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doi:10.1378/chest.06-1025
(Chest. 2007; 131:1042-1049)
© 2007 American College of Chest Physicians
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Airway Wall Thickening in Patients With Cough Variant Asthma and Nonasthmatic Chronic Cough*

Hisako Matsumoto, MD, PhD; Akio Niimi, MD, PhD; Rollin P. Tabuena, MD; Masaya Takemura, MD; Tetsuya Ueda, MD; Masafumi Yamaguchi, MD; Hirofumi Matsuoka, MD; Makiko Jinnai, MD; Kazuo Chin, MD, PhD and Michiaki Mishima, MD, PhD

* From the Departments of Respiratory Medicine (Drs. Matsumoto, Niimi, Takemura, Ueda, Yamaguchi, Matsuoka, Jinnai, Chin, and Mishima), Kyoto University, Kyoto, Japan; and Iloilo Mission Hospital (Dr. Tabuena), Department of Internal Medicine, Iloilo City, Philippines.

Correspondence to: Hisako Matsumoto, MD, PhD, Department of Respiratory Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan; e-mail: hmatsumo{at}kuhp.kyoto-u.ac.jp

Abstract

Background: Chronic cough, which may be of asthmatic or nonasthmatic origin, is an important clinical issue. Airway inflammation, and remodeling demonstrated by subbasement membrane thickening has been associated with cough variant asthma (CVA) as well as with nonasthmatic chronic cough (NAC). CT studies have shown airway wall thickening in patients with asthma who wheeze. We examined airway wall thickness by CT in adult patients with chronic cough and examined its pathophysiologic implication.

Methods: Nonsmoking, steroid-naïve patients with CVA (n = 27), NAC (n = 26), and healthy control subjects (n = 15) were studied. Airway dimensions were assessed by a validated CT technique, in which we measured airway wall area (WA) corrected by body surface area (BSA), the ratio of WA to outer wall area (percentage of wall area [WA%]), absolute wall thickness (T)/{surd}BSA, and airway luminal area/BSA of a segmental bronchus. Correlations between CT parameters and clinical indexes such as disease duration and cough sensitivity were examined.

Results: In patients with CVA, WA/BSA, WA%, and T/{surd}BSA were all significantly greater than those in control subjects. In patients with NAC, WA/BSA and T/{surd}BSA were significantly greater than in control subjects. The increase of WA/BSA and T/{surd}BSA of NAC patients was less than that of CVA patients. In a subset of patients with NAC, WA% correlated with capsaicin cough sensitivity (n = 9, r = 0.75, p = 0.034).

Conclusions: Walls of central airways are thickened in patients with CVA, and also to a lesser degree in patients with NAC. Airway wall thickening in NAC may be associated with cough hypersensitivity.

Key Words: airway wall thickening • cough sensitivity • cough variant asthma • CT • nonasthmatic chronic cough

Airway wall thickening has been observed in postmortem studies of patients with status asthmaticus. The wall thickening is accompanied by airway structural changes, such as subbasement membrane thickening, mucous gland and goblet-cell hyperplasia, increased vascularity, and smooth-muscle hypertrophy and hyperplasia, as well as with chronic inflammation such as mucosal edema and inflammatory cell infiltration.1234 These changes have been further confirmed by studies567 using bronchial biopsy in living patients. With the advent of high-resolution CT, noninvasive assessment of airway dimensions in asthma has become available.8 We and others910111213 have quantitatively assessed airway wall thickening and its clinical implication in asthma.

Chronic cough is a common problem for which patients seek medical attention from primary care physicians and pulmonologists.14 Although chronic cough itself is not fatal, it severely impairs quality of life.15 One of the most common causes of chronic cough is cough variant asthma (CVA),16 which lacks the typical manifestation of asthma such as wheezing or dyspnea but presents airway hyperresponsiveness and bronchodilator responsive coughing.17 CVA is clinically considered as a variant type of asthma as well as a precursor of classic asthma with wheezing.1819 Pathologically, CVA shares common features such as eosinophilic inflammation and remodeling changes, including subbasement membrane thickening and goblet-cell hyperplasia with classic asthma.20212223

Chronic cough due to other causes, such as gastroesophageal reflux disease (GERD) and postnasal drip syndrome, which is currently referred to as upper airway cough syndrome,16 is often grouped as nonasthmatic chronic cough (NAC).22 Patients with NAC also have features of airway inflammation and remodeling. In a study24 examining BAL fluid of patients with NAC, mast cells, eosinophils, and histamine levels were increased; while in another study,25 sputum neutrophilia and increased levels of interleukin-8 and tumor necrosis factor-{alpha} were observed. Increase of bronchoalveolar lymphocytes in idiopathic chronic cough is also reported.26 In terms of remodeling, the presence of submucosal fibrosis in the airways of patients with NAC was first described by Boulet and colleagues.27 A biopsy study22 of NAC has further demonstrated an increase of submucosal mast cells, subbasement membrane thickness, goblet-cell area, vascularity, and smooth-muscle area. Nonasthmatic eosinophilic bronchitis, another cause of chronic cough characterized by airway eosinophilia and absence of airway hyperresponsiveness, also involves subbasement membrane thickening.28 Regardless of the accumulating evidence of airway remodeling based on bronchial biopsies in patients with chronic cough, only one study29 of nonasthmatic eosinophilic bronchitis has examined whole airway wall thickness using CT scans, and has shown that in contrast with the biopsy study,28 wall area of large airways in patients with nonasthmatic eosinophilic bronchitis is not different from that of healthy control subjects and is less than that of intermittent or mild persistent asthmatics with sputum eosinophilia,29 suggesting the importance of assessment by CT that may extend and compensate the information of endobronchial biopsy studies in chronic cough.

In this study, we examined airway dimensions by CT in patients with CVA and those with NAC. Correlations between the CT parameters and clinical indexes, such as age, disease duration, pulmonary function, cough sensitivity, and sputum cell differentials, were also studied.

Materials and Methods

Subjects
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 naïve, and had normal chest radiographic findings. Their cough persisted for > 8 weeks.

Diagnosis of CVA was based on the following criteria20: an isolated chronic cough without wheezing or dyspnea, airway hyperresponsiveness to methacholine, and symptomatic improvement of coughing with the use of inhaled ß2-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 macrolides30; 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 inhibitor31; 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, 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).

Airway responsiveness was tested using a continuous methacholine inhalation method with simultaneous measurement of respiratory resistance (Astograph; Chest).1332 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 µmol/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.33 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 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,34 with a slight modification.12 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-Grünwald-Giemsa method. Inflammatory cell differentials were determined by counting at least 400 nonsquamous 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.912133536 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.35 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/{surd}BSA (Fig 1 ).


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

 
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. {chi}2 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.

Results

Clinical characteristics of the three subject groups are shown in Table 1 . Sputum eosinophils were insignificantly increased in patients with CVA compared with those with NAC (p = 0.076). Log Dmin was significantly lower in the CVA group than in the NAC group (0.23 ± 0.73 U vs 1.40 ± 0.49 U, p < 0.0001). Log C5 was not significantly different between 11 patients with CVA and 9 patients with NAC (GERD, n = 3; SBS, n = 2; PICC, n = 1; unexplained cough, n = 3) [Table 1].


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  		Table 1.. Characteristics of the Three Subject Groups*

 
Representative CT images are shown in Figure 2 . In the CVA group, all three indexes of airway wall thickness were significantly greater than in control subjects (Table 2 ). WA/BSA and T/{surd}BSA in the NAC group were also significantly greater than in control subjects, and WA% was insignificantly increased. WA/BSA (Fig 3 ) and T/{surd}BSA in the NAC group were less than in CVA group (Table 2). There was no difference in Ai/BSA among the three groups. When the NAC patients were separately analyzed by the cause of cough, there was a significant difference in WA/BSA and T/{surd}BSA among control subjects and subgroups of NAC (p = 0.016 and p = 0.003, Kruskal-Wallis test). SBS and unexplained cough subgroups showed a significant increase in WA/BSA (Fig 4 ) and T/{surd}BSA (p < 0.01 and p < 0.05, Dunn posttest) compared with healthy control subjects. PICC and GERD subgroups were not different from control subjects.


Figure 2
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  		Figure 2.. Representative CT images of the selected bronchus (arrows). Top left, A: Healthy control subject. Top right, B: Chronic cough due to GERD. Bottom, C: CVA.

 

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  		Table 2.. Outcomes of CT Indices*

 

Figure 3
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  		Figure 3.. WA/BSA in healthy control subjects (HC), patients with CVA, and patients with NAC. Bars indicate means.

 

Figure 4
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  		Figure 4.. WA/BSA in healthy control subject and subgroups of NAC; p = 0.016, Kruskal-Wallis test; *p < 0.05, Dunn posttest. Bars indicate medians. Unx = unexplained chronic cough. See Figure 3 legend for expansion of abbreviation.

 
In the patients with NAC who underwent capsaicin cough sensitivity test, C5 was inversely correlated with WA% (n = 9, r = – 0.75, p = 0.034) [Fig 5 ; Table 3 ]. Other clinical indexes, such as age, disease duration, pulmonary function, and sputum cell differentials, did not correlate with any of the CT indexes in either group of cough patients (Table 3).


Figure 5
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  		Figure 5.. Correlation between WA% and cough sensitivity in patients with NAC.

 

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  		Table 3.. Correlation Coefficients (r) Between CT and Clinical Indices

 
Discussion

This is the first study that has quantitatively evaluated airway wall thickness using CT in patients with CVA and those with NAC. Airway walls were thickened in patients with CVA, and to a lesser degree in those with NAC compared with healthy control subjects. Cough sensitivity was significantly correlated with one index of wall thickness in patients with NAC.

Our present result that the whole airway wall was thickened in patients with CVA compared to control subjects is consistent with our previous endobronchial biopsy studies that have shown airway eosinophilic inflammation,20 and thickening of airway subbasement membrane in patients with CVA.21 Furthermore, based on our findings22 of increased vascularity, vessel size, and goblet-cell area in CVA in comparison with healthy control subjects, the whole airway wall thickening on CT in patients with CVA may be ascribed to these structural changes.

The airway walls of patients with NAC (SBS, n = 8; GERD, n = 3; PICC, n = 3; GERD and SBS, n = 1; and unexplained [idiopathic] chronic cough, n = 11) were also thickened compared with those of healthy control subjects in this study. Previous biopsy studies2227 have denoted the presence of airway inflammation and remodeling in patients with NAC. Boulet and colleagues27 described increase in epithelial shedding, mononuclear cells, submucosal fibrosis in the bronchial biopsy sample taken from patients with NAC that could be due to GERD (n = 6), postnasal drip syndrome (n = 4), both conditions (n = 5), and undiagnosed condition (n = 4). Our study22 revealed an increase of submucosal mast cells, subbasement membrane thickening, hypervascularity, goblet-cell hyperplasia, and an increase in airway smooth-muscle area in patients with NAC (postnasal drip/rhinitis, n = 6; GERD, n = 5; bronchiectasis, n = 3; and unidentified condition, n = 19). Our finding of airway wall thickening in NAC is presumably explained as a net result of these pathologic changes, as is in CVA. In addition to the wall thickening in the NAC group as a whole, patients with SBS and those with unexplained chronic cough separately analyzed showed thickened airway walls when compared with healthy control subjects. Lack of significant difference in wall thickness between control subjects and GERD or PICC subgroups may be due to small sample size. To our knowledge, this is the first attempt to clarify the airway wall dimensions as assessed by CT in various causes of chronic cough. Although PICC and GERD subgroups were small, we did not exclude these subgroups or another patient having both GERD and SBS from analysis, since they are considered important causes of NAC. Further studies involving larger number of patients are needed.

Cough hypersensitivity is a characteristic feature of chronic dry cough, especially in patients without airway hyperresponsiveness.37 Thus far, only one study22 has investigated on an association of airway structural changes with cough sensitivity. In that study, goblet-cell hyperplasia and epithelial shedding were associated with cough hypersensitivity in patients with NAC. In the present study, log C5 was significantly correlated inversely with WA% in patients with NAC who underwent cough sensitivity testing (n = 9, r = – 0.75, p = 0.034). Although we cannot draw a definitive conclusion because half of the patients with NAC were missed from analysis, and no similar correlation was observed in the CVA group, this association in NAC group may propose a possibility that coughing itself causes airway wall thickening, or conversely airway wall thickening and growth factors involved in the process lead to cough hypersensitivity in NAC. We consider the lack of association in CVA may be due to less involvement of cough hypersensitivity in the pathophysiology of CVA than in NAC, as has been suggested by previous studies.3738

For the first time to our knowledge, we have shown that the increase of airway wall thickness in CVA group was greater than in NAC group. Airway luminal area was not different between the two groups. The greater wall thickening in CVA may have been resulted from thickened outer airway wall that is reported in case of fatal asthma but cannot be assessed by endobronchial biopsy.14 This may not be plausible in CVA, a milder phenotype of asthma, however. The difference in the whole airway wall thickness between the two conditions cannot be explained by our biopsy study in which most of the airway components of asthmatic coughers and NAC patients show similar degrees of remodeling changes.22 Although we need to consider possible disparities between the previous biopsy study and the present CT study, such as causes, duration, and severity of cough, this difference between the two groups is important when the development of airway remodeling in asthma is considered, since the two chronic cough groups may be indistinguishable symptomatically and functionally except the presence or absence of airway hyperresponsiveness.

Values of WA/BSA of healthy control subjects (14.8 ± 3.8 mm2/m2) in the present study were higher than those of control subjects shown in our earlier study (11.2 ± 3.0 mm2/m2).9 In the present study, we used our automatic program that started from seeding a pixel in the airway lumen followed by using a full-width, half-maximal method.35 In some of our earlier studies,936 inner and outer edges of the airway walls were manually traced to obtain outer airway area and Ai on a workstation. The discrepancy between the present and previous studies may be mostly due to the methodologic difference. We previously compared WA/BSA measured automatically and WA/BSA measured manually in 26 asthmatic patients (13 men; age, 55 ± 15 years; FEV1, 90.7 ± 20.6% of predicted). The correlation between WA/BSA automated and WA/BSA manual was strong (r = 0.89, p < 0.0001). However, there was a difference between the two measurements (WA/BSA automated, 20.8 ± 6.9 mm2/m2; WA/BSA manual, 17.3 ± 5.9 mm2/m2), which may explain the discrepancy in WA/BSA in the current and earlier studies. When employing the same automatic program, patients with CVA in the present study who were all symptomatic and untreated showed similar values of WA/BSA (22.8 ± 6.7 mm2/m2) to those of steroid-naïve, mild asthmatic patients (21.1 ± 7.6 mm2/m2).13

As a limitation of the present study, mechanisms of the whole airway wall thickening in CVA and NAC were not clarified. Association of eosinophilic airway inflammation to wall thickening of the large airway has not been demonstrated in a recent study29 of nonasthmatic eosinophilic bronchitis patients, neither was it in our study, in which sputum eosinophil count did not correlate with airway wall dimensions in either group of patients. It is also unclear to what extent reversible components contributed to the whole airway wall thickening in both conditions. Further studies, such as changes of the wall thickness in response to inhaled corticosteroid therapy,36 might give some insights into this issue. Finally, as a possible common mechanism of the airway wall thickening in chronic coughers, bouts of coughing may play a role, as was mentioned above. Accumulated evidence suggests that exposure to a variety of mechanical forces stimulates cell growth and modulates extracellular matrix deposition.39

We conclude that central airway wall is thickened in patients with CVA and, to a lesser degree, in those with NAC. Wall thickening may be associated with cough hypersensitivity in NAC. Present findings give insights into the development of airway remodeling and its physiologic consequence in chronic cough and asthma.

Acknowledgements

We are grateful to Goro Saji and Ryuzo Tanaka for their radiologic technical support. We also thank Dr. Yoshitaka Konda, Kyoto Senbai Hospital, Kyoto, Japan, for performing diagnostic procedures of GERD including esophageal pH monitoring.

Footnotes

Abbreviations: Ai = luminal area; BSA = body surface area; C5 = cough threshold, the lowest concentration of capsaicin that induces five or more coughs; CVA = cough variant asthma; Dmin = cumulative dose of inhaled methacholine at the inflection point at which respiratory resistance begins to increase; GERD = gastroesophageal reflux disease; NAC = nonasthmatic chronic cough; PICC = postinfectious chronic cough; SBS = sinobronchial syndrome; T = absolute airway thickness; WA = airway wall area; WA% = percentage of wall area

The work was performed at Kyoto University Hospital.

Dr. Rollin Tabuena is a recipient of a Monbukagakusho scholarship grant.

The authors have no conflicts of interest to disclose.

Received for publication April 16, 2006. Accepted for publication December 18, 2006.

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