Severe asthma treatment: need for characterising patients

doi:10.1016/S0140-6736(05)71087-4

The Lancet

Volume 365, Issue 9463, 12–18 March 2005, Pages 974-976

https://doi.org/10.1016/S0140-6736(05)71087-4 Get rights and content

Summary

Context

Asthma is readily diagnosed in most cases and usually responds to inhaled corticosteroids with or without long-acting β agonists, theophyllines, or leukotriene-receptor antagonists, adjusted stepwise according to symptoms and lung function. However, up to 40% of adult patients with asthma remain symptomatic, and up to 5% have difficult-to-control asthma despite multiple therapies. It is suggested that higher doses of inhaled steroids with long-acting β₂ agonists should be used for total control of symptoms; and anti-IgE therapy is newly licensed in the USA. However, difficult-to-control asthma is complex and multifactorial, and is often not due to severe or therapy-resistant asthma.

Starting point

Last year saw encouraging reports on omalizumab (anti-IgE therapy) in severe allergic asthma, by Stephen Holgate, Jon Ayres, and their respective colleagues (Clin Exp Allergy 2004; 34: 632–38; Allergy 2004; 59: 701–08). Omalizumab reduced exacerbation rates, improved asthma symptoms and quality of life, and allowed lower doses of inhaled steroid compared with placebo. In placebo-controlled studies with anti-IgE, many patients were able to substantially reduce and even withdraw inhaled steroids in the placebo arm.

Where next

Severe asthma is often defined as persisting symptoms despite high-dose inhaled steroids. This definition is likely to include patients with various reasons for their persisting symptoms, for whom additional treatment is not always required. Before starting new therapy, it is important to systematically evaluate asthmatic patients to accurately define their disease and to identify those whose symptoms are caused by other factors, and thus avoid unnecessary medication. There might also be subgroups that have differing underlying inflammatory processes and who will respond differently to individual treatments.

Section snippets

Definition of severe asthma

Defining asthma severity on the basis of persisting symptoms despite high-dose inhaled steroids is problematic, and systematic evaluations of difficult-to-manage asthma give insight into the role of different factors in this population.8, 9 A universal definition of severe asthma is difficult because of different patterns of disease. For example, frequent severe exacerbations on the background of relatively normal lung function (type 2 brittle asthma¹⁰) would be defined by most as severe but

Other diagnoses and exacerbating factors

Several conditions that cause respiratory symptoms might co-exist in asthmatic patients, leading to an apparent failure to respond to therapy. In both systematic evaluations,8, 9 additional or alternative diagnoses were revealed in just over a third of cases (figure). There are several other additional or co-existent conditions that might make asthma difficult to control: smoking and chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, bronchiectasis, chronic

Poor adherence and psychological factors

One of the commonest reasons for a poor response to asthma therapy is not taking medication. The Brompton study⁹ assessed adherence in those on oral prednisolone: half had low or undetectable serum prednisolone and/or normal cortisol, suggesting non-adherence. In the Belfast cohort,²⁰ 11 of 44 patients taking theophylline and 14 of 25 taking prednisolone had unrecordable serum levels of drug. Non-adherence with steroid therapy in this population must be assessed when defining

Therapy-resistant asthma

Therapy-resistant asthma has been defined as persisting symptoms due to asthma despite high-dose inhaled steroids (2000 μg beclomethasone diproprionate or equivalent) plus long-acting β₂ agonist, with the requirement for either maintenance systemic steroids or at least two rescue courses of steroids over 12 months and despite trials of add-ons such as a leukotriene-receptor antagonist or theophylline.⁸ These are the patients for whom omalizumab might be appropriate.

Key to this definition is

Conclusion

Omalizumab holds great promise for difficult-to-control asthma. However, before using expensive new therapies, patients with difficult-to-manage asthma should be systematically characterised so that new treatments are appropriately targeted.

We thank Mina Gaga for helpful discussions. We declare that we have no conflict of interest.

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This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function.
Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker–low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001).
This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment.
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This study's objectives were to compare the prevalence of mental disorders and consumption of psychiatric medications in asthmatic subjects with non-asthmatic controls and identify risk factors associated with psychiatric conditions.
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The prevalence of psychiatric conditions were higher in asthmatic subjects. Female gender, older age, worse self-rated health, visits to a psychologist and chronic pain were associated with psychiatric conditions in asthmatic subjects.
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Five to ten percent of asthma patients remain symptomatic and/or have asthma attacks despite adequate inhaled and systemic therapy. Eosinophilic, type 2 airway inflammation is seen in half of these patients with severe asthma. There is now convincing evidence that type 2 inflammation drives susceptibility to asthma attacks and is associated with a good response to biological therapies. Monoclonal antibodies targeting immunoglobulin E, interleukin (IL)-5 and IL-4/13 now have established efficacy in severe type 2 asthma. Novel alarmin-blocking and crystal-dissolving therapies are promising. Prescribing biologics, weaning steroids and treating subsequent exacerbations are rapidly evolving clinical challenges.
Controversies in Allergy: Should Severe Asthma with Eosinophilic Phenotype Always Be Treated with Anti-IL-5 Therapies
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Rapid ReviewSevere asthma treatment: need for characterising patients

Summary

Context

Starting point

Where next

Section snippets

Definition of severe asthma

Other diagnoses and exacerbating factors

Poor adherence and psychological factors

Therapy-resistant asthma

Conclusion

J Allergy Clin Immunol

Am J Ophthalmol

Lancet

Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma

Clin Exp Allergy

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma

Allergy

The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics

Eur Respir J

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR

Allergy

Anti-IgE for chronic asthma

Cochrane Database Syst Rev

Soluble tumor necrosis factor alpha (TNF-alpha) receptor (Enbrel) as effective therapeutic strategy in chronic severe asthma

J Allergy Clin Immunol

Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol

Thorax

Systematic assessment of difficult-to-treat asthma

Eur Respir J

Brittle asthma

Thorax

Am J Respir Crit Care Med

Rapid Review
Severe asthma treatment: need for characterising patients