Can Inhaled Corticosteroids Prevent Asthma Exacerbations?

Dhananjay Desai; Salman Siddiqui; Christopher Brightling

Disclosures

Curr Opin Pulm Med. 2011;17(1):16-22. 

In This Article

Asthma Exacerbations: The Role of Inhaled Corticosteroids

Steroids have been used routinely in the management of asthma since the 1960s, and in the 1970s the introduction of ICSs revolutionized treatment. Corticosteroids have broad anti-inflammatory effects and the current view of their mechanism of action is reviewed by Rhen and Cidlowski.[30] Of importance in asthma, corticosteroids reduce the production of pro-inflammatory cytokines, particularly the Th2 cytokines IL-4, 5 and 13; airway spasmogens like leukotriene LTB4 and LTC4 and thromboxane; and the influx and survival of inflammatory cells specifically eosinophils, lymphocytes, macrophages and mast cells.[31,32] Corticosteroids improve asthma symptoms, health status, lung function and AHR. Importantly, the pattern of the underlying airway inflammation is a major determinant of response to corticosteroids with greater improvements in all domains in those asthmatics with eosinophilic airway inflammation.[33]

There are numerous trials of ICSs in asthma, but remarkably few have been placebo-controlled, of significant size, powered adequately, or have followed up patients long enough to address the temporal effect of ICSs on outcomes like exacerbations and lung function. More recent trials of corticosteroid and long-acting beta-agonist (LABA) combination inhalers have focussed more upon exacerbations and have demonstrated a consistent reduction in exacerbation frequency.[34,35,36•] The use of combination inhalers is discussed in detail in this issue by Sears.[37] Here we shall focus upon the earlier trials of the effect of ICSs upon exacerbations.

The START trial[38] aimed to address the effect of ICSs upon lung function and exacerbation frequency in a large group of steroid naïve asthmatic adults and children with mild persistent disease and relatively normal lung function, using budesonide or placebo. That is the largest trial of ICSs to date, which established the role of ICSs in reducing exacerbations and improving lung function. The treatment arm had nearly a 50% reduction in time to first exacerbations with a significantly reduced (2 vs. 4%) number of severe/life threatening events compared to placebo, in addition only 20% of these patient needed additional ICSs therapy compared with 34% in the placebo group. There was a small nonsignificant improvement in forced expiratory volume in 1 s (FEV1) in the treatment arm. Similarly, in another study of mild persistent asthma (OPTIMA),[39] budesonide alone (200 μg/day) reduced the rate of severe asthma exacerbations by nearly 60% and health quality indices including poorly controlled days by 48%. The studies are summarized in Table 1. In a more moderate to severe population (FACET),[9] budesonide therapy reduced the rate of severe asthma exacerbations by almost 50% and mild exacerbations by a third, although the last statistic may be a reflection of periods of poor control. The maximal clinical benefit in all outcomes apart from reduction in exacerbations was seen in a group of patients who were well controlled on low doses of ICSs and in whom ICSs therapy was increased in a four-fold dose during the pre-exacerbation phase. A marked increase in ICSs dose during a pre-exacerbation period appears to be similar to taking a course of systemic steroids. However this strategy is not effective in reducing or preventing exacerbations and other asthma-related outcomes.[48,49•] It also appears that despite a delay in commencing ICSs after diagnosis of asthma in a mild population, intervention confers similar benefit as opposed to non-treatment.[50•]

A comprehensive meta-analysis comparing ICSs to a placebo,[51] showed the overall risk reduction of all (mild and severe) exacerbations was 0.46 across all pooled studies and favoured ICSs. This beneficial effect was seen at all levels of disease severity and differing lung function. Reduction of exacerbations was similar across the FEV1 tertiles. High-dose therapy (>500 μg beclomethasone equivalent) had a further benefit of reduced exacerbations as compared to lower doses.

The potency of an ICS depends on the molecular structure, lipophilicity, delivery device, deposition in the airways, mechanism of action and finally amount of systemic absorption and bioavailability.[36•] At this point, there is no evidence to suggest the superiority of one ICS molecule over the other and tailoring the drug regimes and delivery device to the patient's needs appears to be the best pragmatic approach. Importantly, ICSs are remarkably well tolerated, and though they may induce local side-effects, increased risk of osteoporosis, reduction in growth in children, adrenal suppression and increased risk of pneumonia, all of these risks are small.[9,38–40] Therefore, the benefits in terms of reduction of exacerbation risk and improved symptoms outweigh the potential side-effects.

Beyond ICSs in combination with LABA and other therapies, current guidelines recommend systemic corticosteroids. Systemic corticosteroid therapy can modulate lower airway inflammation beyond the effects of ICSs.[52] There is increasing evidence to support the role of small airways disease particularly in severe asthma.[53–55] However, there is a paucity of evidence that systemic corticosteroid therapy in asthma reduces the risk of exacerbations above the effects of ICSs. In contrast, there is substantial evidence of increased side-effects.[56] Therefore, ICSs should remain the mainstay of therapy for asthma and regular systemic corticosteroid therapy should be restricted to refractory patients assessed and managed in specialist centres whereby careful consideration of confounding factors such as adherence and co-morbidities can be addressed.[57,58]

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