Managing Severe Asthma in Adults: Lessons From the ERS/ATS Guidelines

Kian Fan Chung

Curr Opin Pulm Med. 2015;21(1):8-15.

Abstract and Introduction

Abstract

Purpose of review To review the latest guidelines on severe asthma.

Recent findings An updated definition of severe asthma is provided together with the evaluation steps necessary to reach a diagnosis of severe asthma. The importance of phenotyping is emphasized, and recommendations are provided for therapies specifically directed for severe asthma.

Summary Severe asthma is widely recognized as a major unmet need. It is defined as asthma that requires treatment with high-dose inhaled corticosteroids and a second controller and/or systemic corticosteroid to prevent it from becoming 'uncontrolled' or that remains 'uncontrolled' despite this therapy. Severe asthma is a heterogeneous condition that consists of phenotypes such as eosinophilic asthma. More phenotypes need to be defined. Evaluation of the patient referred to as having severe or difficult-to-control asthma must take into account adherence to treatment, comorbidities and associated factors including side effects from therapies. These need to be addressed. Recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy are presented. Treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty is reviewed and recommendations made. Research efforts into phenotyping of severe asthma will provide both biomarker-driven approaches and newer effective therapies to severe asthma management.

Introduction

Asthma can be considered a complex disease because it is likely to be caused by multi-factorial components and can present in different ways with varied long-term outcomes. The basis for this likely rests on the lack of a diagnostic marker of disease and the current diagnosis resting mostly on a history of intermittent wheeze. Another paradox is that although most patients with a diagnosis of asthma can be adequately treated with a combination therapy of inhaled corticosteroids (ICS) and a bronchodilator, usually long-acting β-agonists (LABAs), there is a core of patients whose asthma remains uncontrolled despite being on these treatments. These patients are generally termed having severe asthma or refractory asthma, particularly if addition of other controller medications on top of combination therapy does not lead to any improvement in asthma control. Such patients taking high-level treatments as exemplified by the steps 4 and 5 of the Global Initiative for Asthma (GINA) guidelines indeed experience the most morbidity, and although consisting of only 5–10% of the asthma population, consume the majority of the healthcare costs for asthma. In a recent study of patients with persistent asthma taken from 10 countries in Europe, the estimated costs for patients with uncontrolled asthma as defined in GINA that included expenses for drugs, doctor visits, tests and hospital admissions and costs linked to loss of productivity and days lost amounted to 2281 Euros compared to 509 Euros in a controlled asthma patient.^[1] Clearly, there is an unmet need in this group of patients called severe. Not only do these patients need to benefit from more efficacious therapies, the whole condition called severe asthma needs to be understood more.

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Table 1. Recommendations from ERS/ATS Task Force on severe asthma
Context: treatment	Recommendation	Strength	Quality of evidence	Values and preferences	Remarks
Anti-IgE antibody (omalizumab)	In patients with severe allergic asthma, we suggest a therapeutic trial of omalizumab both in adults and in children.	Conditional	Low (adults) very low (children)	This recommendation places higher value on the clinical benefits from omalizumab in some patients with severe allergic asthma and lower value on increased resource use.	Those adults and children aged 6 years and above, with severe asthma, who are considered for a trial of omalizumab, should have confirmed IgE-dependent allergic asthma uncontrolled despite optimal pharmacological and nonpharmacological management and appropriate allergen avoidance if their total serum IgE level is 30–700 IU/ml (in three studies the range was wider: 30–1300 IU/ml). Treatment response should be globally assessed by the treating physician taking into consideration any improvement in asthma control, reduction in exacerbations and unscheduled healthcare utilization, and improvement in quality of life. If a patient does not respond within 4 months of initiating treatment, it is unlikely that further administration of omalizumab will be beneficial.
Methotrexate	We suggest that clinicians do not use methotrexate in adults or children with severe asthma.	Conditional	Low	This recommendation places a relatively higher value on avoiding adverse effects of methotrexate and a relatively lower value on possible benefits from reducing the dose of systemic corticosteroids.	Evidence from randomized trials is only available for adults. Because of the probable adverse effects of methotrexate and need for monitoring therapy, we suggest that any use of methotrexate is limited to specialized centres and only in patients who require daily OCS. If a decision to use methotrexate is made, a chest radiograph, complete blood count with differential and platelets, liver function tests, serum creatinine and transfer factor to carbon monoxide (DLCO), are recommended prior to and after commencing therapy.
Macrolide antibiotics	We suggest that clinicians do not use macrolide antibiotics in adults and children with severe asthma for the treatment of asthma.	Conditional	Very low	This recommendation places a relatively higher value on prevention of development of resistance to macrolide antibiotics, and relatively lower value on uncertain clinical benefits.	This recommendation applies only to the treatment of asthma; it does not apply to the use of macrolide antibiotics for other indications, for example, treatment of bronchitis, sinusitis or other bacterial infections as indicated.
Antifungal agents	A We suggest antifungal agents in adults with severe asthma and recurrent exacerbations of allergic bronchopulmonary aspergillosis (ABPA).	Conditional	Very low	The recommendation to use antifungal agents in patients with severe asthma and ABPA places a higher value on possible reduction of the risk of exacerbations and improved symptoms, and a lower value on avoiding possible adverse effects, drug interactions and increased use of resources.	In children, the evidence is limited to isolated case reports. Children should be treated with antifungals only after the most detailed evaluation in a specialist severe asthma referral centre. As antifungal therapies are associated with significant and sometimes severe side effects, including hepatotoxicity, clinicians should be familiar with these drugs and follow relevant precautions in monitoring for these, observing the limits to the duration of treatment recommended for each
	B We suggest that clinicians do not use antifungal agents for the treatment of asthma in adults and children with severe asthma without ABPA irrespective of sensitization to fungi (i.e. positive skin prick test or fungusspecific IgE in serum).	Conditional	Very low	The recommendation not to use antifungal agents in patients with severe asthma without confirmed ABPA (irrespective of sensitization) places a higher value on avoiding possible adverse effects, interactions of antifungal agents with other medications and increased use of resources, and a lower value on uncertain possible benefits.	The recommendation not to use antifungal agents in patients with severe asthma without confirmed ABPA applies only to the treatment of asthma; it does not apply to the use of antifungal agents for other indications, for example, treatment of invasive fungal infections.
Bronchial thermoplasty	We recommend that bronchial thermoplasty is performed in adults with severe asthma only in the context of an Institutional Review Board-approved independent systematic registry or a clinical study (recommendation, quality evidence).	Strong	Very low	This recommendation places a higher value on avoiding adverse effects, on an increased use of resources, and on a lack of understanding of which patients may benefit and a lower value on the uncertain improvement in symptoms and quality of life.	This is a strong recommendation, because of the very low confidence in the currently available estimates of effects of bronchial thermoplasty in patients with severe asthma. Both potential benefits and harms may be large and the longterm consequences of this new approach to asthma therapy utilizing an invasive physical intervention are unknown. Specifically designed studies are needed to define its effects on relevant objective primary outcomes such as exacerbation rates, and on long-term effects on lung function. Studies are also needed to better understand the phenotypes of responding patients, its effects in patients with severe obstructive asthma (FEV₁ <60% of predicted value) or in whom systemic corticosteroids are used, and its long-term benefits and safety. Further research is likely to have an important impact on this recommendation.