Problematic Severe Asthma in Children – The Pandora’s Box
Treatment of Severe, Therapy-resistant Asthma There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma, and most treatments are unlicensed. Data have to be largely extrapolated from trials in children with mild to moderate asthma, and from adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). Most treatments are unlicensed, with the exception of omalizumab.74
In the first category are high-dose ICS (up to 2,000 mcg/day fluticasone equivalent), oral prednisolone, the anti-IgE antibody omalizumab, high-dose long-acting β-2 agonists, low-dose oral theophylline, and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, immunoglobulins, subcutaneous β-2 agonists and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole.
The Exacerbating Phenotype
There is physiological evidence that baseline asthma control and exacerbations are not the same.75,76
Poor baseline control is
characterised by symptoms and marked diurnal variability in peak expiratory flow; acute exacerbation – that is usually virally mediated77
– is indicated by a steep decline in peak flow with no increased variability.
Increasingly, guidelines have separated baseline asthma control from exacerbations. Persistently poor baseline control78 severe exacerbations79–81
and previous are both predictive of future acute
exacerbations. However, children might have good control but still have exacerbations, and increasing conventional medications to the
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limit does not abolish all exacerbations and only increases the risk of side effects. There is clearly overlap, and there is no evidence that increasing ICS dose between exacerbations in a well-controlled child is an effective strategy.
Children with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat. Baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS,82
exacerbations can be considered, but there is no evidence on which therapeutic option to recommend.
Over the past 15 years there has been a lack of consensus about the definition and diagnosis of severe asthma. Research studies in patients with severe asthma have used different inclusion and exclusion criteria, and the nomenclature to describe these patients has been quite confusing. There is now increasing evidence that patients with ‘severe asthma’ form a heterogeneous group, and that many factors may influence the clinical presentation. Children with problematic severe asthma should be assessed in a systematic manner. Less than half of all children referred with ‘problematic severe asthma’ turn out to have true severe, therapy-resistant disease. Children who have ongoing asthma symptoms after all basic management steps have been optimised are a disparate group, with different patterns of inflammation. There is a lack of high-quality evidence on what treatment should be used in these children, and most treatments are unlicensed. For the development of innovative therapies, there is an urgent need for an accurate characterisation of patients with truly severe, therapy-resistant asthma and for sub-phenotyping these patients. International collaborations are essential if progress is to be made. Ultimately we should seek to determine why severe therapy-resistant asthma develops; however, given our present lack of knowledge, this hope still remains in Pandora‘s box. n
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or both at the time of
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