(Chest. 2003;123:411S-416S.)
© 2003
American College of Chest Physicians
Airway Hyperresponsiveness*
Paul M. O’Byrne, MB, FCCP and
Mark D. Inman, MD
* From the Firestone Institute for Respiratory Health, St. Joseph’s Hospital, Hamilton, ON, Canada.
Correspondence to: Paul M. O’Byrne, MB, FCCP, Firestone Institute for Respiratory Health, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON, L8N 4A6 Canada; e-mail: obyrnep{at}mcmaster.ca
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Abstract
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Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Measurements of airway responsiveness are useful in making a diagnosis of asthma, particularly in patients who have symptoms that are consistent with asthma and who have no evidence of airflow obstruction. These tests can be performed quickly, safely, and reproducibly. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness. These changes in airway hyperresponsiveness are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects. They are, however, similar to changes occurring in asthmatic patients that are associated with worsening asthma control. The mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to fully explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients.
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Introduction
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Airway responsiveness is a term that describes the ability of the airways to narrow after exposure to constrictor agonists. Thus, airway hyperresponsiveness is an increased ability to develop this response. Airway hyperresponsiveness consists of an increased sensitivity of the airways to constrictor agonists, as indicated by a smaller concentration of a constrictor agonist needed to initiate the bronchoconstrictor response, a steeper slope of the dose-response, and a greater maximal response to the agonist (Fig 1
).1
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Figure 1.. The change in FEV1 vs baseline, induced by increasing doses of a bronchoconstrictor stimulus (methacholine) in patients with mild, moderate and severe asthma vs healthy individuals. The PC20 value is calculated by interpolating a 20% fall in FEV1 to the log-linear dose-response curve for each individual. Asthmatic subjects have a reduced threshold response (a), indicating increased sensitivity of the airways, an increased slope (b), indicating increased reactivity of the airways, and an increased maximal response (c).
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Airway responsiveness is measured using inhalation challenges with airway constrictor agonists, such as histamine or methacholine, in both clinical and research laboratories. This is because airway hyperresponsiveness has been identified as an important feature in patients with current, symptomatic asthma and, indeed, has been included in the defining characteristics of asthma.2
In addition, the severity of airway hyperresponsiveness correlates with the severity of asthma3
and with the amount of treatment needed to control symptoms.4
The methods for measuring airway responsiveness have been standardized4
and are widely accepted.
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Historical Perspective
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The initial observation that bronchoconstriction occurs more readily in asthmatic patients when compared to non-asthmatic patients after exposure to a constrictor agonist was made in 1921 by Alexander and Paddock,5
who demonstrated "asthmatic breathing" in asthmatic subjects, but not in healthy subjects, after subcutaneous administration of the cholinergic agonist pilocarpine. This observation was confirmed by Weiss et al6
in 1932, who reported that asthmatic subjects, but not healthy subjects, developed bronchoconstriction, as measured by changes in the vital capacity, after being given IV histamine. Tiffeneau and Beauvallet7
were the first to describe the use of acetylcholine inhalation tests to determine the degree of airway responsiveness in asthmatic patients, while Curry8
identified the fact that bronchoconstriction developed in asthmatic subjects after histamine was given intramuscularly, IV, or by nebulization.
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Direct-Acting and Indirect-Acting Stimuli
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It is now known that airway hyperresponsiveness is present in asthmatic subjects to many chemical or physical stimuli other than inhaled histamine or the cholinergic agonists. These include chemical mediators such as cysteinyl leukotrienes C4 and D49
prostaglandin D210
and F2.11
All of these agonists cause bronchoconstriction by stimulating receptors that are present on airway smooth muscle. They are, therefore, considered to be direct-acting measures of airway responsiveness. An important distinction needs to be made between these methods of measuring airway responsiveness and indirect methods. Indirect-acting stimuli are those that cause bronchoconstriction in asthmatic patients by releasing constrictor mediators from cells in the airways. These stimuli include adenosine,12
exercise,13
hyperventilation of cold, dry air,14
and both hypotonic and hypertonic aerosols.15
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Significance of Airway Hyperresponsiveness
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Airway hyperresponsiveness can be demonstrated in almost all patients with current symptomatic asthma.3
Using the method described by Cockcroft et al,3
asthmatic subjects generally have a provocative concentration of a substance (histamine or methacholine) causing a 20% fall in FEV1 (PC20) of < 8 mg/mL. Most non-asthmatic patients will have a PC20 of > 16 mg/mL. There is, however, some overlap, and defining an exact level of airway responsiveness, which would distinguish asthmatic subjects from nonasthmatic subjects, is not possible. This is because there appears to be a continuous distribution of nonspecific airway responsiveness in the general population, with asthmatic subjects in one tail of this distribution.16
In addition, even subjects with normal histamine or methacholine airway responsiveness can develop symptoms of asthma if exposed to specific stimuli to which they are sensitized, such as an inhaled allergen or toluene diisocyanate.17
The severity of airway hyperresponsiveness generally correlates with the severity of asthma. The degree of airway hyperresponsiveness correlates with other important variables in asthma, such as variations in peak expiratory flow rates18
and with the improvement in FEV1 after receiving an inhaled bronchodilator.18
Last, the degree of airway constriction caused by exercise19
or the hyperventilation of cold, dry air in asthmatic subjects is related to the level of airway hyperresponsiveness.14
Airway hyperresponsiveness to inhaled histamine or methacholine has not just been demonstrated in asthmatic patients but also in patients with airflow obstruction apparently due to COPD.20
The degree of airflow obstruction, as indicated by the reduction in FEV1 and FEV1/VC ratio, correlates with the increase in airway responsiveness.20
This suggests that, in patients with airflow obstruction, the airway hyperresponsiveness demonstrated is a result of reduced airway caliber. By contrast, many patients with airway hyperresponsiveness and asthma have normal airway caliber at the time the inhalation challenge is being performed. This can, however, pose a problem in interpreting the result of an inhalation challenge with a constrictor agonist in a patient with significant airflow obstruction at the time of the study. The likelihood of identifying the presence of airway hyperresponsiveness in patients who are suspected of having asthma, based on history and physical examination, and in whom airway caliber is normal is only slightly better than chance alone, even by physicians who are experienced in treating asthma.21
Therefore, objective measurements of airway responsiveness are particularly useful in such patients with normal airway caliber in whom a diagnosis of asthma is being considered. Another important application of measuring airway responsiveness is the diagnosis of occupational asthma.22
The measurement of airway responsiveness also may be useful in determining the optimal treatment requirements of asthmatic patients. In a study by Sont et al,23
data from measurements of methacholine airway responsiveness were provided, in a randomized fashion, to physicians so that they could make decisions about the amounts of inhaled corticosteroids used to treat asthmatic patients. The doses of inhaled steroids in one group of patients were altered to attempt to normalize airway hyperresponsiveness, while in the other group standard clinical criteria were used. The study demonstrated that patients in whom efforts were made to optimize airway hyperresponsiveness required approximately twice the dose of inhaled corticosteroids, and this was associated with a significant reduction in the number of asthma exacerbations and a significant improvement in FEV1. Interestingly, the higher dose of inhaled steroids also caused a significant reduction in the layer of extracellular matrix proteins below the basement membrane.
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Genetics of Airway Hyperresponsiveness
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It has been recognized for many years that familial clustering exists for asthma, and more recently for airway hyperresponsiveness.24
25
This could reflect a genetic predisposition for the development of asthma, a shared environmental risk, or, most likely, a combination of both. Efforts also have been made to examine the genetic basis of airway hyperresponsiveness. Studies of monozygotic and dizygotic twins have suggested that there is a genetic basis for the development of airway hyperresponsiveness but that environmental factors are more important.26
Also, measurements of airway hyperresponsiveness in young infants (mean age, 4.5 weeks) have indicated that airway hyperresponsiveness can be present very early in life, and that a family history of asthma and parental smoking were risk factors for its development.27
More recently, reports of a genetic linkage of airway hyperresponsiveness have published. One study28
has identified genetic linkage between histamine airway hyperresponsiveness and several genetic markers on chromosome 5q, near a locus that regulates serum IgE levels. Another study has identified linkage between a highly polymorphic marker of the ß subunit of the high-affinity IgE receptor on chromosome 11q and methacholine airway hyperresponsiveness, even in patients with nonatopic asthma.29
Thus, a genetic basis for airway hyperresponsiveness seems very likely. However, the genetic linkage studies need to be confirmed by other investigators in different patient populations. One specific gene polymorphism (Glu 27) of the nine identified of the ß2-adrenoceptor also has been associated with increased methacholine airway hyperresponsiveness,30
while another polymorphism (Gly 16) has been associated with the presence of nocturnal asthma.31
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Mechanisms of Airway Hyperresponsiveness
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Many different factors have been suggested to be involved in causing the airway hyperresponsiveness seen in asthma patients (Fig 2
). Fundamentally, different inflammatory processes are thought to be important. It is believed that the increased number of eosinophils in asthmatic airways produce many of the tissue changes seen in the disease, including epithelial damage, thickening of the basement membrane, and the release of mediators with the capacity to cause bronchial smooth muscle contraction and exudation of plasma, resulting in thickening of the airway wall. Indeed, it is possible that a number of these different mechanisms interact to produce airway hyperresponsiveness, but it seems that different mechanisms are involved in causing different components of airway hyperresponsiveness. It is likely that one mechanism is responsible for the underlying airway hyperresponsiveness in asthmatic patients, differentiating them from healthy individuals, while another mechanism is important for the changes in airway hyperresponsiveness seen in asthmatic subjects during the course of the disease.
Persistent Airway Hyperresponsiveness
It is likely that airway wall thickening, which has been described in patients with varying degrees of asthma severity, could explain some of the differences in airway hyperresponsiveness between healthy individuals and asthmatic patients. The thickness of the airway wall seen in autopsy specimens is greater in patients with fatal cases of asthma than in patients with milder disease and in non-asthmatic patients.32
It is not exactly clear which tissue contributes the most to airway wall thickening in asthma patients. One factor that may be involved is the subepithelial thickening seen in bronchial biopsy specimens from most asthmatic patients. Furthermore, bronchial smooth muscle may have a larger volume in asthmatic patients.33
Last, the exudation of plasma can cause edema and, thus, thickening of the airway wall. Together, these factors may, by geometric mechanisms, enhance the airway luminal resistance induced by a certain degree of airway smooth muscle shortening. Another feature of the asthmatic airway that correlates with the degree of airway hyperresponsiveness is loss of epithelial structure.34
Possibly, the partial loss of the epithelial barrier allows greater amounts of bronchoconstrictor mediators to reach the smooth muscle or other cells that amplify the bronchoconstricting effect of the inhaled mediators. Alternatively, the release of bronchodilating substances from the epithelium could be reduced by epithelial damage, which could enhance bronchial smooth muscle contraction.
Variable Airway Hyperresponsiveness
Bronchial wall eosinophilic inflammation is a prominent feature of asthma. However, it is unlikely that ongoing eosinophilic inflammation by itself is the sole cause of airway hyperresponsiveness, because eliminating eosinophilic inflammation with inhaled corticosteroids improves, but does not eliminate, airway hyperresponsiveness. However, fluctuations in the extent of eosinophilic inflammation may underlie the changes in airway hyperresponsiveness that are seen during the course of the disease. This has been studied to a greater degree in clinical models of asthma, particularly allergen-induced asthma.35
Different forms of allergen exposure, such as challenge with a single dose of allergen,35
36
exposure to repeated low doses of allergen,37
or seasonal exposure to a pollen allergen,38
all increase eosinophilic airway inflammation, as judged by biopsy specimen, lavage sample, or induced sputum sample, as well as enhance the airway hyperresponsiveness already present in these asthmatic individuals. Furthermore, eliminating or decreasing the allergen load, by measures of allergen-avoidance, improves, but does not eliminate, airway hyperresponsiveness.39
Single high-dose allergen exposure, repeated low-dose allergen exposure, natural allergen exposure, and spontaneously occurring exacerbations of asthma all increase methacholine or histamine airway hyperresponsiveness by, on average, 1 to 2 doubling doses from a stable baseline. These changes in airway hyperresponsiveness are likely to be clinically significant, since they occur on top of the persisting airway hyperresponsiveness that is present in all asthmatic patients and that is associated with increases in the variability of lung function and in symptoms of asthma.
While we have proposed that there may be separate mechanisms responsible for the underlying airway hyperresponsiveness of asthma and for the variability seen throughout the course of the diseases, it is quite likely that this distinction is not complete. It is likely that the underlying mechanisms responsible for inflammatory cell recruitment and mediator release may, in the short term, be responsible for variability in airway hyperresponsiveness, as well as, in the longer term, for the underlying structural changes that are responsible for persistent airway hyperresponsiveness.
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Conclusions
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Measurements of airway responsiveness to inhaled bronchoconstrictor mediators (most often methacholine) can be useful in making a diagnosis of asthma, particularly in patients with symptoms that are consistent with asthma but who have no evidence of airflow obstruction. Methacholine inhalation tests can be performed quickly, safely, and reproducibly by experienced technicians, once the factors known to influence the tests are appropriately controlled for.
Inhaled allergens initiate processes that increases airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (in the range of 1 to 2 doubling doses) are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects, in whom the differences are in the range of 4 to 8 doubling doses. These allergen-induced changes are, however, important, as they are similar to the changes occurring in asthmatic patients who already have airway hyperresponsiveness, which is associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatic patients. Nevertheless, the mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to explain the underlying mechanisms of persistent airway hyperresponsiveness in asthmatic patients.
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Footnotes
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Abbreviation: PC20 = provocative concentration of a substance causing a 20% fall in FEV1
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References
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Abstract
Introduction
