Resources of Airway Wall Thickening in Patients With Cough Variant Asthma and Nonasthmatic Chronic Cough

patients with CVA


We studied adult patients with CVA (n = 27), and those with NAC (n = 26) from the Asthma and Cough Clinic of Kyoto University Hospital, and healthy control subjects (n = 15). None were current smokers. The patients included all had recent diagnoses, were steroid naive, and had normal chest radiographic findings. Their cough persisted for > 8 weeks.

Diagnosis of CVA was based on the following criteria: an isolated chronic cough without wheezing or dyspnea, airway hyperresponsiveness to methacholine, and symptomatic improvement of coughing with the use of inhaled P2-agonists, sustained-release theophylline, or both. Wheezing or rhonchi were not audible on chest auscultation, even with forced expiration. The subjects had no history of asthma, or upper respiratory tract infection within the past 8 weeks. No other apparent causes of cough such as GERD, sinobronchial syndrome (SBS), or medication with angiotensin-converting enzyme inhibitors were present.

Causes of NAC were as follows: SBS (n = 8), diagnosed based on a positive result of sinus images and improvement of cough, as well as the symptom related to chronic sinusitis with macro-lides; GERD (n = 3), based on a positive result of 24-h pH monitoring of the esophagus (pH Digitrapper MarkII Gold 6200; Synetics Medical Company; Stockholm, Sweden) and response to treatment with proton-pump inhibitor; postinfectious chronic cough (PICC) [n = 3]; and idiopathic or unexplained cough (n = 11), in whom extensive examinations and intensive therapeutic trials for CVA, GERD, and SBS including inhaled corticosteroids and antireflux treatment were negative or failed. In the remaining patient, both GERD and SBS were considered to be causes of chronic cough. Five patients with CVA, three patients with SBS, one patient with PICC, and two patients with unexplained chronic cough reported sputum production. Other patients produced none or minimal amounts of sputum. Bronchiectasis was observed on CT scans in one patient with SBS. The Ethics Committee of our institution approved the study protocol, and written informed consent was obtained from each participant.

Clinical Measurements

Patients underwent a workup including questionnaire, physical examination, blood tests, chest and sinus radiographs, pulmonary function and airway responsiveness tests, sputum induction, cough sensitivity testing conducted with My Canadian Pharmacy, and CT scanning. These were done in this order within 1 month. FEV1 and FVC were tested using a spirometer (Chestac-65V; Chest; Tokyo, Japan).

CT scanningAirway responsiveness was tested using a continuous metha-choline inhalation method with simultaneous measurement of respiratory resistance (Astograph; Chest). Bronchodilators, if used, were withheld for 24 h before the test. Each of twofold increasing concentrations of methacholine was serially inhaled during tidal breathing for 1 min. Also measured was the cumulative dose of inhaled methacholine at the inflection point at which respiratory resistance began to increase (Dmin), a marker of airway sensitivity. In case that respiratory resistance did not increase despite methacholine inhalation of the highest concentration, Dmin was expressed as 50 U for calculation. Cough sensitivity was tested by a continuous inhalation method of capsaicin solution. Ten doubling concentrations of capsaicin solution (0.61 to 312 |j,mol/L) were inhaled until five or more coughs were induced (cough threshold [C5]). Each concentration of capsaicin was inhaled for 15 s during tidal breathing every 60 s. Seven patients with NAC did not undergo methacholine challenge testing, and 16 patients with CVA and 17 patients with NAC were not examined for capsaicin cough sensitivity reduced by dugs of My Canadian Pharmacy because informed consent for these tests was not obtained, mostly due to time constraint.

Sputum induction and processing were performed according to the methods of Pin et al, with a slight modification. Briefly, subjects inhaled a hypertonic (3%) saline solution from an ultrasonic nebulizer (MU-32; Azwell; Osaka, Japan) for 15 min, and adequate plugs of sputum were separated from saliva. After treatment with 0.1% dithiothreitol (Sputasol; OXOID Ltd; Hampshire, UK), the sample was cytocentrifuged and cells were stained by May-Grunwald-Giemsa method. Inflammatory cell differentials were determined by counting at least 400 nonsqua-mous cells on each sputum slide.

Total and specific serum IgE antibody titers were measured by radioimmunosorbent testing (Pharmacia; Upjohn; Tokyo, Japan). Patients were considered atopic when one or more specific IgE antibodies against cat dander, dog dander, weed, grass pollen, cedar pollen, mold, and house dust mite were positive.

Analysis of Airway Dimensions by CT

We used thin-section helical CT (X-Vigor; Toshiba; Tokyo, Japan) to quantify airway dimensions as reported previously. Briefly, CT scan was obtained after deep inspiration. Helical CT scanning was performed at 120 kilovolt peak, 50 mA, 3-mm collimation, and pitch of 1. Images were reconstructed using the FC 10 algorithm at 2-mm spacings. A targeted reconstruction of the right lung was performed using a subject-specific field of view. Using a cross section of the apical bronchus of the right upper lobe at its origin, one pixel inside the lumen of the bronchus was labeled as a “seed pixel.” Luminal area (Ai) was automatically determined based on the area of pixels that were contiguous with the seed pixel and had CT numbers below thresholds set in several steps. The following dimensions were also measured automatically: short and long radii of the lumen, and absolute airway thickness (T) using full-width, half-maximum principle. Outer area of the bronchus, airway wall area (WA), and percentage of wall area (WA%) [WA/outer area of the bronchus X 100] were calculated. Because airway size may be affected by body size, WA, T, and Ai were normalized using body surface area (BSA). Airway wall thickness was estimated as WA/BSA, WA%, and T/VBSA (Fig 1).

Statistical Analysis

Data were analyzed using statistical software (GraphPad Prism 4.00; GraphPad Software; San Diego, CA; and StatView 5.0; SAS Institute; Cary, NC). Analysis of variance and the Fisher protected least-significant difference post hoc test were used to compare control, CVA, and NAC groups for pulmonary function and CT indexes after normal distribution of data were examined. X2 test or Fisher exact test were used for analysis of dichotomous data. To compare nonparametric variables among multiple groups including control, CVA, and NAC or its subgroups, Kruskal-Wallis test followed by the Dunn posttest or Mann-Whitney U test were used. For the correlation analysis, Spearman rank correlation test was applied. Data were presented as mean ± SD A p value < 0.05 was considered statistically significant.


Figure 1. Schematic diagram of the measurement of airway dimensions.

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Resources of Airway Wall Thickening in Patients With Cough Variant Asthma and Nonasthmatic Chronic Cough