Lung Computational Models and the Role of the Small Airways in Asthma

Abstract

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) 2 resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date. Objectives: To validate the use of forced oscillation R5 2 R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma. Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 2 R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137). Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 2 R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 2 R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 2 R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Applications of oscillometry in clinical research and practice

“…In a recent publication, using computational modeling and patient data, we show that R 5-20 is a direct measure of airway narrowing and that this correlated with asthma control and quality of life when patients were treated. 6 Results from the recently published ATLANTIS study also lends strong support to the correlation between R 5-20 and A X and small airways disease in asthma. Oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical small airways disease score and differed between small airways disease groups.…”

“…The difference between R 5 and R 20 is the heterogeneous component of R rs , and the heterogeneity can arise from central or peripheral airways. However, since in most cases of asthma and chronic obstructive pulmonary disease (COPD), these manifest more in the small airways, at least once obstruction is sufficient to increase R rs , and small airway heterogeneity is more commonly the source of R [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . As a result, the difference between Resistance at 5 Hz (R 5 ) and Resistance at 20 Hz (R 20 ) can pertain to the resistance of the smaller airways.…”

“…As a result, the difference between Resistance at 5 Hz (R 5 ) and Resistance at 20 Hz (R 20 ) can pertain to the resistance of the smaller airways. 13,15,23,[26][27][28] While there has been some debate regarding the interpretations of R [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] in the past, the accumulated evidence is now supportive of interpreting R [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] as reflecting changes in the smaller airways. In a recent publication, using computational modeling and patient data, we show that R 5-20 is a direct measure of airway narrowing and that this correlated with asthma control and quality of life when patients were treated.…”

“…Current data suggest that reported measures of small airways dysfunction such as R [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] are primarily promoted by narrowing within the small airways (more so than by central airways disease) and that heterogeneity is also an important determinant of the measures. 8,40 Furthermore, a quantitative imaging biomarker study suggests that reversal of the normal ventilation gradient in the lung is an important determinant of R [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . 41 Heterogeneous ventilation of the lung correlates with parameters of oscillometry, in particular with the frequency dependence of resistance and the area under the reactance curve (A X ) and, interestingly, also demonstrates some correlation with patient reported outcomes.…”

“…5 The measurements should also provide the clinician with a clear understanding of what part of the respiratory system is affected. Dr. Siddiqui discussed the interpretation of oscillometry data and pointed out that oscillometry can separate lung function into peripheral and central airways 6,7 and Dr. Dandurand gave an example from his clinic of a patient who when put on a small particle treatment to target the small airways, did remarkably better. Similarly, this was also shown in a study where small particle inhalers were compared with standard inhalers; by using oscillometry the authors were able to demonstrate that the primary effect of the small particle was located in the small airways, something that spirometry did not register.…”