Lung hyperinflation, perception of bronchoconstriction and airway hyperresponsiveness

Louis-Philippe Boulet MD, FRCPC

Hélène Turcotte MSc

Unité de recherche en pneumologie, Centre de recherche, Hôpital Laval, Institut Universitaire de cardiologie et de pneumologie, Université Laval, Québec, QC, Canada G1V 4G5

 

Manuscript submitted 10th August, 2006

Manuscript accepted 21st November, 2006

 

Clin Invest Med 2007; 30 (1): 2-11.

Abstract

Purpose: To compare the influence of underlying airway inflammation and lung hyperinflation on dyspnea during induced bronchoconstriction in subjects with mild asthma (or asymptomatic airway hyperresponsiveness (AAHR).

Methods: Fourteen mild asthmatic and 14 AAHR subjects had methacholine and 5'-adenosine monophosphate (AMP) challenges, and induced sputum analysis. Changes in inspiratory capacity (IC) and respiratory symptom scores were measured after challenges. Perception of respiratory symptoms was recorded on a modified Borg scale.

Results: The mean baseline FEV₁, IC, mean provocative concentration of methacholine inducing a 20% decrease in FEV₁ (PC₂₀), the mean PC₂₀ AMP and median inflammatory cell counts were similar in both groups. After methacholine, mean (±SD) reductions in FEV₁ were 24.7±10.3% in mild asthma and 35.6±19.1% in AAHR (P>0.05); reductions in IC were, respectively, 10±12% and 24±20% (P>0.05); mean breathlessness scores at PC₂₀ were 1.1 in mild asthma and 0 in AAHR P=0.003), and mean chest tightness scores were 1.2 in mild asthma and 0.8 in AAHR (P>0.05).  Maximum chest tightness scores following MC correlated with the maximum decrease in IC in mild asthma (r_s=0.75,P=0.009) and with the maximum decrease in FEV₁ in AAHR (r_s=0.60,P=0.04). After AMP, symptom scores were not significantly correlated with decreases in FEV₁ or IC. The number of inflammatory cells was not correlated with decreases in IC after methacholine, AMP or with their PC_20s, although inflammation was minimal in both groups.

Conclusion: Lower breathlessness scores in AAHR compared to mild asthma were not explained by differences in lung hyperinflation nor in airway inflammation.

Keywords: Asthma, airway hyperinflation, inspiratory capacity, induced sputum

 

List of Abbreviations

AAHR              Asymptomatic airway

                        hyperresponsiveness

AHR                Airway hyperresponsiveness

AMP                Adenosine 5’-monophosphate

ATS                 American Thoracic Society

B                      Breathlessness

CT                   Chest tightness

BD                   Bronchodilator

COPD              Chronic obstructive pulmonary disease

ECRHS            European Community Respiratory Health Survey

FEF_25-75%           Forced expiratory flows 25-75%

FEV₁                Forced expiratory volume in one second

FRC                 Functional residual capacity

FVC                 Forced vital capacity

IC                    Inspiratory capacity

IS                     Induced sputum

MC                  Methacholine challenge

PC₂₀                  Provocative concentration inducing a 20% decrease in FEV₁

RV                   Residual volume

SD                   Standard deviation

TLC                 Total lung capacity

VO_2max               Maximal oxygen consumption

 

Although the degree of airway hyperresponsiveness (AHR) does not always correlate with clinical features, AHR is universally observed in symptomatic asthma.^1,2 A proportion of individuals with no history of asthma or other respiratory diseases, who have no current symptoms and are not taking any respiratory medication have an increased airway response to agents such as histamine or methacholine.^3-5  However, we do not know why these patients are asymptomatic in the presence of AHR.^6-8 One mechanism that could influence the perception of respiratory symptoms is dynamic lung hyperinflation. This is considered to be an important determinant of the sensation of dyspnea in obstructive airway diseases, as is airway inflammation.^9,10 The intensity of dyspnea during induced bronchoconstriction in asthma has indeed been associated with the reduction in inspiratory capacity (IC), as a result of lung hyperinflation.^10-12 

Another potential contributor to the absence of symptoms in asymptomatic AHR (AAHR) could be a lower grade of airway inflammation than in asthma.^13,14 Both airway inflammation and structural changes can contribute to AHR.^15,16  The degree of airway inflammation has previously been associated with the severity of clinical features of asthma, including the frequency of exacerbations.¹⁷  We have suggested that AAHR is associated with airway remodeling and inflammation, but that these processes are less active in AAHR than in asthma and other diseases.¹⁸  Moreover, airway challenges such as with methacholine cause airflow limitation principally by acting directly on airway smooth muscle, while indirect challenges, such as with adenosine 5’-monophosphate (AMP), act by increasing mediator release from mast cells. The latter have been shown to reflect better the overall degree of airway inflammation.¹⁹ Comparative responses to AMP challenge and to methacholine challenge (MC) remain to be documented in AAHR.

We hypothesized that, for a given decrease in expiratory flows, subjects with AAHR have less dynamic hyperinflation following airway challenges than do mild symptomatic asthmatic subjects, as well as less airway inflammation as assessed by induced sputum (IS) analysis and AMP challenge. Such reduced change in lung volume would correlate with a reduced perception of respiratory symptoms after induced bronchoconstriction.

 

Methods

The study was approved by the institutional Ethics Committee and all subjects gave written informed consent.

 

Patients

Twenty-eight subjects (19 female, 9 male) participated in this study (Table 1). They were non-smokers or ex-smokers (n=6, <6 pack-year) for ≥1 year and had no respiratory infections in the previous 4 weeks.

 

Table 1. Subject characteristics
	Asthma (n=14)	AAHR (n=14)	P
Age (yr) (range)	27 (20-41)	28 (20-46)	0.87
Baseline FEV1*	101.7 ± 10.3	95.9 ± 13.2	0.20
Baseline FVC*	110.6 ± 8.8	99.0 ± 13.6	0.01
Baseline FEF25-75%*	98.4 ± 24.3	99.5 ± 20.2	0.90
Baseline IC*	104.1 ± 18.9	101.0 ± 18.4	0.67
PC20 on screening methacholine(mg/ml) (Mean and range)	2.19 (0.30-16)	4.15 (1.78,9.68)	0.13
AAHR = asymptomatic airway hyperresponsiveness; FEV1 = forced expiratory volume in one second; FEF25-75% = forced expiratory flows between 25-75% of FVC; FVC = forced vital capacity; IC = inspiratory capacity; PC20 on screening methacholine = provocative concentration of methacholine inducing a 20% decrease in FEV1. *Data are presented as mean % of predicted values ± SD

 

 

AAHR was defined as a positive response to a provocative concentration (PC₂₀) of methacholine ≤16 mg/ml inducing a 20% decrease in forced expiratory volume in one second (FEV₁), and no past or present history of asthma symptoms or of asthma medication use. AHR was detected but subjects had no symptoms compatible with asthma.  Subjects with AAHR were identified among volunteers recruited from the community by radio and newspapers advertising to act as normal controls for studies on asthma.

Subjects with mild asthma had current symptoms compatible with asthma, such as chest tightness, breathlessnness, cough, phlegm production and/or wheeze, and a positive MC. Baseline FEV₁ was ≥70% of the predicted value and asthma was stable, requiring only inhaled short-acting β₂-agonist on demand to control symptoms. None had received an anti-inflammatory agent for at least 3 months nor had used nasal or inhaled corticosteroids in the previous month or during the study. They were recruited from the outpatient and asthma clinics of Laval Hospital, Quebec, Canada.

 

Order of Testing

Each subject made 4 visits to the laboratory within a 15-day period. The visits were done at the same time of day at intervals of at least 24 hr. Visit 1 was a screening visit while Visits 2 to 4 were conducted in random order.

During Visit #1 all subjects underwent an evaluation, including the administration of a respiratory questionnaire to confirm the asymptomatic or asthmatic status. Expiratory flows, including FEV₁, forced vital capacity (FVC), IC and a standard tidal breathing MC were conducted, with quantification and qualitative evaluation of induced-symptom scores. Following MC, an IS was obtained for analysis of differential cell counts. The European Community Respiratory Health Survey (ECRHS) respiratory symptom questionnaire was administered.²⁰

Visit #2 included an AMP inhalation test with measurements of FEV₁, FVC, IC and induced symptom scores.

On Visit #3, body plethysmography was conducted to assess total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV) and IC. FEV₁ and FVC were measured pre- and post-bronchodilator (bd). The ΔFEV₁/ΔFVC bronchodilator response (post- minus pre-bd) was recorded to evaluate flow-dominant responders (ratio >1) and volume-responders (ratio <1).²¹

During Visit #4 a standard tidal breathing MC was conducted with measurement of FEV₁, FVC, IC and symptom scores.

 

Measurement of Expiratory Flows

Spirometry was performed with an ATS-approved spirometer (Medisoft, Dinant, Belgium). according to standard recommendations²² and using Knudson’s predicted values.²³

 

Evaluation of Symptoms

Respiratory symptoms were evaluated during the tests using a modified Borg scale ranging from 0 (no symptoms) to 10 (maximum bearable symptoms).²⁴  At baseline and after each inhalation of methacholine and AMP.²⁵, a list of five symptoms: breathlessness (B), chest tightness (CT), phlegm production, wheeze and cough was shown to the subjects. They were asked if they presently experienced any symptoms on the list and had to evaluate separately each symptom in the order of their choice.

 

Methacholine Challenges

Methacholine challenges with concentrations up to 16 mg/ml were conducted according to standardized methods, with measures of symptom scores.²⁶

 

Induced Sputum Analysis

Sputum was obtained with hypertonic saline as previously described.^27,28 Subjects inhaled increasing concentrations of saline (3 to 5%) for 7 minutes each through a mouthpiece without a valve or nose clip, after which differential cell counts were obtained.

 

AMP Inhalation Test

Airway responsiveness to doubling concentrations of AMP, up to 320 mg/ml, was measured using the 2-minute tidal breathing method for histamine applied to AMP.^1,29 

 

Statistical Analysis  and Sample Size Calculation

Based on previous studies reporting changes in dynamic lung hyperinflation in asthma, it was estimated that 14 subjects per group would be sufficient to observe significant differences between groups.¹⁰ The PC₂₀ values (methacholine, AMP) were log-transformed before analysis. Subjects with PC₂₀ >320 for AMP were considered equal to 320 to calculate the mean PC₂₀; the mean PC₂₀ is thus underestimated in both groups. Results are expressed as mean ± SD for expiratory flows and volumes and as median and range for cell differentials.  Borg scores for symptoms at PC₂₀ were calculated by interpolation of the scores at nearest decreases of FEV₁ below and above 20%.³⁰   Baseline values of FEV₁ for the tests were compared by ANOVA and an unpaired-t test was used for comparisons between groups. Symptom scores were compared by Mann-Whitney U two-sample test. Relationships between pulmonary function parameters, symptom scores and airway inflammation (sputum eosinophilia) were estimated by linear regression analysis or Spearman rank correlation.³⁰  P values <0.05 were considered significant.  For multiple comparisons, the Bonferroni correction was applied.

 

Results

Subject Characteristics at Baseline

All subjects had a PC₂₀ methacholine ≤16 mg/ml. There were no differences between asthma and AAHR subjects with respect to baseline FEV_1, FEF_25-75% and IC (P>0.05, Table 1). FVC was lower in AAHR than in asthma subjects (P=0.01).

 

Airway Inflammation

Airway inflammation was generally minimal in all subjects, as assessed by cell-count analysis of induced sputum, and there was no difference in airway inflammation between those with asthma and with AAHR. Median cell counts for asthma and AAHR subjects, respectively, were: eosinophils — 0.25% (range 0-4) and 0.25% (0-27); neutrophils — 27% (3-69) and 30% (7-67); macrophages — 66% (28-94) and 69% (29-79); lymphocytes — 1.75% (<1-4) and 3.3% (0-47); and bronchial cells — 0.5% (0-8) and 0.5% (0-4). Numbers of inflammatory cells were not significantly correlated with maximum decreases in FEV₁ or with IC on MC or AMP challenge, nor with PC₂₀ methacholine or PC₂₀ AMP.

 

Pulmonary Function

The only difference found between subjects with AAHR and those with asthma with respect to baseline lung volumes was the FVC that was slightly lower in subjects with AAHR (P=0.04) (Table 2).

 

TABLE 2. Expiratory flows and lung volumes (body plethysmography)
	Asthma (n = 14)	AAHR (n = 14)	P
FEV1*	101.4 ± 10.1	96.7 ± 10.8	0.24
FVC*	106.6 ± 8.6	99.1 ± 10.1	0.04
FEF25-75%*	89.2 ± 16.1	93.9 ± 22.8	0.54
IC*	108.5 ± 13.8	101.4 ± 19.1	0.28
Total lung capacity* (TLC)	104.5 ± 12.2	97.4 ± 12.6	0.14
Functional residual capacity (FRC)	103.1 ± 20.2	100.3 ± 15.6	0.69
FEV1 improvement post-bd (%)	6.0 ± 3.2	3.2 ± 6.3	0.18
AAHR = asymptomatic airway hyperresponsiveness; FEV1= forced expiratory volume in one second; FEF25-75% = forced expiratory flows 25-75%; FVC = forced vital capacity; IC = inspiratory capacity; and bd = bronchodilator * Data are presented as mean % of predicted values ± SD

 

 

The mean ΔFEV₁/ΔFVC was 2.2 ± 1.7 in subjects with asthma and 0.4 ± 2.2 in those with AAHR (P=0.019). The 13 asthma and 7 AAHR subjects were flow-dominant responders, while the others were volume responders.²¹ The mean increase in FEV₁ post- minus pre-bd was 243 ± 78 ml for the asthma subjects and 151 ± 143 ml for the AAHR subjects (P=0.04), while the mean change in FVC was, respectively, 142 ± 69 ml and 14 ± 216 ml (P=0.04).

 

Direct and Indirect Challenges

Mean PC₂₀ methacholine was 3.83 (-1SD = 1.15, +1SD = 12.7) mg/ml in subjects with asthma and 4.22 (1.16, 15.4) mg/ml in subjects with AAHR (P>0.05). Maximum decreases in FEV₁, FEF_25-75% and FVC were not different between the two groups (Table 3).

 

TABLE 3. Maximum decreases in FEV1, IC, FEF25-75% and FVC following MC and AMP challenge *
		Asthma (n = 14)	AAHR (n = 14)	P
FEV1	MC	24.7 ± 10.3	35.6 ± 19.1	0.07
	AMP	20.8 ± 9.3	11.1 ± 20.7	0.12
IC	MC	10.2 ± 12.1	24.0 ± 20.0	0.04
	AMP	10.1 ± 12.6	0.6 ± 23.5	0.14
FEF25-75%	MC	35.2 ± 19.3	37.9 ± 18.6	0.71
	AMP	14.5 ± 33.3	15.1 ± 23.9	0.96
FVC	MC	14.4 ± 10.0	26.0 ± 18.4	0.05
	AMP	11.8 ± 8.6	9.8 ± 9.8	0.57
AAHR = asymptomatic airway hyperresponsiveness; MC = methacholine challenge; AMP = adenosine 5’-monophosphate test; FEV1 = forced expiratory volume in one second; FEF25-75% = forced expiratory flows 25-75%; FVC= forced vital capacity; and IC = inspiratory capacity. *Data are presented as mean % decreases ± SD

 

 

Mean PC₂₀ on AMP test was 24.8 (range 2-294) mg/ml in subjects with asthma and 87.5 (15->320) mg/ml in those with AAHR (P=0.08). Eleven subjects with asthma and 7 with AAHR had a decrease in FEV₁ of ≥20%. At baseline, no respiratory symptoms were reported in either group. Maximum decreases in FEV₁, FEF_25-75%, IC and FVC were not different between the two groups. PC₂₀ AMP was not correlated with baseline IC in either study group.

 

Correlations between Tests

PC₂₀ MC and PC₂₀ AMP were correlated in AAHR (r=0.67, P=0.008) but not in asthma (r=0.22, P=0.46). There were no correlations between the responses to MC and AMP for the maximum decrease in FEV₁, IC, FEF_25-75%, and FVC induced by each of these tests (P>0.05).

 

Perception of Induced Bronchoconstriction

Before MC, there were no differences in the perception scores for symptoms at baseline (no symptoms in both groups, P>0.05).  Furthermore, mean perception scores at 20% decrease in FEV₁ were greater in subjects with asthma than in those with AAHR for breathlessness with scores of, respectively, 1.1 (range 0-4) and 0 (P=0.003), while symptoms of chest tightness, with respective mean scores of 1.2 (0-4) and 0.8 (0-5); phlegm production: 0.07 (0-1) and 0.04 (0-0.5); wheeze: 0.9 (0-5) and 0.3 (0-3), and cough:0.7 (0-2), and 0.4 (0-5) were similarly perceived in both groups (Fig. 1, P>0.05).

 

FIGURE 1. Comparison of symptom scores at PC20 MC between subjects with asthma and those with asymptomatic AHR. Although subjects with AAHR did not perceive breathlessness, their perception of other asthma symptoms was similar to that perceived by subjects with asthma.

 

The asthma group had higher maximum symptom scores for breathlessness than the group with AAHR (respectively, mean:1.0, range 0-3.5 and 0 ; P=0.007); other maximum symptom scores were similar in both groups. Maximum respiratory symptom score for chest tightness (mean:1.5, range 0-4, in asthma subjects and mean: 2.3, 0-7 in AAHR subjects; P>0.05). was correlated with the maximum decrease in FEV₁ in subjects with AAHR (r_s=0.60, P=0.04) (Fig. 2a) and with the maximum decrease in IC in asthma subjects (r_s=0.75, P=0.009) (Fig. 2b). The maximum perception score for cough in AAHR subjects correlated with maximum decrease in FEV₁ (r_s=0.97, P=0.005). Other symptom scores were not significantly correlated with the maximum decreases in FEV₁ or in IC on MC in either group.

 

FIGURE 2. (a) Maximum scores for chest tightness following MC were correlated with the maximum decrease in FEV1 in subjects with AAHR but not in those with asthma. (b) Maximum scores for chest tightness following MC were correlated with the maximum decrease in IC in subjects with asthma but not in those with AAHR.

 

 

AMP challenge

Mean perception scores for breathlessness at PC₂₀ were greater in subjects with asthma than in those with AAHR: 2.6 (range 0-9.0, n=11) and 0 (0, n=7) (P=0.002); while symptoms of chest tightness: 1.7 (range 0-6.4) and 1.3 (0-4.9), phlegm production: 1.4 (0-9.0) and 0.7 (0-3.0), wheeze: 1.9 (0-9.0) and 0.7 (0-3.8), and cough:1.9 (0-6.0) and 1.2 (0-3.2) were similarly perceived in both groups (P>0.05). In both groups maximum respiratory symptom scores were not significantly correlated with the maximum decrease in FEV₁ or in IC following AMP challenge.

 

Comparisons of symptom scores on MC and AMP challenge

Symptom scores for breathlessness, chest tightness, phlegm production and wheeze at PC₂₀ were not different following MC or AMP challenge in subjects with asthma or in those with AAHR.  Cough was perceived more intensely after AMP than after MC in subjects with asthma (P = 0.007) but not in those with AAHR (P = 0.08). Symptom scores for chest tightness at PC₂₀ after MC were slightly correlated with those obtained at PC₂₀ after AMP challenge in the whole but not in subjects with asthma or AAHR separately (all subjects: r_s= 0.49, P = 0.04; Asthma: r_s= 0.51, P = 0.11 (n=11); AAHR: r_s= 0.49, P = 0.19 (n=7)). No correlations were observed for the other symptoms between MC and AMP challenge.

 

Discussion

We found a lower perception score for breathlessness following methacholine and AMP- induced bronchoconstriction in subjects with AAHR than in those with asthma. However, those scores were not correlated with the changes in IC or with the degree of airway inflammation.  We also observed that, in subjects with asthma, at maximum decrease in IC following MC, but not in those with AAHR, symptoms of chest tightness correlated with the change in IC although no difference was observed in the perception of chest tightness between both groups. Besides, in subjects with AAHR, symptoms of chest tightness and of cough correlated with the maximum decrease in FEV₁.

Baseline and MC induced dynamic hyperinflation, and the degree of airway inflammation assessed by induced sputum and AMP challenge, were similar in the two groups of subjects. Therefore, our hypothesis that a smaller degree of dynamic hyperinflation resulting from a milder inflammatory process in subjects with AAHR than in patients with asthma could explain the absence of symptoms in AAHR subjects cannot be retained. Although the mean decrease in IC after MC in AAHR subjects was more than twice what was observed in subjects with asthma, AAHR subjects did not perceive breathlessness while those with asthma did.

The lack of an association between the breathlessness score and the change in IC during methacholine challenge in asthma is not in keeping with previous observations and may be due to the milder type of asthma in the study subjects: changes in FRC, assessed by the changes in IC, may have not occurred in our subjects because of insufficiently severe airflow obstruction, the subjects having sufficient time to exhale completely.¹⁰

In acute asthma, persistent inspiratory muscle activity during exhalation may also increase FRC and be a source or a consequence of breathing discomfort.  The low degree of bronchoconstriction in the present study may account for the differences observed with previous studies. However, it was likely sufficient to reflect current day-to-day changes in airway calibre, at least in asthma.

Chest tightness has been considered specific to asthma, and in this regard we found that perception scores for this symptom following methacholine challenges were correlated with the maximum decrease in IC in asthma subjects only.³¹ Our observation that the degree of inflammation evaluated by IS analysis did not correlate with PC₂₀ AMP, as previously reported, could be explained by the mild degree of inflammation in our subjects.^32,33  Furthermore, since IS primarily evaluates inflammation in medium-sized and large airways³⁴, peripheral airway inflammation — which could not be detected by IS — could have contributed to the observed IC changes in this study.

Chest tightness and dynamic hyperinflation are not always correlated. Moy et al demonstrated that symptoms of chest tightness, when subjects undergo methacholine challenge, could occur at very mild degrees of bronchoconstriction.³⁵ Binks et al showed that chest tightness may occur in association with bronchoconstriction, in subjects ventilated passively on a mechanical ventilator and that production of an elevated FRC with ventilator generated positive end expiratory pressure did not result in chest tightness.³⁶ Furthermore, Taguchi et al suggested that dyspnea sensation may result from stimulation of airway receptors when they observed a reduced sensation of dyspnea during histamine-induced bronchoconstriction under airway anesthesia by lidocaine aerosol inhalation.³⁷

We observed a correlation between maximum decreases in FEV₁ and IC following MC, but again, breathlessness scores were not correlated with the decrease in IC. This could be due to the limited number of patients or to the presence of mechanisms other than volume changes. Subjects with asthma were mostly flow-dominant responders, suggesting an improvement post-bronchodilation primarily in large airway resistance.

PC₂₀ methacholine and PC₂₀ AMP were not correlated in asthma and respiratory symptoms at PC₂₀ for these two stimuli were not correlated in asthma nor in AAHR, suggesting, as previously described, that both challenges do not reflect the same airway features.^38,39

Previous studies had shown an increased perception of symptoms during indirect challenges such as AMP in comparison with methacholine challenge, possibly due to release of mast cell mediators and activation of airway sensory nerves.^39-41 In our study, only cough was increased in subjects with asthma after AMP. However, although they were not significantly different, mean symptom scores were slightly higher at PC₂₀ AMP than at PC₂₀ methacholine. The absence of differences between the perception of respiratory symptoms at PC₂₀ methacholine and PC₂₀ AMP in our study could be explained by the low degree of airway inflammation in our subjects.

In summary, no differences were found between asthma and AAHR groups in baseline or dynamic lung hyperinflation, airway inflammation from induced-sputum analysis, and lung volumes. Breathlessness scores were lower in subjects with AAHR than in those with asthma after MC and AMP challenge but changes in IC did not explain this feature. Symptoms of chest tightness correlated with the degree of hyperinflation in subjects with asthma following MC suggesting, at least in these subjects, an influence of the degree of hyperinflation on the perception of this symptom while perception of chest tightness and of cough in subjects with AAHR was related to changes in FEV₁ but not to those in inspiratory capacity. This, added to the fact that subjects with asthma but not those with AAHR perceived breathlessness at PC₂₀ methacholine and PC₂₀ AMP, may suggest a different sensitory threshold in both groups of subjects in detecting variations in these respiratory parameters.

 

Acknowledgments

This study was supported by an unrestricted grant from Altana Pharma Canada

 

References

1.   Cockcroft DW, Killian DN, Mellon J et al.  Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin. Allergy 1977; 7:235-43

2.   Josephs LK, Gregg I, Holgate ST.  Does non-specific bronchial responsiveness indicate the severity of asthma? Eur. Respir. J. 1990; 3:220-7

3.   Jansen DF, Timens W, Kraan J et al.  (A) Symptomatic bronchial hyper-responsiveness and asthma. Respir. Med. 1997; 91:121-34

4.   Laprise C, Boulet LP.  Asymptomatic airway hyperresponsiveness: a three-year follow-up. Am. J. Respir. Crit. Care Med. 1997; 156:403-9

5.   Cockcroft DW, Murdock KY, Berscheid BA. Relationship between atopy and bronchial responsiveness to histamine in a random population.  Ann. Allergy 1984; 54:26-9

6.   Boulet LP.    Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma ? Am. J. Respir. Crit. Care Med. 2003; 167:371-8

7.   Catellier P, Turcotte H, Deschesnes Fet al. Changes in lung volumes and poor perception of bronchoconstriction-induced respiratory symptoms. Ann. Allergy Asthma Immunol . 1998; 81:315-21

8.   Gibson PG, Mattoli S, Sears MR et al.  Increased peak flow variability in children with asymptomatic hyperresponsiveness. Eur. Respir. J. 1995; 8:1731-5

9.   O'Donnell DE, Revill SM, Webb KA.  Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 164:770-7

10.Lougheed DM, Webb KA, O'Donnell DE. Breathlessness during induced lung   hyperinflation in asthma: the role of the inspiratory threshold load. Am. J. Respir. Crit. Care Med. 1995; 152:911-20

11.Lougheed MD, Flannery J, Webb KA et al.  Respiratory sensation and ventilatory mechanics during induced bronchoconstriction in spontaneously breathing low cervical quadriplegia. Am. J. Respir. Crit. Care Med. 2002; 166:370-6

12.Newton MF, O’Donnell, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002;  122:1042-50

13.Boulet LP, Turcotte H, Cartier A et al.  Influence of beclomethasone and salbutamol on the perception of methacholine-induced bronchoconstriction. Chest 1998; 114:373-9

14.Salome CM, Reddel HK, Ware SI et al.  Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am. J. Respir. Crit. Care Med. 2002; 165:15-21

15.Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J. Allergy Clin. Immunol. 1998; 102:S17-S22

16.Boulet LP. Physiopathology of airway hyperresponsiveness. Curr.  Allergy Asthma Rep. 2003;  3:166-71

17.Bousquet J, Cabrera P, Berkman N et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 2005; 60:302-8

18.Laprise C, Laviolette M, Boutet M et al. Asymptomatic airway hyperresponsiveness : relationships with airway inflammation and remodelling. Eur. Respir. J. 1999; 14:63-73

19.Joos GH, O’Connor B, Anderson SD et al. ERS Task Force. Indirect airway challenges. Eur. Respir. J. 2003;  21:1050-68

20.European Community Respiratory Health Survey.  Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS) 1996; 9:687-95

21.Paré PD, Lawson LM, Brooks LA. Patterns of response to inhaled bronchodilators in asthmatics. Am. Rev. Respir. Dis. 1983; 127:680-5

22.American Thoracic Society. Standardization of spirometry -- 1987 update.  Am. Rev. Respir. Dis. 1987;  136:1285-98

23.Knudson RJ, Lebowitz MD, Holberg CJ et al.  Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am. Rev. Respir. Dis. 1983; 127:725-34

24.Simon PM, Schwartzstein RM, Weiss JW et al.  Distinguishable types of dyspnea in patients with shortness of breath. Am. Rev. Respir. Dis. 1990; 142:1009-14

25.Boulet LP, Leblanc P, Turcotte H.  Perception scoring of induced bronchoconstriction as an index of awareness of asthma symptoms. Chest 1994; 105:1430-3

26.Juniper E, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method. In:AB Draco (ed) Laboratory procedure and standardization. Canadian Thoracic Society. Lund, Sweden 1992.

27.Pin I, Gibson PG, Kolendowicz R et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992; 47:25-9.

28.Pizzichini E, Hargreave FE, Pizzichini E et al. Assessment of airway inflammation.  In:  Barnes P, Grunstein M, Leff A, Woolcock A  (eds) Asthma. Vol. 2 Lippincott-Raven; Philadelphia PA, 1997; 1433-50.

29.Avital A, Springer C, Bar-Yishay E, Godfrey S (1995) Adenosine, methacholine and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 50:511-6

30.Altman DG, Gore SM, Gardner MJ et al. Statistical guidelines for contributors to medical journals. Brit. Med. J. 1983; 286:1489-93

31.Harver A, Mahler DA, Schwartzstein RM et al. Descriptors of breathlessness in healthy individuals: distinct and separable constructs. Chest. 2000; 118:679-90.

32.Polosa R, Ciamarra I, Mangano G et al.  Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis. Eur. Respir. J. 2000; 15:30-5

33..  Beier J, Beeh KM, Kornmann O et al. Dissimilarity between seasonal changes in airway responsiveness to adenosine-5’-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum. Int. Arch. Allergy Immunol. 2003; 132:76-81

34.Gershman NH, Liu H, Wong HH et al, Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are samples at different time points. J. Allergy Clin. Immunol. 1999;  104:322-8

35.Moy ML, Woodrow Weiss J et al. Quality of dyspnea in bronchoconstriction differs from external resistive loads. Am J Respir Crit Care Med 2000; 162: 451-5

36.Binks AP, Moosavi SH, Banzett RB et al. ‘‘Tightness’’ sensation of asthma does not arise from the work of breathing. Am J Respir Crit Care Med 2002; 165: 78-82

37.Taguchi O, Kikuchi Y, Hida W et al. Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 1991; 71: 2183-90

38.Prieto L, Gutierrez V, Linana J, Marin J. Bronchoconstriction induced by inhaled adenosine 5’monophosphate in subjects with allergic rhinitis. Eur Respir J 2001; 17 : 64-70.

39. Marks GB, Yates DH, Sist M, Ceyhan B, De Campos M, Scott DM, Barnes PJ. Respiratory sensation during bronchial challenge testing with methacholine, sodium metabisulfite, and adenosine monophosphate. Thorax 1996, 51; 793-8.

40.Rutgers SR, ten Hacken NH, Koeter GH, Postma DS. Borg scores before and after challenge with adenosine 5’monophosphate and methacholine in subjects with COPD and asthma. Eur Respir J 2000; 16 : 486-90.

41.Rafferty P, Beasley R, HolgateS. The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5’monophosphate in atopic asthma. Am Rev Respir Dis 1987; 136: 369-73.

 

 

Correspondence to:

 

Dr. Louis-Philippe Boulet

Hôpital Laval

2725 Chemin Sainte-Foy

Québec, Québec, Canada G1V 4G5

email lpboulet@med.ulaval.ca