Evaluation and treatment of severe asthma--论文代写范文精选

严重的哮喘是一种异构条件组成的表型,如嗜酸性哮喘。具体建议使用痰嗜酸性粒细胞和一氧化氮，以及ige抗体,甲氨蝶呤、大环内酯物抗生素、抗真菌剂和支气管热成型术来指导治疗。

Abstract

Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.

A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.

When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.

Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

Executive Summary

The European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force on severe asthma includes an updated definition of severe asthma, a discussion of severe asthma phenotypes in relation to genetics, natural history, pathobiology and physiology, as well as sections on evaluation and treatment of severe asthma where specific recommendations for practice are made. See the unabridged online version of the document for detailed discussion of the definition of severe asthma, phenotypes and recommendations for practice.

When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) (see table 4 for doses in adults and children) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.”

The purpose of this document is to revise the definition of severe asthma, discuss the possible phenotypes and provide guidance about the management of patients with severe asthma. The target audience of these guidelines is specialists in respiratory medicine and allergy managing adults and children with severe asthma. General internists, paediatricians, primary care physicians, other healthcare professionals and policy makers may also benefit from these guidelines. This document may also serve as the basis for development and implementation of locally adapted guidelines.

Introduction

Although the majority of asthma patients can be effectively treated with currently available medications, a substantial subset exists who remain difficult-to-treat. These patients account for a relatively large proportion of resource expenditure. Much remains unclear regarding the best approaches to the management of these patients, or concerning the underlying mechanisms driving this process. In 1999 and in 2000, the first definitions of severe/refractory asthma were published respectively in the European Respiratory Journal and in the American Journal of Respiratory and Critical Care Medicine, with variations of these adopted by subsequent cohorts [1, 2]. In 2009, a 23 member joint Task Force from the ATS and the ERS consisting of adult- and paediatric-trained specialists and scientists with extensive experience of managing and investigating patients with asthma, particularly severe asthma, was formed to: 1) update the previous definitions, 2) identify potential mechanisms/phenotypes of severe asthma, 3) outline its evaluation and 4) provide recommendations on treatment, with respect to both adults and children. Another objective of this Task Force was to summarise the findings of the past 12 years that have elapsed since the previous reports [1, 2] and to propose directions for step-wise improvement in our understanding of severe asthma. Severe asthma is now widely accepted as a heterogeneous disease, consisting of multiple phenotypes and studies are beginning to define phenotypic biomarkers, and phenotype-targeted biological therapies are increasingly showing efficacy.

Methods

Committee composition and processes of disclosing and managing potential conflicts of interest, evidence synthesis, developing recommendations and peer review of the guidelines are described in detail in the online-only full-text document of these guidelines.

Briefly, this guideline represents a collaborative effort between the ATS and ERS. The Committee consisted of clinicians and researchers with recognised expertise in severe asthma and in the guideline development following the GRADE approach [3]. All committee members disclosed their potential conflicts of interest according to the ATS and ERS policies. During all deliberations members with perceived conflicts of interest abstained from decisions about specific recommendations related to the potential conflict of interest. The views and interests of the ATS and ERS as well as of any commercial entity that provided external funding for both professional societies had no influence on the final recommendations.

Disclosure of potential conflicts of interest

Committee members disclosed all potential conflicts of interest according to the ATS and ERS policies. The chairs (K.F.C. and S.E.W.) reviewed and resolved all potential conflicts of interest of committee members. All potential conflicts of interest (including those of the chairs) were discussed with the chair of the Ethics and Conflict of Interest Committee of the ATS. During all deliberations, members with perceived conflicts of interest abstained from decisions about specific recommendations related to the potential conflict of interest. The ATS methodologist (J.L.B.) did not participate in the vote on any of the recommendations.

The ATS and ERS provided meeting facilities during their annual conferences and financial support for conference calls. The views and interests of the ATS and ERS as well as of any commercial entity that provided external funding for both professional societies had no influence on the final recommendations.

Evidence summaries (online supplementary material 1) for each question were prepared following the GRADE approach [3] and reviewed by all committee members. We based the evidence summaries on existing up-to-date well-executed systematic reviews, if necessary supplemented with additional recent RCTs. When there was no recent valid systematic review available we did not perform rigorous systematic reviews, but we systematically searched for relevant studies (online supplementary material 2).

We labelled the recommendations as either “strong” or “conditional” according to the GRADE approach. We used the words “we recommend” for strong recommendations and “we suggest” for conditional recommendations. table 2 provides suggested interpretation of strong and conditional recommendations by patients, clinicians and health care policy makers.

Phenotypes and clusters of severe asthma

It is increasingly evident that severe asthma is not a single disease, as evidenced by the variety of clinical presentations, physiological characteristics and outcomes. To better understand this heterogeneity the concept of asthma phenotyping has emerged. A phenotype is defined as the composite, observable characteristics of an organism, resulting from interaction between its genetic make-up and environmental influences, which are relatively stable, but not invariable, with time. Phenotyping integrates biological and clinical features, ranging from molecular, cellular, morphological and functional to patient-oriented characteristics with the goal to improve therapy (fig. 1). Detailed efforts in this regard require organisation and integration of these defining characteristics into clinically recognisable phenotypes. Ultimately, these phenotypes should evolve into asthma “endotypes”, which combine clinical characteristics with identifiable mechanistic pathways. Their identification to date remains speculative at best [11]. In general, temporal stability of phenotypes will be required to provide evidence of their clinical usefulness. The ultimate clinical usefulness of these severe asthma phenotypes will be determined by their therapeutic consequences (see the evaluation section).

There are currently two strategies to delineate phenotypes: hypothesis-based and unbiased approaches. Unbiased analyses are being applied to a broad range of clinical, physiological and biological characteristics, utilising unsupervised hierarchical clustering stepwise discriminant and other approaches [12–15]. The Severe Asthma Research Program (SARP), using predominantly clinical characteristics, identified five clusters of asthma amongst adult patients with mild, moderate and severe asthma. They included three groups of mild, moderate and severe early-onset atopic asthma (based on range of lung function, medication use and frequency of exacerbations), a more severe late-onset obese group of primarily older females with moderate FEV1 reductions and frequent oral corticosteroid use, and a later onset but long duration very severe, less atopic group, with less reversible airflow limitation [15]. Another adult asthma cohort analysis from the Leicester group included sputum eosinophil counts and identified four clusters including a similar early-onset atopic-asthma, an obese non-eosinophilic asthma, an early-onset symptom predominant-asthma, and a later onset inflammation predominant asthma [14]. In both cluster analyses, severe asthmatics were distributed among several clusters supporting the heterogeneity of severe asthma. Finally, a SARP study of children found four clusters: 1) later-onset with normal lung function, 2) early-onset atopic with normal lung function, 3) early-onset atopic with mild airflow limitation, and 4) early-onset with advanced airflow limitation [16].

These three studies derived phenotypes by less biased analysis, although the data entered into the analyses varied, as did the approaches. Whereas the SARP adult cluster classification related primarily to lung function, age at onset and level of therapy, the Leicester cluster indicated that an eosinophilic phenotype may be more common in later onset severe asthma. Interestingly, these unbiased phenotypes have substantial overlap with phenotypes previously recognised clinically (late-onset eosinophilic and early-onset atopic/allergic), supporting the identification of these phenotypes in particular [17, 18].

Natural history and risk factors

Little is understood regarding the prevalence of severe asthma in adults or children, especially when using rigorous definitions as outlined here. However, figures of 5–10% of the total asthma population are often estimated.

It is likely that some of the difficulty in estimating these figures is also due to asthma heterogeneity. This heterogeneity of severe asthma and its phenotypes and lack of long term studies limit our understanding of the natural history of severe asthma, including whether severe asthma develops early in the course of the disease, or whether it develops over time. There is increasing evidence that severe asthma phenotypes are related to genetic factors, age of asthma onset, disease duration, exacerbations, sinus disease and inflammatory characteristics [14, 16, 17, 19–21]. Early childhood-onset asthma (over a range of severity) is characterised by allergic sensitisation, a strong family history and, more recently, non-allergy/atopy related genetic factors [14, 17, 22]. Late-onset severe asthma is often associated with female sex and reduced pulmonary function despite shorter disease duration. In some subgroups, it is associated with persistent eosinophilic inflammation, nasal polyps and sinusitis and often aspirin sensitivity (aspirin-exacerbated respiratory disease) and respiratory tract infections, but less often with specific genetic factors [14, 15, 17, 23, 24]. However, at least some of these apparently late-onset cases may have been symptomatic with abnormal airway physiology early in life, but the relation to severe asthma development is less clear [25].

Occupational exposures have also been associated with late-onset, and often severe asthma [26]. Obesity is associated with both childhood and adult onset severe asthma, but the impact of obesity may differ by age at onset and degree of allergic inflammation [27, 28]. Tobacco smoke and environmental air pollution are routinely linked as risk factors for more severe asthma [29, 30]. Both personal smoking and obesity have been linked to corticosteroid insensitivity, also associated with severe asthma [31, 32]. Recurrent exacerbations in adult severe asthma are more frequent in patients with comorbid conditions such as severe sinus disease, gastro-oesophageal reflux, recurrent respiratory infections and obstructive sleep apnoea [33]. Sensitisation to fungi such as Aspergillus has also been associated with severe asthma development in adults [34, 35].

Genetics and epigenetics

Genetic approaches in complex diseases such as asthma can predict risk for development (susceptibility) or progression (severity). Comprehensive genetic association studies using genome-wide association approaches have identified and replicated gene variants important in determining asthma susceptibility which is often based on the loose description of a physician diagnosis of asthma rather than a comprehensive clinical characterisation [22, 36]. Other studies have compared more severe asthma with non-asthma controls or smaller cohorts with mild disease and have identified similar genes [20]. Differences in asthma susceptibility genes also appear to differ by age at onset of disease, a characteristic critical to both biased and unbiased phenotyping approaches [22, 37]. Understanding the functional biology of these gene variants may help identify biomarkers in relation to phenotypes and new pharmacotherapies. For example, single nucleotide polymorphisms in the interleukin (IL)-4 receptor-α specifically associate with persistent airways inflammation, severe asthma exacerbations and submucosal mast cells supporting functional alterations in the IL-4 pathway influencing allergic inflammation in some severe asthmatics [19]. Another recent paper showed that variation in IL-6 receptor associated with lower lung function and more severe asthma subphenotypes suggesting another therapeutic target [38]. Finally, there is evidence that genetic variation in a number of genes may interact and influence lung function, asthma susceptibility and severity [39]. Another mechanism predisposing to more severe or difficult-to-treat asthma may relate to pharmacogenetics, where responsiveness to asthma therapy is altered or reduced in some individuals. Asthmatics with reduced therapeutic responsiveness to controller therapies such as inhaled corticosteroids or even specific novel biological therapies could exhibit more difficult-to-control asthma and be classified as more severe [40, 41].（essay代写)

51Due网站原创范文除特殊说明外一切图文著作权归51Due所有；未经51Due官方授权谢绝任何用途转载或刊发于媒体。如发生侵犯著作权现象，51Due保留一切法律追诉权。（essay代写)
更多essay代写范文欢迎访问我们主页 www.51due.com 当然有essay代写需求可以和我们24小时在线客服 QQ:800020041 联系交流。-X（essay代写)