The standard technique for measuring variability in airflow obstruction is the portable peak flow meter. This simple tool for monitoring asthma control has also been useful in aiding diagnosis, particularly for occupational asthma. While specific inhalation testing remains the gold standard, serial measurement of peak expiratory flow (PEF) has been used in epidemiological studies of occupational asthma. A simple comparison between pre- and postshift for demonstrating variability with a significant fall between pre- and postshift measurements supports the diagnosis of occupational asthma [2]. Lung function testing for the demonstration of reversible or inducible airflow obstruction relies on the standard spirometric measurement of forced expiratory volume in 1 second (FEV1). An improvement in FEV1 of greater than 12% and 200 mL from baseline in response to bronchodilator administration defines significant reversibility of airflow obstruction which is diagnostic of asthma. Conversely, a fall in FEV1 from baseline of 15% for indirect challenges (e.g., inhaled hypertonic saline, mannitol, adenosine monophosphate or exercise challenge) or 20% for direct challenges (e.g., inhaled methacholine or histamine) signifies significant inducibility of airflow obstruction which is diagnostic of asthma.

Whilst these techniques of measuring variability, reversibility or inducibility of airflow obstruction remain fundamental to our current clinical diagnosis of asthma, they rely on a single summation measure of airflow at the lips to a forced expiratory manoeuvre (PEF and FEV1). The complex asymmetrical dichotomous branching structure of the airway tree through 23 generations from the trachea to the terminal bronchioles and alveolar ducts indicate potential for complex flows with regional heterogeneity in different segments of the airway tree, particularly towards the periphery of the lung. In a normal airway tree, the region of maximum resistance to airflow is in the proximal 4 to 8 generations of airway (Fig. 1). Hence, this region of maximum resistance may be regarded as the "choke point" of the airway tree to a forced expiratory manoeuvre, and is the major determinant of measures such as PEF and FEV1. The bulk of bronchial smooth muscle in the airway tree is wrapped around airways of these generations and any rapid change in resistance in this part of the airway tree will be reflected by significant changes in the PEF and FEV1. Hence, it follows that bronchial smooth muscle spasm and relaxation in these proximal generations of airways are the major contributor to the observed variability, reversibility and inducibility of airflow obstruction used in the diagnosis of asthma.

Airways with an internal diameter less than 2 mm that do not contain cartilage in their walls and extend from the 8th generation airways to the periphery of the lung are collectively referred to as the "small airways" [3]. Compared to the large (> 2 mm) airways, the cross-sectional surface area and airway volume of the small airways are far greater, but contribute only 10% of the total airway resistance [4, 5]. Current measures of airway resistance and airflow with standard spirometric techniques such as FEV1 and PEF, do not capture the resistance in this part of the airway tree. Hence, these distal small airways are regarded as the "silent zone" of the airway tree, since extensive disease can be present with little abnormality in conventional lung function tests. In chronic obstructive pulmonary disease (COPD), obstruction of these small airways due to loss of parenchymal support with emphysema and bronchiolitis with mucus production and airway wall thickening, is the primary pathophysiology responsible for its clinical manifestations. However, pathology and dysfunction in these small airways have also long been suspected to contribute to the pathogenesis and natural history of asthma. Studies in the 1970s using density dependence of maximum expiratory flow with inhalation of helium-oxygen mixtures showed physiological abnormalities in the distal airways in asthma [6]. In the early 1990s direct measurement of pressure-flow relationship with a fiberoptic bronchoscope wedged into a subsegmental bronchus showed significant physiological and mechanical changes in the distal airways in a small group of symptomatic asthma patients compared with normal subjects [7]. However, these techniques are invasive and/or are not clinically practical.

The main techniques most widely researched which can measure small airways function without requiring the forced expiratory manoeuvre are the forced oscillation technique (FOT) and the multiple breath washout technique (MBW).

This ventilation heterogeneity in the periphery of the lung as detected by the MBW and FOT has emerged as an important marker of asthma disease activity, even in the absence of changes in standard spirometric measurements. Ventilatory heterogeneity in the conductive region (Scond) of the lung has been shown to be a strong determinant of the inducibility of airflow obstruction, i.e., airway hyperresponsiveness [15] as well as asthma symptom control [16]. It also a marker of, and may predispose to catastrophic asthma, through complex pulmonary airway tree behaviour in sudden airway narrowing and avalanche-like reopening [17]. In a group of patients with a severe exacerbation of asthma, that there was a significant correlation between ventilation heterogeneity in the acinar (Sacin), region of the lung and FEV1 percent predicted [18] but not with ventilation heterogeneity in the small conducting airways (Scond). Patients with ventilatory heterogeneity have also been shown to have more frequent asthma exacerbations [19]. This mounting physiological evidence supports the importance of small airways dysfunction in asthma, even in the absence of currently accepted spirometric evidence of asthma activity. These results add a further dimension to our understanding of asthma, and help gain significant insights on clinically important asthma phenotypes, by defining acinar or conductive "physiotypes" of ventilation heterogeneity.

High-resolution computed tomography (CT) has been used to assess airway wall thickness of larger airways to determine airway remodelling and demonstrate evidence of small airways obstruction with gas trapping on expiration [20]. Small airways are difficult to image as their cross-sectional area is smaller than the spatial resolution of conventional CT. Hence, CT results are limited mainly to structural analyses of larger airways. Magnetic resonance imaging (MRI) has capability of exquisite spatial resolution of solid organs but relies on a unique tissue contrast of water and fat protons (1H) in their local tissue environments. MR imaging of the lung is difficult because of its low physical and proton density giving rise to a weak MR signal. MR imaging of the lung is further complicated by the many air-tissue interfaces that introduce magnetic susceptibility effects, causing a rapid decay of the MR signal in the lung. However, recent advances in contrast enhanced CT and MRI imaging have opened up an exciting new research field of functional lung imaging.