Cystic Fibrosis: The Role of the Small Airways

Introduction

Although there is ongoing debate as to when cystic fibrosis transmembrane conductance regulator (CFTR)-related disease is initiated, there is consensus that disease manifestations presents where CFTR plays an important role in organ physiology.⁽¹⁾ In the lung, this means that CF is mainly a disease of the airways rather than the lung parenchyma, although some evidence exists that inflammation may extend to the alveoli in severe disease.⁽²⁾ CFTR plays an important functional role in controlling fluid transport through airway epithelial cells, but it not expressed in significant quantity in the alveoli where fluid transport is regulated though other mechanisms.⁽³⁾ Most evidence would suggest that CF babies are born with normal airways and lungs. However, this view has been challenged by recent studies in a pig model of CF where large airway abnormalities in cartilage development were found, and limited evidence from CT studies in infants would also suggest differences in shape of the trachea.⁽⁴⁾ Although this is an interesting new aspect of CFTR-related pathology, it is unlikely to be of major functional consequences for CF-related disease manifestation as the primary functional abnormality in the lung is thought to be an imbalance between fluid secretion due to defective CFTR-related chloride secretion and sodium hyperabsorption due to increased activity of the epithelial sodium channel.⁽⁵⁾ Recent data from the pig model have also challenged the view that sodium hyperabsorption is a primary abnormality, and it has been difficult to establish the presence on airway surface liquid depletion in specimens from humans or large animal models.⁽⁶⁾ This may indicate that CFTR dysfunction may be crucial in responding to insults that require increased secretion of fluid while compensatory mechanisms such as the P2Y receptor-mediated chloride transport are still sufficient to compensate fluid balance in CF airways during times of relative stability. This view would be supported by the nonhomogeneous distribution of CF lung disease, the presence of both normal and abnormal mucociliary transport in different regions of the CF lung, and the negative effect of viral infection that reduce alternative chloride transport in CF patients.^(7,8)

Histological specimens of CF infants are scarce, but early studies in newborn infants dying of meconium ileus have described dilatation of mucus glands in the airways as the first abnormality.^(9–12) These changes were primarily found in smaller airways, leading to the concept that this may be the region demonstrating initial pathology. Studies clarifying this have been hampered by at least two hurdles: (1) to define what constitutes a “small airway,” and (2) to measure and track abnormalities in this region of the lung. Both of these are crucial factors not only for early detection of disease in patients, but also for targeted treatment approaches. Small airways have been traditionally described by size, and the term of a diameter of less than 2 mm has been used to characterize small airways;⁽¹³⁾ this does not take into account developmental changes, as an airway of 2 mm is located in more central airways in an infant compared with an adult subject. This becomes crucial, if aerosol therapy is to target a specific area of the airways in subjects of different sizes. Alternatively, anatomic classifications have been used as a more accurate term referring to airways generations, but this is not very practical for clinical purposes. Therefore, there is no ideal definition describing the region of interest clinically in growing individuals.

Regardless of the definition, there are some physiological differences between small and large airways that are important both for diagnostic testing and therapeutic interventions. Airways divide dichotomously. Although the individual airways decrease in size, the surface area remains relatively constant until generation 8 to 10, when there is a large increase in overall surface area changing from about 3 cm² to 180 cm².^(13,14) This change in surface area is associated with a significant drop in pressure driving airflow and a change in the flow pattern from turbulent to laminar. In parallel, airway structure changes from airways will cartilaginous support to airway supported by muscular and fibrous tissue only. The combination of lower intramural pressure, smaller lumen, and reduced airway stability make small airways more prone to collapse.⁽¹⁵⁾

Multiple factors affect and alter small airway function in CF that have been reviewed recently.⁽¹⁶⁾ Histological studies in patients with severe lung disease undergoing lung transplantation have shown significant mucus accumulation in small airways as the prominent feature in CF.⁽¹⁷⁾ Unlike other obstructive lung diseases lung diseases such as chronic obstructive pulmonary disease (COPD) where most of the small airways are patent, more than 50% of the lumen was found to be taken up by mucus in lungs of CF patients.⁽¹⁷⁾ How significant this mucus obstruction is in patients with milder disease in not entirely clear, and other factors contribute to reduced small airway function. In addition, surfactant is traditionally thought to only play a role in maintaining patency of the alveolar space, but studies using bronchoalveolar lavage (BAL) fluid from patients with relatively mild lung disease have demonstrated that, if surfactant function is tested in a setup mimicking its ability to maintain patency of small airways, this function is significantly impaired.⁽¹⁸⁾ Therefore, multiple factors make small airways more vulnerable to pathological changes in CF.

Techniques to Define and Track Small Airway Abnormalities

An ideal test to reflect small airway abnormalities in CF should be sensitive in detecting early changes, be noninvasive, not require radiation, be responsive to interventions, and predict long-term outcome. Unfortunately, no test fulfills all of these requirements at the present time. The most sensitive imaging technique to date is computer tomography, which requires radiation, although the administered doses are decreasing with newer equipment and dose-adjusted protocols over time.^(19–21) Capturing small airway abnormalities has been challenging even with this technique and often depends on quantifying secondary events such as gas trapping and decreased perfusion in areas of airway obstruction. The latter two could potentially be visualized with magnetic resonance imaging (MRI)-based technology, which is currently subject of ongoing research efforts.⁽²²⁾ Mucosal biopsies can demonstrate changes in small airway structure, but are not suitable in a clinical setting.⁽²³⁾

Due to the large surface area and the relatively low flow rates lung function tests that depend on forced expiratory maneuvres are not ideally suited to capture small airway abnormalities. Spirometry, namely, forced expiratory volume in one second (FEV₁), is the best established parameter to define the severity and track lung disease over time in CF patients, but the test has limited sensitivity to capture small airways abnormalities.⁽²⁴⁾ Flows at lower lung volume are more sensitive, but also have higher variability, which reduces their utility in clinical practice and clinical trials.⁽²⁵⁾ However, some interventional studies in CF have shown a more impressive signal for flows at lower lung volume compared to FEV₁ in patients with milder disease.⁽²⁶⁾ As newer aerosol devices can achieve higher deposition in the small airways, interventions targeting the small airways may be better captured with flow at lower lung volumes that with other spirometric parameters. This is supported by a recent study with dornase alfa delivered via a device aiming to achieve higher concentrations in small airways, where significantly higher improvements in flows at lower lung volumes were demonstrated.⁽²⁷⁾

The Lung Clearance Index (LCI), a measure of ventilation inhomogeneity determined during Multiple Breath Washout (MBW) has been shown to be a marker of small airway disease.⁽²⁸⁾ Studies in CF patients have shown that the LCI is more sensitive at detecting lung disease than spiromety, predicts structural lung damage and, when preformed in preschool children, predicts lung function later in life.^(29–33) The LCI can be determined during tidal breathing, and the upper limit of normal is consistent across most age groups. Therefore, the LCI is a potentially useful measure to capture lung abnormalities early on, but also as an endpoint for clinical trials in CF patients with mild lung disease. We have recently performed two studies to assess the responsiveness of LCI to two interventions that are known to either improve mucocliary clearance (hypertonic saline) or mucus clearance (dornase alfa).^(34,35) These studies targeted specifically patients with normal FEV₁, and both trials were able to detect a treatment response using LCI that was not seen in FEV₁. Interestingly, flows at low lung volume changed significantly in the dornase alfa trial and not in the hypertonic saline study, indicating that the two measures may provide independent information for peripheral airway diseases. Further studies are currently undergoing to delineate the utility of this lung function test in CF patients.

Implication for Treatment

Another major challenge for small airway diseases is to efficiently target abnormalities in this region of the lung with therapeutic interventions. This is less of a challenge for therapies administered systemically, but many medications in CF are administered via inhalation to achieve high levels of the drug in the airways while minimizing systemic side effects.⁽³⁶⁾ Aerosols and nebulizers are often adjusted to generate a certain spectrum of particle that are more or less likely to target larger versus smaller airways; the deposition is rarely specific enough to only reach one region of the lung. This may be less of an issue for mucolytics and antibiotics as mucus accumulation and bacterial infection is often present in both the large and the small airways. However, as pointed out earlier, a recent study suggest that targeting smaller airways may results in improved flows at lower lung volumes for treatment with dornase alfa.⁽²⁷⁾ This needs to be further explored as treatment strategies are being applied earlier in infants and young children to define the best particle size distribution tailored to specific age groups. Targeting the smaller airways specifically may be an important factor in optimizing osmotic therapy, as adequately restoring airway surface liquid in the peripheral airways may require large volume of an osmotic agents that would result in “flooding” of the central airways unless aerosol therapy specifically can target this region of the airways.⁽³⁷⁾ Studies are currently underway to assess hypertonic saline as an early intervention therapy in infants and young children, but the optimal delivery device and dose to maximize efficacy is still unclear.

In summary, cystic fibrosis is considered a small airway disease, and efforts are under way to better capture abnormalities in this region of the lung. It is unlikely that one measure alone will capture all aspects of small airway disease in CF, and ongoing studies will better delineate how best to capture and track small airway disease. This will allow for better assessment of early intervention therapies and will help to optimize inhalation therapy directed against CFTR-related pathology where it initially occurs.