Reviews and feature article
Severe asthma: Advances in current management and future therapy

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Effective treatment of severe asthma is a major unmet need because patients’ symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting β2-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to β2-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D2, IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy.

Section snippets

SMART strategies

Several studies have shown that in patients with moderate-to-severe asthma, there is an improvement in asthma control and significant reduction in severe exacerbations if a budesonide/formoterol combination inhaler is used as a reliever instead of a short-acting β2-agonist, whereas maintenance therapy with budesonide/formoterol is administered twice daily as usual.6 This strategy is now known as single inhaler maintenance and reliever therapy (SMART) and could presumably be used with any

New corticosteroids

Several ICSs are currently available for clinical use, and all have similar clinical efficacy, but there are differences in pharmacodynamic properties so that systemic exposure might differ. Because patients with severe asthma might require higher doses of ICSs, there is an advantage in developing systemic corticosteroids with fewer systemic side effects. Ciclesonide is a recently developed ICS and appears to have the least systemic effects and local side effects because the prodrug is

New bronchodilators

Bronchodilators play an important role in reducing symptoms in patients with severe asthma, and currently, LABAs are the bronchodilators of choice, usually given in combination with ICSs in a fixed-dose inhaler. Bronchodilators are essential in the management of asthma because they relieve and prevent bronchoconstriction. There have been several advances in the development of bronchodilators for the treatment of severe asthma.

Anti-IgE

Omalizumab is the only novel therapy that has specifically been approved for the treatment of severe asthma. Omalizumab is an mAb that binds the Fc portion of IgE and thus prevents activating its high-affinity IgE receptor (FcεRI) on mast cells, basophils, and dendritic cells, as well as a low-affinity receptor (FcεRII) expressed on several immune and inflammatory cells, including macrophages, eosinophils, and T and B lymphocytes. Numerous clinical trials have demonstrated the clinical efficacy

Targeting inflammatory mediators

More than 100 mediators are involved in the complex inflammation of asthma, making it unlikely that blocking the synthesis or receptor for a single mediator could be very effective. ICSs are highly effective in suppressing the synthesis of multiple inflammatory mediators, but in patients with severe asthma, they appear to be less effective, making it possible that adding a mediator antagonist to high doses of ICSs might be beneficial. In addition, the inflammation seen in some patients with

Broad-spectrum anti-inflammatory treatments

The fact that the symptoms of patients with severe asthma might not be controlled by high doses of ICSs plus LABAs and sometimes even oral corticosteroids has prompted a search for alternative anti-inflammatory therapies that can be added to existing therapies to provide additional control. In addition, inflammation in some patients with severe asthma is predominantly neutrophilic so that inhibitors of neutrophilic inflammation are needed, and corticosteroids are poorly effective against

Mast cell inhibitors

Mast cell activation is important as a driving mechanism in some patients with severe asthma.53 There are several approaches to inhibiting mast cell activation (Fig 3),5 and anti-IgE has already been shown to be of value in the treatment of some patients with severe asthma. Stem cell factor is a key regulator of mast cell survival in the airways and acts through the receptor c-Kit on mast cells.110 Plasma concentrations of stem cell factor are increased in patients with severe asthma.111

The problem of corticosteroid resistance

Resistance to the anti-inflammatory effects of corticosteroids might be an important factor in determining asthma severity. Several molecular mechanisms have now been described to account for corticosteroid resistance in asthmatic patients, including activation of p38 MAPK activity (as described above), increased expression of an alternatively spliced variant of the glucocorticoid receptor GRβ, increased production of macrophage migratory inhibitory factor (MIF), and reduced expression of HDAC2.

Macrolides

There is evidence that some patients with severe asthma are chronically infected with atypical bacteria, such as Mycoplasma pneumoniae and Chlamydia pneumoniae.133 In patients with infection confirmed by means of PCR and culture, there was a significant improvement in FEV1 after a 6-week course of clarythromycin.134 However, in a larger trial of patients with poorly controlled asthma, treatment with clarithromycin over a 16-week period did not produce any clinically meaningful improvement in

Bronchial thermoplasty

Bronchial thermoplasty delivers controlled thermal energy to the bronchial wall to selectively reduce the amount of airway smooth muscle and has been studied in patients with severe asthma. It is usually administered as 3 outpatient bronchoscopic procedures separated by 3 weeks. In a large controlled trial of almost 200 patients with severe asthma, bronchial thermoplasty compared with a sham procedure produced a small improvement in asthma-specific quality-of-life scores (although this was far

Future directions

It is now becoming clear that there are several distinct phenotypes of severe asthma and that these might require different therapeutic approaches. For example, patients whose symptoms were not controlled on maximal inhaled therapies that have high sputum eosinophilia and frequent exacerbations might benefit from anti–IL-5 therapy with mepolizumab or reslizumab. By contrast, neutrophilic asthma might respond to anti-inflammatory therapies that target neutrophilic inflammation, including PDE4

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    Disclosure of potential conflict of interest: P. J. Barnes receives research support from GlaxoSmithKline, AstraZeneca, Novartis, Boehringer Ingelheim, and Pfizer.

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