Reviews and feature article
Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review

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Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.

Section snippets

Asthma symptoms and control

Several studies have investigated the association between asthma symptoms or control and small-airways dysfunction, as reflected by different parameters of the small airways. Symptoms were assessed with asthma questionnaires or self-reported by the patient.

Takeda et al15 measured large- and small-airways function with impulse oscillometry in 65 patients with stable asthma and assessed associations with health status, dyspnea, and asthma control using the St George's Respiratory Questionnaire,

Occurrence of an asthma exacerbation

Bourdin et al21 showed that frequent (≥2/y) exacerbators have a higher degree of small-airways dysfunction as reflected by the SBNT phase III slope than infrequent exacerbators (<2/y), whereas FEV1 percent predicted values were comparable between these 2 groups (Fig 2, B). These findings are in line with those of in't Veen et al,33 who demonstrated that frequent exacerbators have a higher SBNT closing volume and closing capacity than infrequent exacerbators.

Air trapping can be assessed by using

Nocturnal asthma

We identified several studies investigating the association between small-airways dysfunction and nocturnal asthma. First, Kraft et al39 showed that peripheral airways resistance, as measured with a wedged bronchoscope, is increased in patients with nocturnal compared with nonnocturnal asthma. A further study investigated both endobronchial and transbronchial biopsy specimens at daytime (4 am) and nighttime (4 pm) in 11 patients with nocturnal asthma, which was defined as a 15% or greater

Change of small-airways function during a provocation test

Two studies have used the wedged bronchoscope technique to investigate the response of the small airways to a provocation test.45, 46 In one study peripheral airways resistance increased faster in patients with asthma than in healthy control subjects after local application of histamine.45 The other study demonstrated that greater peripheral airways resistance is associated with more BHR to methacholine.46 Together, these results confirm the sensitivity of the small airways to nonallergic

Involvement of the small airways in the response to exercise

Fonseca-Guedes et al61 found a significant correlation between the exercise-induced decrease in FEF25%-75% and FEV1, particularly in patients with moderate-to-severe asthma. Interestingly, in patients with mild asthma, a significant decrease in FEF25%-75% (≥26%) was observed, whereas FEV1 did not decrease by more than 10%. In addition, Rundell et al62 analyzed lung function and asthma symptoms in ice hockey players before and after exercise and observed a significantly lower baseline FEF25%-75%

Effects of allergen exposure on small-airways dysfunction

Asthma and allergies are strongly associated, and allergen exposure can provoke asthma symptoms in sensitized subjects. Allergen exposure can result in an immediate airways response, the so-called early asthmatic response, followed by a late-phase response in a subset of asthmatic patients.74

The role of the small airways in the allergic response has been investigated by the change in the FEF50% after breathing a mixture of helium-oxygen compared with room air.75, 76 Because of the lower gas

Association of small-airways dysfunction and exposure to particulate air pollution

Both in children and adults with asthma, higher levels of particulate air pollution have been associated with an increase in respiratory symptoms and use of rescue medication and a decrease in lung function.90, 91, 92, 93, 94 Particulate air pollution can be categorized according to particle size. Particulate matter larger than 10 μm in diameter (PM10) reflects the coarse particle fraction that will mainly deposit in the larger airways, particulate matter of less than 2.5 μm in diameter (PM2.5)

Effect of asthma treatment on small-airways function and symptoms

Several studies have investigated the effect of treatment targeting the small airways on asthma control. In a recent study Farah et al106 investigated the predictive value of the change in asthma control after either ICS uptitration in patients with poorly controlled asthma (ACQ >1.5) or those with steroid-naive asthma or ICS downtitration in the case of patients with well-controlled asthma. A higher level of small-airways dysfunction, as reflected by higher Sacin and Scond values, was the only

Conclusions

This systematic review demonstrates that small-airways dysfunction is associated with clinical features of asthma: worse control of asthma,15, 16, 20, 21 higher numbers of exacerbations,21, 27, 33 nocturnal asthma,40, 41, 44 more severe BHR,55, 56, 59, 60 exercise-induced asthma,61, 64, 67, 68, 69, 70, 71 and the late-phase allergic response (Table II).

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    Supported by Chiesi.

    Disclosure of potential conflict of interest: D. S. Postma has received grants from the Dutch Asthma Foundation, NWO, ZonMw, SAB, AstraZeneca, and Chiesi and has received travel support from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Nycomed/Takeda. M. van den Berge has consulted for GlaxoSmithKline and Novartis and has received payment for a lecture for Nycomed. The rest of the authors declare that they have no relevant conflicts of interest.

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