To the Editor:
Bronchial hyperresponsiveness (BHR), i.e. increased narrowing of the airways after exposure to non-allergic stimuli, is a hallmark of asthma. BHR is a risk factor for asthma development and, additionally, a marker of worse disease outcome in asthma [1, 2]. It is generally acknowledged that obstruction of the large airways due to inflammation and remodelling contributes to more severe BHR. This is plausible, given that BHR is expressed as the concentration or dose of a stimulus that induces a 20% fall in forced expiratory volume in 1 s (FEV1). Recent studies suggest that asthmatics with BHR have more severe small airways obstruction [3, 4]. However, little is known about the converse, i.e. the association between small airways obstruction and the severity of BHR. Our aim was to assess: 1) whether asthma patients with small airways obstruction express more severe BHR than those without small airways obstruction; and 2) whether small airways obstruction is associated with more severe BHR independently of FEV1.
We analysed data from patients with mild-to-moderate asthma who were included in a previously published study on inhaled corticosteroids (ICS) in primary care [5]. All subjects underwent spirometry before and after 1 mg terbutaline, measuring FEV1, forced vital capacity (FVC) and mean expiratory flow at 50% of FVC (MEF50). BHR was assessed using a histamine challenge test, measuring the provocative dose causing a 20% fall in FEV1 (PD20) (histamine). All patients were hyperresponsive to histamine (PD20 <9 mg). Small airways obstruction was defined as a MEF50 of less than or the same as the lower limit of normal (LLN); other small airways parameters, such as the mean expiratory flow between 25–75% of FVC (MEF25–75), residual volume/total lung capacity and FVC/slow vital capacity, were not available in our database. We compared asthma patients with and without small airways obstruction using unpaired t-tests, Mann–Whitney U-tests or Chi-squared tests as appropriate. In addition, a multivariate linear regression analysis was performed to assess whether MEF50 is independently associated with the PD20 histamine (log2 transformed). We added FEV1, age, sex, height and use of ICS as covariates.
Of the 94 patients, 34 had small airways obstruction (MEF50 ≤ LLN). Table 1 shows that patients with small airways obstruction had more severe BHR (geometric mean PD20 histamine 0.2 versus 0.6 mg respectively, p<0.01). In addition, FEV1, FVC and FEV1/FVC values were significantly lower and reversibility values were significantly higher in patients with small airways obstruction. Patients with small airways obstruction using ICS had a significantly higher daily dose of ICS than patients without small airways obstruction (800 versus 500 μg per day beclomethasone dipropionate equivalent). A lower MEF50 value was significantly associated with more severe BHR in the multivariate linear regression analysis, independently from FEV1, age, sex, height and ICS use (b = 0.813, p = 0.01). We repeated this analysis with MEF50/FVC instead of MEF50, and with MEF50 % predicted and FEV1 % pred instead of the absolute values. These analyses showed similar results.
This study shows that asthma patients with small airways obstruction have more severe BHR independently of the level of FEV1. Despite intensive research over the past 40 years, the mechanisms underlying BHR have still not been clarified. It is known that the severity of BHR is related to airway wall inflammation in asthma. Other factors that influence BHR are the structural changes of the airways such as deposition of connective tissue components, increased vessel formation and smooth muscle mass and oedema, contributing to thickening and increased stiffness of the airways. These processes are known to occur in the large airways and there is now increasing evidence to suggest that they also occur in the small airways. Small airways obstruction, i.e. lower MEF25–75 values, has previously been reported to be present in children with BHR and in adults with mild asthma and BHR [3, 4]. Another study showed that patients with hyperresponsiveness to mannitol have more severe small airways obstruction [6]. Together, these and our results suggest that an unexplained part of BHR originates from the small airways.
A limitation of our study may be the use of MEF50 as a marker of small airways obstruction. Obstruction in the proximal airways may also lead to airflow limitation with reduced MEF50. As the patients with a MEF50 ≤ LLN had a reduced FEV1, we performed a multiple linear regression analysis in which we corrected for FEV1. In this analysis, MEF50 was associated with the severity of BHR independently of FEV1. In addition, we performed our analysis with MEF50/FVC, since FVC is known to influence MEF50 levels, and with MEF50 % pred and FEV1 % pred. The results remained similar, demonstrating the robustness of our findings.
We found that small airways obstruction is associated with the severity of BHR in asthma, independently of FEV1, and this may have important implications for asthma management. Treatment with large-particle ICS rapidly improves FEV1 in asthma, an effect that remains stable thereafter. In contrast, improvement in BHR occurs gradually and ICS do not completely abolish the presence of BHR in most asthmatics, even after longstanding treatment [7]. This may have implications for asthma management; Sont et al. [8] showed that ICS treatment tailored according to the severity of BHR improves the clinical outcome and airway remodelling of asthma. In addition, targeting the small airways with currently available small-particle ICS may be more effective in reducing BHR originating in the small airways. A recent study demonstrated that treatment with small-particle ICS is at least equally effective in achieving asthma control as large-particle ICS treatment at half the dose [9]. Moreover, we have recently shown that small-particle ICS induces a greater improvement of BHR to AMP than large-particle ICS, but only when the provocation was performed using small-particle AMP (1.74 versus 0.8 doubling doses, respectively) [10]. Taken together, our findings suggest that the currently applied provocation tests have important shortcomings for investigating BHR originating from the small airways. First, the read-out for airway obstruction during provocation is FEV1,which mainly a large airways parameter. Secondly, the DeVilbiss 646 (DeVilbiss Healthcare, Somerset, PA, USA) is the recommended nebuliser for provocation tests; this nebuliser produces relatively large particles of 3.7 μm [10]. Therefore, most particles will deposit in the large airways and few particles will actually reach the small airways. Thus, current provocation tests will underestimate the BHR of small airways. This is important, because BHR of the small airways may contribute to asthma symptoms and control in real life.
We conclude that the small airways contribute significantly to the severity of BHR, a contribution that is independent of the level of FEV1. We hypothesise that the contribution of the small airways to the severity of BHR in asthma is much larger than has been considered to date. Performing studies with provocation tests with small airways measurements, e.g. impulse oscillometry, and small-particle stimuli will give better insights into BHR of the small airways. Further studies should show whether small-particle ICS improves BHR more rapidly and/or to a larger extent than large-particle ICS, with the ultimate benefit being to asthma patients in clinical practice.
Footnotes
Statement of Interest
Statements of interest forM. van den Berge and D.S. Postma can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
- ©ERS 2013