It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease ...subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called “asthma endotypes.” An “endotype” is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.
Fungi and allergic lower respiratory tract diseases Knutsen, Alan P., MD; Bush, Robert K., MD; Demain, Jeffrey G., MD ...
Journal of allergy and clinical immunology,
02/2012, Letnik:
129, Številka:
2
Journal Article
Recenzirano
Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is ...significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum , with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida , Penicillium , and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain TH 2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.
Refining the definition of hypereosinophilic syndrome Simon, Hans-Uwe, MD, PhD; Rothenberg, Marc E., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
07/2010, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming ...increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition.
Novel targeted therapies for eosinophilic disorders Wechsler, Michael E., MD, MMSc; Fulkerson, Patricia C., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
09/2012, Letnik:
130, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic ...disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.
Eosinophils are multifunctional leukocytes that increase in various tissues in patients with a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse ...inflammatory responses. In this review the clinical association of eosinophils with diseases of the skin, lung, and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, cause, and treatment are discussed.
Specifically, asthma phenotypes have been proposed to involve clinical characteristics, physiologic measures, inflammatory parameters, and laboratory data, as well as the response to different ...treatments.3,4 When the phenotypic characteristics of large cohorts of asthmatic patients are studied, diverse clusters of disease can be observed.5,6 Overall, these findings therefore argue that asthma is not a single disease but rather a syndrome of several subtypes with overall similar symptomatology among all patients with the diagnosis but with different fundamental mechanisms and pathobiological processes causing disease in different patients. Because IRMs are being developed for the treatment of asthma, linking the target molecule, cell, or both of each treatment to the asthma endotype is important for deciding the inclusion criteria in clinical studies and decisions for specific treatment selections.
Eosinophilia in Pulmonary Disorders Woolnough, Kerry; Wardlaw, Andrew J
Immunology and allergy clinics of North America,
08/2015, Letnik:
35, Številka:
3
Journal Article
Recenzirano
Lung disease associated with marked peripheral blood eosinophilia is unusual and nearly always clinically significant. Once recognized, it is generally easy to manage, albeit with long-term systemic ...corticosteroids. A failure to respond to oral steroids in the context of good compliance suggests a malignant cause for the eosinophilia. An important development is the introduction of antieosinophil therapies, particularly those directed against the interleukin 5 pathway, which is hoped to provide benefit in the full spectrum of eosinophilic lung disease as well as asthma, reducing the burden of side effects and resultant comorbidities.
A theoretical risk of "rebound" worsening of eosinophilic airway inflammation associated with negative outcomes has been suggested3 on the basis of in vitro observations that anti-IL-5 therapy is ...associated with upregulation of IL-5 synthesis by TH2 cells, upregulation of IL-5R expression by eosinophils, and persistence of preformed IL-5 in complex with the drug for a variable period of time after cessation of therapy.4 As part of a follow-up analysis, subjects completing a 12-month study of mepolizumab in refractory asthma1 were observed for 12 months with assessments every 3 months. The rise in exacerbations at 3 to 6 months after stopping mepolizumab was preceded by a rise in sputum and blood eosinophils, supporting suggestions that these events are related but have different time courses.5-8 The finding of increased asthma symptoms following cessation of mepolizumab was unexpected because symptoms were not modified significantly during the treatment period.1 However, mean symptom scores for subjects receiving mepolizumab were lower than for subjects in the placebo group at the end of the treatment phase of the study.
Background Epithelial dysfunction has been implicated in asthma pathophysiology, but no studies have directly assessed ciliary function in asthma. Objective To study the ciliary function and ...epithelial ultrastructure of patients with asthma and healthy controls. Methods We studied ciliary beat frequency and beat pattern by using digital high-speed video imaging and ultrastructure by transmission electron microscopy of bronchial epithelial strips from 7 subjects with mild, 7 with moderate, and 19 with severe asthma and 9 healthy controls. Results The median (interquartile range) ciliary beat frequency was decreased in moderate (6.5 4.4-8.5 Hz) and severe asthma (6.7 6.1-7.6 Hz) compared with controls (10.5 9.7-11.8 Hz; P < .01). Dyskinesia and immotility indices were higher in severe asthma (65% 43%-75%; 6.3% 1%-9.5%, respectively) compared with controls (4% 0%-6.7%; 0%, respectively; P < .01). These abnormalities were related to disease severity (ciliary beat frequency, rs = –0.68; dyskinesia index, rs = 0.86; immotility index, rs = 0.65; P < .0001). The ultrastructure of the epithelium was abnormal in severe asthma with a reduction in ciliated cells, an increase in dead cells, and ciliary disorientation compared with all other groups ( P < .05). Compared with patients with mild asthma and healthy controls, patients with severe asthma showed increased ciliary depletion, microtubular defects, mitochondrial damage, and cytoplasmic blebbing ( P < .01). All of these changes were related to disease severity. Conclusion Ciliary dysfunction and ultrastructural abnormalities are closely related to asthma severity. Ciliary dysfunction is a feature of moderate to severe asthma, and profound ultrastructural abnormalities are restricted to severe disease. Whether these changes contribute to the development of severe asthma phenotype remains to be determined.
Background IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit ...from antifungal treatment. Objectives We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. Methods Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. Results Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, −0.05 to −0.11), or any of our secondary outcome measures. Conclusion We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.
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