  44. (1989). Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis
  45. (1985). bronchial hyperreactivity and late-phase asthmatic reactions. Clin Allergy
  46. (2004). Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med
  47. (1998). CD44 and CD69 represent different types of cell-surface activation markers for human eosinophils.
  48. (1989). Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis
  49. (1997). Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings, and bronchoalveolar lavage fluid. Thorax
  50. (2000). Changes in sputum eosinophils predict loss of asthma control.
  51. (2007). Changing pattern of sputum cell counts during successive exacerbations of airway disease. Respir Med
  52. (2007). Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol
  53. (1994). Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma.
  54. (2002). Chronic sinusitis in severe asthma is related to sputum eosinophilia.
  55. (1971). Classification of depressed patients: a cluster analysis derived grouping.
  56. (1987). Classification of parasuicide by cluster analysis. Types of suicidal behaviour, therapeutic and prognostic implications.
  57. (2004). Clinical assessment of airway remodeling in asthma: utility of computed tomography. Clin Rev Allergy Immunol
  58. (2008). Clinical consequences of ADRbeta2 polymorphisms. Pharmacogenomics
  59. (2005). Clinicianassessed poor compliance identifies adults with severe asthma who are at risk of adverse outcomes.
  60. (2008). Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med
  61. (1994). Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: a laboratory tidal breathing protocol.
  62. (1995). Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ
  63. (1995). Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage.
  64. (2006). COPD and bronchitis are just components of airway disease.
  65. (2001). Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes.
  66. (1959). Definitions, and Classification of Chronic Pulmonary Emphysema and Related Conditions: A Report of the Conclusions of a Ciba Guest Symposium. Thorax
  67. (2000). Delayed eosinophil apoptosis in asthma.
  68. (2006). Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J
  69. (1999). Development and validation of a questionnaire to measure asthma control. Eur Respir J
  70. (1997). Dexamethasone inhibits prolonged survival and autocrine granulocyte-macrophage colony-stimulating factor production by human eosinophils cultured on laminin or tissue fibronectin. J Allergy Clin Immunol
  71. (1999). Differences between asthma exacerbations and poor asthma control. Lancet
  72. Difficult to treat asthma in adults.
  73. (1997). Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia.
  74. (1998). Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma.
  75. (2004). Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
  76. (2004). Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol
  77. (1992). Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis
  78. (1999). Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax
  79. (2000). Effect of IL-5, glucocorticoid, and Fas ligation on Bcl-2 homologue expression and caspase activation in circulating human eosinophils. Clin Exp Immunol
  80. (1997). Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET)
  81. (1999). Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax
  82. (2003). Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med
  83. (1995). Effects of an antibody to interleukin-5 in a monkey model of asthma.
  84. (2000). Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet
  85. (2006). Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med
  86. (1981). Elevated levels of the eosinophil granule major basic protein in the sputum of patients with bronchial asthma. Mayo Clin Proc
  87. (1990). Enander I et al. Eosinophilic inflammation in asthma.
  88. (1994). Endotoxin contamination causes neutrophilia following pulmonary allergen challenge.
  89. (1990). Endotoxin from Haemophilus influenzae enhances IgE-mediated and non-immunological histamine release. Allergy
  90. (2001). Endotoxin-stimulated innate immunity: A contributing factor for asthma.
  91. (2008). Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet
  92. (1996). Eosinophil apoptosis and the resolution of airway inflammation in asthma.
  93. (1995). Eosinophil cationic protein (ECP) and eosinophil protein X (EPX) concentrations in serum and bronchial lavage fluid in asthma. Effect of prednisolone treatment. Clin Exp Allergy
  94. (1986). Eosinophil differentiation factor also has B-cell growth factor activity: proposed name interleukin 4.
  95. (1999). Eosinophil influx to the nasal airway after local, low-level LPS challenge in humans.
  96. (2007). Eosinophil trafficking in allergy and asthma.
  97. (2003). Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.
  98. (1990). Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med
  99. (2007). Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J
  100. (2000). Eosinophilic bronchitis - what is it and why is it important? Clin Exp Allergy
  101. (1988). Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am Rev Respir Dis
  102. (2010). Eosinophils in health and disease: the LIAR hypothesis. Clin Exp Allergy
  103. (2001). Eosinophils promote allergic disease of the lung by regulating CD4(+) Th2 lymphocyte function.
  104. (2008). Eosinophils: biological properties and role in health and disease. Clin Exp Allergy
  105. (1999). Evaluation of apoptosis of eosinophils, macrophages, and T lymphocytes in mucosal biopsy specimens of patients with asthma and chronic bronchitis. J Allergy Clin Immunol
  106. (1992). Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax
  107. (2001). Evidence for systemic rather than pulmonary effects of interleukin-5 administration in asthma. Thorax
  108. (1991). Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway.
  109. (1999). Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med
  110. (1997). Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J
  111. (2005). Exhaled nitric oxide: a predictor of steroid response.
  112. (1997). Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics.
  113. (1991). Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma.
  114. (2008). Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J
  115. (2004). Global strategy for asthma management and prevention.
  116. (1995). Hargreave FE. Exacerbations of asthma without sputum eosinophilia. Thorax
  117. (2001). Heterogeneity of Airway Inflammation in Persistent Asthma : Evidence of Neutrophilic Inflammation and Increased Sputum Interleukin-8. Chest
  118. (1994). Histamine increases anti-CD3 induced IL-5 production of TH2-type T cells via histamine H2-receptors. Agents Actions
  119. (2005). How corticosteroids control inflammation: Quintiles Prize Lecture
  120. (1998). How Many Clusters? Which Clustering Method? Answers Via Model-Based Cluster Analysis. The Computer Journal
  121. (2005). How representative are clinical study patients with asthma or COPD for a larger "real life" population of patients with obstructive lung disease? Respir Med
  122. (1989). Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood
  123. (1982). Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma. Lancet
  124. (1990). Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis
  125. IL-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leucocyte integrin
  126. (2002). IL-5 promotes eosinophil trafficking to the esophagus.
  127. (1989). IL-5-dependent conversion of normodense human eosinophils to the hypodense phenotype uses 3T3 fibroblasts for enhanced viability, accelerated hypodensity, and sustained antibody-dependent cytotoxicity.
  128. (1993). Immunohistochemistry on resin sections: a comparison of resin embedding techniques for small mucosal biopsies. Biotech Histochem
  129. (1990). Immunology
  130. (1998). Impaired perception of dyspnea in patients with severe asthma. Relation to sputum eosinophils. Am J Respir Crit Care Med
  131. (1996). Increased levels of CD34+ hemopoietic progenitor cells in atopic subjects.
  132. (1999). Increased mature and immature CCR3 messenger RNA+ eosinophils in bone marrow from patients with atopic asthma compared with atopic and nonatopic control subjects.
  133. (2000). Induced sputum cell counts in healthy adults.
  134. (2000). Induced sputum cellularity. Reference values and distribution in normal volunteers.
  135. (2006). Inflammatory subtypes in asthma: Assessment and identification using induced sputum. Respirology
  136. (2006). Influence of body mass index on the response to asthma controller agents. Eur Respir J
  137. (2002). Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax
  138. (1993). Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. Am Rev Respir Dis
  139. (2000). Innate immunity.
  140. (1996). Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
  141. (1994). Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines.
  142. (2001). Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma.
  143. (1999). Interleukin-5: From molecule to drug target for asthma.
  144. (1950). Intrinsic asthma. Postgrad Med
  145. (1996). Latent class analysis in medical research. Stat Methods Med Res
  146. (2006). Low sputum eosinophils predict the lack of response to beclomethasone in symptomatic asthmatic patients. Chest
  147. (2002). Mast-cell infiltration of airway smooth muscle in asthma.
  148. (2005). Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med
  149. (1997). Membrane-bound and soluble alpha IL-5 receptor mRNA in the bronchial mucosa of atopic and nonatopic asthmatics. Am J Respir Crit Care Med
  150. (2009). Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.
  151. (2009). Mepolizumab in refractory eosinophilic asthma. Thorax 2010; 65(4):370.
  152. (2003). Methods for the assessment of endobronchial biopsies in clinical research: application to studies of pathogenesis and the effects of treatment.
  153. (1999). Molecular basis for selective eosinophil trafficking in asthma: A multistep paradigm.
  154. (1992). Molecular basis of the membrane-anchored and two soluble isoforms of the human interleukin 5 receptor alpha subunit.
  155. (1989). Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood
  156. (2003). Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions. Eur Respir J
  157. (1995). Multi-colony stimulating activity of interleukin 5 (IL-5) on hematopoietic progenitors from transgenic mice that express IL-5 receptor alpha subunit constitutively.
  158. (2005). Multi-dimensional phenotyping: towards a new taxonomy for airway disease. Clin Exp Allergy
  159. (2006). Multiple inflammatory hits and the pathogenesis of severe airway disease. Eur Respir J
  160. (2002). New insights into the relationship between airway inflammation and asthma. Clin Sci (Lond)
  161. (2010). New therapies for asthma: is there any progress? Trends Pharmacol Sci
  162. (2002). Non-eosinophilic asthma: importance and possible mechanisms. Thorax
  163. (1999). Non-eosinophilic corticosteroid unresponsive asthma. Lancet
  164. (1999). Nonasthmatic chronic cough: No effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can Respir J
  165. (2007). Noneosinophilic asthma: a distinct clinical and pathologic phenotype.
  166. (1962). Numerical taxonomy. Nature
  167. (2001). Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness. Thorax
  168. (2002). Occupational asthma due to low molecular weight agents: eosinophilic and non-eosinophilic variants. Thorax
  169. (1996). Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes.
  170. (1982). Optimisation methods of cluster analysis.
  171. (2007). Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax
  172. (1973). Pattern classification and scene analysis.
  173. (1987). Peripheral blood eosinophil counts and bronchial responsiveness. Thorax
  174. (2007). Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics
  175. (1989). Pharmacological control of human basophil histamine release stimulated by eosinophil granule major basic protein. Immunology
  176. (1995). Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects.
  177. (2001). Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys.
  178. (2001). Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids.
  179. (2003). Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax
  180. (1993). Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression. Am Rev Respir Dis
  181. (1996). Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med
  182. (1999). Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J
  183. (1949). Preliminary observations on the effect of adrenocorticotrophic hormone in allergic disease. Bull Johns Hopkins Hosp
  184. (1990). Preparation and characterization of human interleukin-5 expressed in recombinant Escherichia coli.
  185. (1995). Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation.
  186. (1998). Psychosocial aspects of asthma in adults. Thorax
  187. (2004). Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700. J Allergy Clin Immunol
  188. (2007). Recent asthma exacerbations: a key predictor of future exacerbations. Respir Med
  189. (1993). Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. Blood
  190. (1987). Recombinant human interleukin 5 is an eosinophil differentiation factor but has no activity in standard human B cell growth factor assays.
  191. (2003). Reduced eosinophil apoptosis in induced sputum correlates with asthma severity. Eur Respir J
  192. (2006). Refractory asthma phenotypes and the response to sputum eosinophil guided therapy. Thorax 61[12], ii31.
  193. (1999). Regulation of eosinophil apoptosis: transduction of survival and death signals. Int Arch Allergy Immunol
  194. (1997). Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice.
  195. (1993). Respiratory viruses and exacerbations of asthma in adults. BMJ
  196. (2006). Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.
  197. (2005). Severe asthma treatment: need for characterising patients. Lancet
  198. (2007). Severe asthma: lessons from the Severe Asthma Research Program.
  199. (2007). Severe exacerbations predict excess lung function decline in asthma. Eur Respir J
  200. (2002). Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol
  201. (2001). Smoking and airway inflammation in patients with mild asthma. Chest
  202. (2008). Society. British Guideline on the Management of Asthma. Thorax
  203. (2009). Sousa A et al. Mepolizumab and exacerbations of refractory eosinophilic asthma.
  204. (1999). Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis.
  205. (1983). Sputum and blood eosinophils during corticosteroid treatment of acute exacerbations of asthma.
  206. (2005). Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids.
  207. (2000). Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet
  208. (2005). Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax
  209. (1997). Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med
  210. (2008). Statistical analysis of exacerbation rates
  211. (2010). Statistics and bioinformatics in nutritional sciences: analysis of complex data in the era of systems biology.
  212. (2006). Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma.
  213. (1991). Structure-function analysis of interleukin-5 utilizing mouse/human chimeric molecules.
  214. (1927). Studies in asthma: a clinical survey of 1074 patients with asthma followed for 2 years.
  215. Studies on Trichinosis, with especial reference to the increase of the eosinophilic cells in the blood and muscle, the origin of these cells and their diagnostic importance.
  216. (1993). Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis
  217. (1988). T cellreplacing factor (TRF)/interleukin 5 (IL-5): molecular and functional properties. Immunol Rev
  218. (1969). The classification of depression by numerical taxonomy.
  219. (2007). The demise of anti IL-5 for asthma, or not.
  220. (2000). The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking and degranulation and the induction of bronchial hyperreactivity.
  221. (2003). The endophenotype concept in psychiatry: etymology and strategic intentions.
  222. (2003). The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J
  223. (1987). The eosinophilic leukocyte and the pathology of fatal bronchial asthma: evidence for pathologic heterogeneity.
  224. (2005). The epidemiology of obesity and asthma.
  225. (2010). The false discovery rate: a key concept in large-scale genetic studies. Cancer Control
  226. (1964). The History Of Asthma From Hippocrates To Meltzer.
  227. (1991). The immunobiology of eosinophils.
  228. (1990). The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors. Clin Exp Allergy
  229. (2006). The mechanisms, diagnosis, and management of severe asthma in adults. Lancet
  230. (1978). The mechansim of antibodydependent, eosinophil-mediated damage to schistosomula of Schistosoma mansoni in vitro: a study by phase-contrast and electron microscopy.
  231. (1960). The pathology of asthma, with special reference to changes in the bronchial mucosa.
  232. (1922). The Pathology of Fatal Asthma. Arch Intern Med
  233. (2007). The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial. J Allergy Clin Immunol
  234. (2001). The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med
  235. (2009). The prevalence of nonadherence in difficult asthma.
  236. (2007). The treatment of missing data.
  237. (1958). The use of corticosteroids in the treatment of asthma and related conditions. Postgrad Med J
  238. (2007). The Use of Exhaled Nitric Oxide to Guide Asthma Management: A Randomised Controlled Trial. Am J Respir Crit Care Med
  239. (1997). The use of induced sputum to investigate airway inflammation. Thorax
  240. (1998). The use of multivariate statistical methods in psychiatry. Stat Methods Med Res
  241. (1975). Total eosinophil counts in the management of bronchial asthma.
  242. (1989). Toxicity of eosinophil cationic proteins for guinea pig tracheal epithelium in vitro. Am Rev Respir Dis
  243. (2005). Treatment allocation by minimisation. BMJ
  244. (1958). Treatment of chronic asthma with prednisolone. Significance of eosinophils in the sputum. The Lancet
  245. (2008). Treatment of patients with the hypereosinophilic syndrome with mepolizumab.
  246. (1912). Uber lokale eosinophilie in den bronchien und in der lung anaphylaktischen meerschweinchen. Arch Exp Pathol Pharmakol
  247. Understanding Factor Analysis.
  248. (2005). Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.
  249. (1999). Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest
  250. (1989). Validation of a vertical visual analogue scale as a measure of clinical dyspnea. Rehabil Nurs
  251. (1989). Visual analogue scales: measurement of subjective phenomena. Nurs Res
  252. (2008). Weight loss and asthma: a systematic review. Thorax
  253. (2004). Where do we stand? Asthma in the UK today. .
  254. Zur kenntniss der asthmatischen sputums. Fortschritte der Medizin

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.