Inhaled corticosteroids moderate lung function decline in adults with asthma

Short abstract

Further evidence of the benefit of long term inhaled corticosteroids in asthma

Inhaled corticosteroids are the mainstay of asthma treatment. They have earned this central place in our therapeutic armamentarium by their rapid alleviation of persistent asthma symptoms, improvement in lung function, prevention of exacerbations including those severe enough to require hospitalisation, and by preventing asthma deaths, even at low doses.¹,² They appear indicated as maintenance therapy for asthma patients who have more than occasional respiratory symptoms,³ and probably need to be used regularly to provide benefit.⁴ A recent study suggesting the contrary used a protocol of initial intense treatment with inhaled and oral corticosteroids which is not readily applicable clinically.⁵

Patients with asthma have a more rapid decline in lung function over time which results in significant irreversible airways obstruction in a substantial minority (estimates range from 23% to 33%).⁶,⁷,⁸,⁹ Such fixed airflow limitation in asthma appears to be a manifestation of airway remodelling.¹⁰ While corticosteroids have many actions which might be expected to limit such remodelling, there is no consensus as to their efficacy in vivo.¹¹ Several studies have suggested that the decline in lung function might be less in those making regular use of inhaled corticosteroids, but the number of subjects taking corticosteroids regularly has been small.¹²,¹³ Furthermore, even among subjects with mild asthma, inhaled corticosteroids appear to be limited in their capacity to prevent deterioration in lung function.¹⁴ The benefit of inhaled corticosteroids may be greater if used earlier in the course of the disease,¹⁵,¹⁶ although certain aspects of remodelling appear resistant to short courses of inhaled corticosteroids independent of the duration of symptoms.¹⁷ When beneficial effects of inhaled corticosteroids on remodelling have been observed, this has been achieved only after 12 months of treatment—much slower than their anti‐inflammatory effect.¹⁸

In this issue of Thorax Lange and colleagues, using information from the Copenhagen City Heart Study, describe a reduction in the decline in forced expiratory volume in 1 second (FEV₁) over 10 years in patients with asthma aged over 30 years who were using inhaled corticosteroids throughout the observation period.¹⁹ Overall, inhaled corticosteroids reduced the annual decline in FEV₁ by 23 ml/year compared with asthma patients not using inhaled corticosteroids, and this benefit was of similar magnitude in smokers and non‐smokers. To put the size of this benefit into context, smoking over the 10 year observation period was associated with a 10 ml/year faster decline in lung function.

There are several limitations to the study which are acknowledged by the authors. Firstly, asthma is defined by self‐report only and the diagnosis of asthma might be more secure among those taking inhaled corticosteroids. The group not taking inhaled corticosteroids may contain more subjects with chronic obstructive pulmonary disease (COPD) who are well known to have rapid declines in FEV₁.²⁰ Furthermore, those subjects taking inhaled corticosteroids might also be consistently more compliant with environmental measures which would contribute to the lesser decline in FEV₁. Conversely, asthma patients who use inhaled corticosteroids might be expected to have more severe asthma and thus a greater decline in lung function. Such confounding by indication would cause an underestimation of the benefit of inhaled corticosteroids on decline in lung function in the current study. Finally, the choice of FEV₁ as an index of remodelling and irreversible loss of lung function is not optimal. A better index would have been the post‐bronchodilator FEV₁/FVC.⁸ Part of the decline in FEV₁ observed in the study by Lange and colleagues may be related to ongoing poor asthma control rather than to irreversible airflow limitation.

Even with these limitations, the study by Lange et al provides strong evidence that regular treatment with inhaled corticosteroids favourably alters the natural history of airway disease over the long term in patients with asthma. Stronger evidence is unlikely to be obtained, given the length of follow up required to be confident as to the significance of a reduction in FEV₁ decline²¹ and the ethical implications of withholding inhaled corticosteroids in a randomised trial.

While the benefit of inhaled corticosteroids on the decline in lung function was seen for the group as a whole, it is likely that the degree of benefit varied significantly between patients. The prognosis of asthma is highly variable, with many patients having consistently mild disease.²² For these patients, a small dose of inhaled corticosteroids can be expected to provide maximum benefit while, for others, fixed airflow limitation will develop with the usual approach to treatment.⁷ The AMPUL study group have already shown that remodelling may be decreased by intensifying asthma treatment in response to the degree of airway hyperresponsiveness,²³ while examination of sputum allows us to identify patients less likely to respond to inhaled corticosteroids and for whom new approaches are needed.²⁴

Thus, despite the further evidence of the benefit of inhaled corticosteroids in asthma provided by the study by Lange and colleagues, it behoves us to characterise our patients better in order to maximise the benefit of treatment in individual patients.