Review article
Refractory asthma

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Definition

Refractory asthma describes a small subset of asthmatic patients with disease that is unresponsive to standard therapies, in particular corticosteroids. Severe asthma, as defined in the National Heart, Lung, and Blood Institute Guidelines on the treatment of asthma, refers to disease that is characterized by continual symptoms, frequent nocturnal exacerbations, and severe airflow obstruction [3].

A key feature in the definition of refractory asthma is the presence of airflow obstruction that is

Diagnosis

The term refractory asthma can only be applied to individual patients in whom the diagnosis of asthma is certain. Airflow obstruction is a feature of many diseases other than asthma, including chronic obstructive pulmonary disease; emphysema from other causes, such as α1-antitrypsin deficiency; cystic fibrosis; allergic bronchopulmonary aspergillosis; vasculitis (Churg-Strauss syndrome); and chronic eosinophilic pneumonia. Even after asthma has been diagnosed, there are a number of comorbid

Prevalence

Although asthma affects almost 10% of the general population, refractory asthma accounts for about 5% of all patients with asthma [17]. Furthermore, the exact prevalence of this disease is limited by the variety of terms used when describing this phenomenon and the lack of a standardized definition. Despite the fact that severe, refractory asthma affects a small minority of asthma patients, these individuals are an important subset because their quality of life is disproportionately affected,

Pathology of severe asthma

In addition to the variations seen among clinical phenotypes of severe asthma, some investigators have described pathologic features that correspond to clinically distinct patterns. For example, Wenzel et al [18] have reported two pathologically distinct subgroups of patients with severe asthma: one group with a pulmonary parenchyma predominance of eosinophils and one with eosinophil numbers equivalent to normal controls. In this study, patients with clinically severe asthma were compared with

Mechanisms of action of corticosteroids in asthma

Most asthmatic patients are responsive to the anti-inflammatory properties of corticosteroids. After entering the cell, corticosteroid molecules bind to a glucocorticoid receptor (GCR) in the cytoplasm. After the loss of the heat shock protein subunits, the glucocorticoid-GCR (GC-GCR) complex becomes activated and translocates to the nucleus where it may modulate expression of a number of genes. First, the GC-GCR binds to a glucocorticoid response element (GRE), which is located upstream from a

Treatment

An increased understanding of the pathogenesis of asthma, including refractory asthma, has directed therapeutic efforts to new approaches. Refractory asthma patients require a more aggressive approach to control of their disease and to limit irreversible loss of pulmonary function. The unfortunate requirement of these patients for large doses of corticosteroids places refractory asthma patients at increased risk for adverse effects of this treatment. Because of this risk and the need for an

Summary

Treating patients with refractory asthma remains an ongoing challenge. Although most patients respond to large doses of systemic corticosteroid, the adverse effects associated with such a treatment limit its general use. Clinicians treating patients with refractory asthma must consider tapering systemic corticosteroid at every opportunity. Recent advances in the understanding of the pathogenesis of refractory asthma and corticosteroid resistance have fueled further study in the mechanisms of

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