We identified references for this Review by searches of PubMed with the following search terms “severe asthma” or “therapy-resistant asthma” or “difficult asthma” from 1995 to June, 2010. Only papers published in English were included. Articles were chosen on the basis of their relevance to the paper and we also searched their bibliographies for references. We also included articles from our personal archives.
ReviewManagement of severe asthma in children
Introduction
Although the evidence base for the treatment of mild-to-moderate asthma in children is expanding,1, 2 paediatric asthma beyond stage 3 of the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines3 has been the subject of few good-quality studies. Several reviews have been published4, 5, 6 but primary data are sparse. Reviews have emphasised the wide differential diagnosis in children, the need to involve the school, as well as the home,4 the role of viral infections,5 and the importance of monitoring longitudinal change in lung function.6 Children with true therapy-resistant asthma constitute less than half of children referred with problematic severe asthma, and undergo detailed assessments of symptoms, spirometry, and inflammation, including invasive investigations such as bronchoscopy, before new therapies are used. This process helps to diagnose different forms of asthma: asthma, which is clinically characterised by poor control and multiple exacerbations, brittle asthma, with chaotic swings in peak flow, and severe asthma with fungal sensitisation, and persistent airflow limitation. Pathologically, asthma is characterised on the basis of proximal luminal inflammation, as persistently eosinophilic, neutrophilic, or paucicellular asthma. In this Review, we focus on children of school age and adolescents. We are not aware of any randomised controlled trials of treatment in true, therapy-resistant paediatric asthma, so we have based recommendations on personal practice, with cautious extrapolation from published papers on adult severe asthma and paediatric mild-to-moderate asthma. Many cases of apparently treatment-unresponsive asthma arise because the basics (eg, adherence, inhaler technique, dose and frequency, minimisation of allergen, and smoke exposure) have not been dealt with correctly.7, 8, 9 In a study in which two add-on regimens in symptomatic children were compared, despite being prescribed at least 400 μg budesonide per day plus a long-acting β2 agonist, only 55 of 292 children assessed for eligibility could be randomised; of the other 237 children, 89 were non-adherent and 59 had mild or no asthma.7 In two well designed negative trials8, 9 in which the use of fractional exhaled nitric oxide (FeNO) was studied as an add-on to standard monitoring of uncontrolled asthma, similar problems occurred. In the first study,8 in the run-in period when basic management was assessed, the improvements in both groups were so great that there was little, if any, scope for further improvement. In the second study,9 in which detailed FeNO telemonitoring was used to adjust treatment, with intensive three weekly telephone contacts in control and active groups, both groups had the same amount of improvement in symptoms and reduction in inhaled corticosteroids. Despite guideline-based therapy and measurement of inflammatory markers (“inflammometry”), leading to excellent baseline control, many children still had severe exacerbations that required oral steroid therapy. This failure to control exacerbations indicates the dissociation between control and exacerbations, and that the problem of exacerbations merits more attention, which we further discuss later.
Thus, for a child with apparently severe asthma, the first step is to confirm the diagnosis and ensure that basic management strategies are in place. These strategies should affirm that an appropriate drug delivery device is used, that adherence to treatment is good, and that exposure to environmental triggers is minimised.10
Section snippets
Domains of severity in paediatric asthma
The four suggested domains of severity are given in panel 1. This classification assumes that acute exacerbations and baseline control, although overlapping, are distinct features,12, 13 which we further discuss later. Referral to specialist care will usually be prompted by symptoms (either exacerbations or poor control, or both), concerns about safety of the amount of medication, and future risk after an admission to intensive care.
Patterns of difficulty that trigger referral to specialist care
The different problems that trigger referral were characterised in one study as either “chaotic” (more than 30% variability in spirometry) or “non-chaotic” (less than 15% variability).14 These characteristics can be broken down into one or more of the categories provided in panel 2, listed in no particular order. These categories are unrefined, and novel biomarkers and mathematical analyses19, 20 will hopefully soon enable us to improve on clinical categorisation. We use these groupings because
The entry label: “problematic severe asthma”
When the child is initially referred, it will not be clear whether (1) the diagnosis is wrong (“not asthma at all”), and a diagnostic re-evaluation (not discussed in this Review) is essential; (2) the asthma is mild, but exacerbated by one or more comorbidities (“asthma plus”); (3) whether this is “difficult-to-treat asthma” because of potentially reversible factors such as poor adherence to treatment or poor inhalation technique; or (4) they have true “severe, therapy-resistant asthma”, which
The first step: is it likely to be true severe, therapy-resistant asthma?
As a first step, we recommend a detailed re-evaluation, including both a hospital-based session and a nurse-led home visit.25 The current evidence base for the benefit of many measurements is poor, and much work is aimed at prospectively generating research data.
The next steps: invasive investigation?
Once the clinician is satisfied that the basic management needs are right, there is even less evidence to help decide on the next steps. Our personal practice is to use a two-stage, invasive protocol. The aims of this protocol are to identify the following. (1) Whether there is an additional unsuspected diagnosis. (2) Whether there is discordance between symptoms and airway inflammation, particularly if the child is symptomatic with no evidence of inflammation. Giving patients increasingly
Steroid responsiveness
There is no accepted definition of steroid resistance in children, and the mechanisms are unclear. Congenital steroid resistance from mutations in the corticosteroid receptor is rare.107 Acquired steroid resistance can extend over a range and can be overcome by high doses, albeit at the risk of increased side-effects. There are many potential mechanisms of steroid resistance,108, 109 but these have been studied mostly in adults and the relevance in children is not clear. What is clear is that,
Treatment of severe, therapy-resistant asthma
Unfortunately, treatment of severe, therapy-resistant asthma relies on a series of individual trials of single patients. In our clinical practice, we initially use drugs licensed in children before trying unlicensed and experimental therapy. Treatment strategies are summarised in Table 2, Table 3, and some aspects are discussed in more detail later. This section reflects personal practice, not an evidence-based approach.
Future treatment options
Future treatment options include therapies trialled in adults, and consideration of specific paediatric factors.
Anti-interleukin-5 antibody, other monoclonal antibodies, and bronchial thermoplasty all show promise in adults141, 142, 165, 166 but there are no data in children. The value of carefully characterising patients rather than treating anyone with severe asthma is evident in adult studies of anti-interleukin-5;141, 142 it is likely that this same careful approach will be needed for
Future perspectives
Current strategies mainly use sputum to monitor proximal airway luminal inflammation. However, other compartments might be important and discordant. In bronchoscopic studies in children, airway mucosal and luminal changes can be different,178 and it is unclear which is most important. We have no non-invasive biomarkers for mucosal inflammation. Distal airway inflammation may cause poorly controlled or nocturnal asthma.179, 180, 181 In a study in adults, nocturnal asthma was associated with an
Search strategy and selection criteria
References (185)
- et al.
Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial
J Allergy Clin Immunol
(2007) Effects of viral respiratory infections on lung development and childhood asthma
J Allergy Clin Immunol
(2005)Facing the challenges of childhood asthma: what changes are necessary?
J Allergy Clin Immunol
(2005)- et al.
Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial
Lancet
(2008) - et al.
Differences between asthma exacerbations and poor asthma control
Lancet
(1999) - et al.
Difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma
J Allergy Clin Immunol
(1998) - et al.
Severe childhood asthma: a common international approach?
Lancet
(2008) - et al.
National Institutes of Health/National Heart, Lung and Blood Institute Severe Asthma Research Program
J Allergy Clin Immunol
(2006) - et al.
Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma
J Allergy Clin Immunol
(2007) - et al.
High-resolution CT features of severe asthma and bronchiolitis obliterans
Clin Radiol
(2002)