Peripheral ventilation heterogeneity determines the extent of bronchoconstriction in asthma.

In asthma, bronchoconstriction causes topographically heterogeneous airway narrowing, as measured by three-dimensional ventilation imaging. Computation modeling suggests that peripheral airway dysfunction is a potential determinant of acute airway narrowing measured by imaging. We hypothesized that the development of low-ventilation regions measured topographically by three-dimensional imaging after bronchoconstriction is predicted by peripheral airway function. Fourteen asthmatic subjects underwent ventilation single-photon-emission computed tomography/computed tomography scan imaging before and after methacholine challenge. One-liter breaths of Technegas were inhaled from functional residual capacity in upright posture before supine scanning. The lung regions with the lowest ventilation (Ventlow) were calculated using a thresholding method and expressed as a percentage of total ventilation (Venttotal). Multiple-breath nitrogen washout was used to measure diffusion-dependent and convection-dependent ventilation heterogeneity (Sacin and Scond, respectively) and lung clearance index (LCI), before and after challenge. Forced expiratory volume in 1 s (FEV1) was 87.6 ± 15.8% predicted, and seven subjects had airway hyperresponsiveness. Ventlow at baseline was unrelated to spirometry or multiple-breath nitrogen washout indices. Methacholine challenge decreased FEV1 by 23 ± 5% of baseline while Ventlow increased from 21.5 ± 2.3%Venttotal to 26.3 ± 6.7%Venttotal (P = 0.03). The change in Ventlow was predicted by baseline Sacin (rs  = 0.60, P = 0.03) and by LCI (rs  = 0.70, P = 0.006) but not by Scond (rs  = 0.30, P = 0.30). The development of low-ventilation lung units in three-dimensional ventilation imaging is predicted by ventilation heterogeneity in diffusion-dependent airways. This relationship suggests that acinar ventilation heterogeneity in asthma may be of mechanistic importance in terms of bronchoconstriction and airway narrowing.NEW & NOTEWORTHY Using ventilation SPECT/CT imaging in asthmatics, we show induced bronchoconstriction leads to the development of areas of low ventilation. Furthermore, the relative volume of the low-ventilation regions was predicted by ventilation heterogeneity in diffusion-dependent acinar airways. This suggests that the pattern of regional airway narrowing in asthma is determined by acinar airway function.

[1]  D. Bailey,et al.  Objective analysis of tomographic ventilation-perfusion scintigraphy in pulmonary embolism. , 2007, American journal of respiratory and critical care medicine.

[2]  John P Mugler,et al.  Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. , 2006, Chest.

[3]  W. Busse,et al.  Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. , 2008, Journal of applied physiology.

[4]  Nathan J. Brown,et al.  Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects , 2003, European Respiratory Journal.

[5]  C. Salome,et al.  The role of the small airways in the clinical expression of asthma in adults. , 2012, The Journal of allergy and clinical immunology.

[6]  Hsiao-Wen Chung.  Fractal analysis of nuclear medicine images again: validity and interpretation of results from new analysis methods. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[7]  C. Salome,et al.  Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma. , 2013, Journal of applied physiology.

[8]  G H Guyatt,et al.  Development and validation of a questionnaire to measure asthma control. , 1999, The European respiratory journal.

[9]  John P Mugler,et al.  Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. , 2003, The Journal of allergy and clinical immunology.

[10]  Yanping Sun,et al.  Probing airway conditions governing ventilation defects in asthma via hyperpolarized MRI image functional modeling. , 2009, Journal of applied physiology.

[11]  D. Bailey,et al.  V/Q imaging in 2010: a quick start guide. , 2010, Seminars in nuclear medicine.

[12]  N Berend,et al.  Structure of a human pulmonary acinus. , 1991, Thorax.

[13]  Janet Stocks,et al.  Consensus statement for inert gas washout measurement using multiple- and single- breath tests , 2013, European Respiratory Journal.

[14]  C. Salome,et al.  Increased airway closure is a determinant of airway hyperresponsiveness , 2008, European Respiratory Journal.

[15]  M Paiva,et al.  Evidence of acinar airway involvement in asthma. , 1999, American journal of respiratory and critical care medicine.

[16]  Sylvia Verbanck,et al.  Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation , 2007, Thorax.

[17]  H. Malcolm Hudson,et al.  Accelerated image reconstruction using ordered subsets of projection data , 1994, IEEE Trans. Medical Imaging.

[18]  D. Bailey,et al.  Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma. , 2012, Journal of applied physiology.

[19]  K Murase,et al.  Quantitative analysis of pulmonary emphysema: three-dimensional fractal analysis of single-photon emission computed tomography images obtained with a carbon particle radioaerosol. , 1998, AJR. American journal of roentgenology.

[20]  Yuchiao Chang,et al.  Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma. , 2006, American journal of respiratory and critical care medicine.

[21]  Nathan J. Brown,et al.  Predictors of airway hyperresponsiveness differ between old and young patients with asthma. , 2011, Chest.

[22]  P. Paré,et al.  Mechanism of methacholine dose-response plateaus in normal subjects. , 1998, American journal of respiratory and critical care medicine.

[23]  Richard B Buxton,et al.  Vertical distribution of specific ventilation in normal supine humans measured by oxygen-enhanced proton MRI. , 2010, Journal of applied physiology.

[24]  G. Musch,et al.  Ventilation Defect Formation in Healthy and Asthma Subjects Is Determined by Lung Inflation , 2012, PloS one.

[25]  O. Usmani,et al.  Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung , 2012, Thorax.

[26]  H. Tiddens,et al.  Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis , 2007, Thorax.

[27]  R. Pellegrino,et al.  Regional expiratory flow limitation studied with Technegas in asthma. , 2001, Journal of applied physiology.

[28]  K. Lutchen,et al.  Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics , 2007, European Respiratory Journal.

[29]  V. J. Kelly,et al.  Peripheral lung function in patients with stable and unstable asthma. , 2013, The Journal of allergy and clinical immunology.

[30]  J. Hankinson,et al.  Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. , 2000, American journal of respiratory and critical care medicine.

[31]  A. B. Crawford,et al.  Distribution of inhaled 99mtechnetium labelled ultrafine carbon particle aerosol (Technegas) in human lungs. , 1990, The European respiratory journal.

[32]  Kenneth Lutchen,et al.  The difference in ventilation heterogeneity between asthmatic and healthy subjects quantified using hyperpolarized 3He MRI. , 2009, Journal of applied physiology.

[33]  C. Jenkins,et al.  Optimal asthma control, starting with high doses of inhaled budesonide. , 2000, The European respiratory journal.