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Helsinki, Finland
Dr. Haahtela is Professor of Clinical Allergology, Skin and Allergy Hospital, Helsinki University Central Hospital.
Correspondence to: Tari Haahtela, MD, Professor of Clinical Allergology, Skin and Allergy Hospital, PO Box 160, Helsinki, Finland 00029; e-mail: tari.haahtela{at}hus.fi
It is acknowledged that asthmatic inflammation of the bronchial mucosa should be the primary target of the treatment of asthma. In patients with early asthma, lung function will usually normalize completely after the inflammation is relieved.1 The patient will usually become asymptomatic, but the disease is not cured. The inflammation may recur frequently and become persistent, requiring more or less regular treatment. In Finland, a 10-year national asthma program2 focused on the early detection and treatment of inflammation, and the burden of asthma has decreased considerably. For example, disability pensions decreased 76% from 1993 to 2003, and the increase in the costs ended.2 Early intervention saves money and protects patients from suffering.
Patients take medication to relieve symptoms but also to reduce harm in the future. Do inhaled corticosteroids reduce the risk of lung function decline over time? This has been debated,3456 but the evidence has been insufficient to make firm conclusions in patients with mild-to-moderate asthma.3 This is a key question because recommendations on the regular use of inhaled corticosteroids depend on the answer. If inhaled corticosteroids do not prevent accelerated lung function decline, which takes place in patients with chronic asthma,7 their regular use may not be that important.8
O'Byrne and coworkers9 address that question in this issue of CHEST (see page 1478), and suggest that early intervention with an inhaled corticosteroid (budesonide, 200 to 400 µg once daily) slightly reduces the loss of lung function (FEV1) over a period of 3 years.9 The patients had recent-onset, mostly mild but still persistent asthma (ie, symptoms for < 2 years). The results are an extension of the so-called START study (inhaled steroid treatment as regular therapy in early asthma study),10 which indicated that once-daily, low-dose therapy with budesonide decreases the risk of severe exacerbations and improves asthma control.
In the study by O‘Byrne et al,9 the curious fact was that the marked difference in FEV1 values between the patients treated with budesonide and those treated with placebo had already developed during the first 6 weeks of treatment. After that, both groups showed slight and almost parallel decreases in prebronchodilator and postbronchodilator FEV1 values (budesonide group, 0.7% per year; placebo group, 0.4% per year). Placebo was not inferior to budesonide after the initial decline, but it should be kept in mind that by the end of the 3 years 45% of the patients in the placebo group had received nonstudy corticosteroids. Also, patients receiving budesonide, if they had become asymptomatic, do not usually adhere very well to the medication regimen.11 Nevertheless, the function decline was small in this group of patients with a recent onset of the disease, which raises the question of the clinical importance of airway remodeling in patients with mild asthma. The parallel decline of FEV1 in the two groups, after the initial difference, also poses another question. Is there a corticosteroid-resistant element in the asthmatic process, or are higher steroid doses needed?
Asthma is a syndrome that has been difficult to define precisely. Asthma is an "umbrella" diagnosis that is characterized clinically by reversible bronchial obstruction. But, it covers several genotypes (ie, in terms of factors affecting disease severity or responses to various drugs). We have to recognize that on the population level most cases of asthma are intermittent or mild (70 to 80%); these patients are probably not facing any significant lung function loss over time whatever their treatment. In fact, we need to pay much more attention to patients at the mild end of the asthma spectrum, who constitute the majority of patients. What are the evidence-based strategies needed to treat both children and adults in the long term? How intensive should the initial treatment be? When is intermittent treatment sufficient, and how long should the treatment periods be?
Most asthma studies have been performed in patients with moderate persistent asthma (to have room for improvement and for the possibility of showing treatment differences), and the results are often carelessly generalized to whole asthmatic populations. Along with better options for measuring not only lung function but the inflammatory component of asthma,1213 we can focus better on the early, often milder stages of the disease when lung function is still mostly preserved.
But there exist the "decliners," those patients (estimates range from 20 to 30% of asthmatic patients) in whom significant irreversible airways obstruction develops over time. Is the possible "slowing-down" effect of corticosteroids seen more readily in those patients? Recent 10-year observational data14 from Denmark have indicated that this may be the case. In a general population sample, the treatment of asthma with inhaled corticosteroids was associated with a less steep decline in FEV1 of 18 mL/yr compared with patients not receiving this treatment (p = 0.01).
The first results in the mid-1990s indicated that delays in initiating therapy with inhaled corticosteroids may lead to an impaired functional response.15 However, the study was not designed to determine the effect of the delay in the first place. The nonrandomized studies by Agertoft and Pedersen16 and Selroos et al17 pointed in the same direction: delay was harmful. However, the prospective Childhood Asthma Management Program study18 questioned the benefit of therapy with inhaled corticosteroids on the lung function of children, but as no significant FEV1 decline was seen in the placebo group, the treatment effect was difficult to demonstrate.
It is probable that we will never receive the ultimate answer to the question, do inhaled corticosteroids alter the long-term functional (natural) course of asthma? The length of the follow-up required, ethical considerations, and costs will prevent that. These doubts should not, however, hinder us from using the most effective treatment and from using it early enough. The results of the studies by O‘Byrne et al9 and Lange et al14 reinforce our current practice of preventing all asthma events with the regular use of inhaled corticosteroids (the dose can vary) in patients who have symptoms on most days.
Footnotes
Dr. Haahtela has received speaker fees from and/or been on the advisory boards of Alk-Abello AstraZeneca, MSD, Novartis, Orion Pharma, and UCBPharma.
References
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