American Journal of Respiratory and Critical Care Medicine

Asymptomatic increase in airway response to various stimuli has been described in epidemiologic studies. Although its significance is still uncertain, in some subjects, asymptomatic airway hyperresponsiveness (AHR) may be more than a simple curiosity, and in fact, could be a marker of high risk for developing asthma in the near future—the term “asthma” refers to symptomatic asthma in this article. Asymptomatic AHR should, however, be differentiated from the common situation where symptoms have not been recognized in patients with mild asthma.

AHR, the characteristic feature of asthma in which the airway responds both too much and too easily to various stimuli, is one of the most frequent abnormalities of the respiratory system (1). It is associated with variable airway obstruction after physical, chemical, or pharmacologic stimuli and to increased circadian fluctuation of expiratory flow. AHR can be quantified by the provocative concentration (PC) or provocative dose (PD) of an agent such as methacholine, which induces a given fall in FEV1 as much as 20% (PC20 or PD20 FEV1). Unfortunately these tests only measure one aspect of the increase in airway response (2). Indeed, an increase in the slope of the dose–response curve (airway reactivity) or in maximum bronchoconstrictor response may also be observed, although these are less commonly reported.

The prevalence of AHR in the general population varies from 4 to 35% (3). In one study that used as its cutoff point a PC20 FEV1 of 2 mg/ml or less, the prevalence of AHR was 23% (4). Burney and coworkers looked at histamine responses in 511 subjects aged 18 to 64 years, randomly selected from two areas of the south of England. AHR was documented in 14% of the cohort, and it was associated with positive skin-test responses to common allergens and with smoking history (5). It was also more prevalent in women, in individuals who had ever wheezed or had reported symptoms of rhinitis in the preceding month, in atopic individuals, and in smokers. When Paoletti and coworkers looked at AHR in 1,694 subjects from a general sample population (8–73 years old), the PD of methacholine giving a 10, 15, and 20% decrease in FEV1 was reached in 55, 39, and 26% of subjects, respectively (6).

Regarding the pediatric population, the prevalence of respiratory symptoms and AHR in children aged 6 to 11 years in three regions of Australia and New Zealand was 14.9 to 20.1% (7). In another study reported by Backer and associates on 527 children aged 7 to 16 years, 16% of the population in that study had AHR, when defined as a PC20 FEV1 histamine equal to or less than 8 mg/ml (8). Symptoms of asthma, rhinitis, and eczema correlated with the prevalence and degree of AHR, and they were influenced by a family history of atopy. In 1989, Peat and coworkers studied 380 schoolchildren prospectively on three different occasions (two-year intervals) and found that the cumulative prevalence of AHR was 27% (9).

In the general population, AHR follows a continuous unimodal log-normal distribution, with patients with asthma representing the “hyperresponsive” part of the distribution curve (10, 11). Although such unimodal distribution of responsiveness may suggest that AHR is not a pathologic condition, it has been shown that there is a significantly higher prevalence of respiratory symptoms in the more hyperresponsive subjects, thus suggesting clinical relevance (12, 13). Cockcroft and coworkers showed a correlation between the degree of airway responsiveness, asthma symptoms, and need for medication (12), and Xu and associates documented a clear dose–response relationship between AHR and incidence of asthma symptoms (13).

Although AHR was initially considered a static property of the airways, it has become increasingly clear that it is a dynamic process that can vary over time. It can appear or become worse after exposure to various environmental sensitizers, and it can decrease spontaneously or after antiinflammatory therapy. Rijcken and coworkers showed, for instance, that when AHR that they defined as a PC10 FEV1 (fall in FEV1 of 10% or more) was measured in a random population of adults during an 18-year period, 41% of individuals were always nonresponders (PC10 ⩾ 32 mg/ml), 11% were always responders (PC10 ⩽ 16 mg/ml), and 48% changed responder status (change of two or more concentration steps over a three-year period) (14). Although airway responsiveness may normalize for variable periods of time in some subjects, whether it is during adolescence, after withdrawal from sensitizing exposure or most commonly after corticosteroid treatment, it will persist in the majority of subjects even if they are appropriately treated over prolonged periods of time (1517).

Exposure to proinflammatory agents such as allergens, occupational sensitizers, and infections has been shown to increase airway responsiveness in subjects with and without asthma, and this may cause asthma in the latter group (18). The mechanisms by which asthma and AHR develop in this setting, however, are still debated.

Asthma, particularly allergic asthma, is associated with a predominance of Th2 cells that secrete mediators such as interleukin (IL)-3, IL-4, IL-5, and granulocyte macrophage-colony stimulating factor. These mediators provide a signal to B cells to switch to the production of the IgE (IL-4, IL-13) and perpetuate eosinophilic airway inflammation (IL-3, IL-5, granulocyte macrophage-colony stimulating factor) (18). Specific proinflammatory mediators, especially arachidonic acid metabolites, are also involved in the pathogenesis of AHR (18, 19). Such an inflammatory process can alter airway function through the release of mediators acting on airway smooth muscle and wall edema, and bronchial secretions.

In addition, airway remodeling, which can be defined as a change in the composition, nature, and quantity of structural airway elements, may result from an abnormal repair process, which can itself be secondary to the inflammatory insult. It can also be the result of a genetic predisposition to develop those changes after various stimuli or be related to other mechanisms such as inherent airway epithelium abnormalities (20, 21). Recent data have shown that epithelial activation by IL-13 or IL-4 plays a critical role in initiating this remodeling through the release of transforming growth factor β2 (22).

AHR is considered to be one of the major consequences of airway inflammation and remodeling. Indeed, the degree of AHR has been shown to correlate both with an increase in airway inflammatory cells and in some altered structural components, such as a deposition of subepithelial collagen or proteoglycans in the airway wall (20, 23). The frequently observed lack of association between AHR and airway inflammation supports the assertion that other factors such as remodeling may be involved (24).

Airway inflammation can initially be present without AHR, but it may be necessary to add some degree of airway remodeling to develop symptoms from this condition (20). Bronchial biopsies of subjects with asthma typically show airway epithelium damage, mucosal edema, subepithelial fibrosis, and infiltration by activated mast cells, eosinophils, and lymphocytes. The restructuring or remodeling of the airways, either after the inflammatory process itself or after damage to the bronchial epithelium from another cause, has been implicated in the functional airway changes observed in asthma, including AHR. Changes in airway structure in asthma not only involve epithelial damage and subepithelial fibrosis but also a number of other features, such as increased airway vasculature, deposition of proteoglycans in the airway wall, and various airway smooth muscle changes. Increased airway response to triggers may possibly develop when airway inflammation and remodeling have progressively increased over months or years, and symptomatic asthma could represent the final outcome of such a process. It is known that in atopic subjects with or without asthma, inflammation and remodeling are associated, but it remains to be determined whether this relationship and the comparative time-course of these changes are similar in subjects without atopy. Another way airway inflammation and remodeling may lead to AHR could be, as suggested recently, through an airway smooth muscle mast cell myositis (26); this hypothesis comes from the observation that the main difference on immunopathology of airways of subjects with eosinophilic bronchitis (no AHR) and asthma, was an infiltration of airway smooth muscle by mast cells. However, exactly how those changes translate into AHR and symptoms over time remains to be investigated.

Although AHR can be documented in virtually all patients who experience symptoms of asthma, a significant proportion of individuals with no past or present history of asthma or of other respiratory diseases, no current symptoms, and no respiratory medication show an increased physiologic airway response (fall in expiratory flows) to agents such as histamine or methacholine or to stimuli such as exercise (3, 10, 2631).

The prevalence of asymptomatic AHR in the general population varies greatly from one survey to another. In a review of this issue, Jansen and coworkers reported a range of prevalences from 2 to about 50%, although most surveys report a prevalence under 15% (3). In children, the prevalence is relatively the same, and it varies from 8 to 33% (3). Some of these observed variations may be attributable to the different methods used for bronchoprovocation and calculation of AHR, to different definitions of asymptomatic AHR, or to differences in the atopic status of the population. In one study, for instance, the prevalence of AHR in a random population of 400 subjects, defined by a histamine PC20 less than 8 mg/ml, was 5.9% for subjects without atopy and asthma and 9.2% for subjects with atopy and without asthma (32).

By contrast, the proportion of subjects with no respiratory symptoms in large populational studies of subjects with AHR usually varies from 20 to 60% in most cases, although it is usually slightly more than 30% (3). For example, no symptoms were reported in 36.9 (26), 19.3 (10), 37.4 (27), 31.6 (28), 34.7 (29) and 55.5% (30) of hyperresponsive subjects of these different studies.

Asymptomatic AHR has been documented in specific populations, such as that of industrial workers. Enarson and coworkers showed that 10.2% of 1,392 male workers from various industries with no respiratory symptoms had a PC20 methacholine less than 8 mg/ml (33). AHR can also be associated with atypical clinical presentations, for example in the form of an isolated cough, although this is usually considered to be asthma (34).

A more rapid decline in pulmonary function has been shown in subjects with AHR and in patients with asthma as compared with normal subjects, and this decline correlates with the severity of AHR (35, 36). It also seems that this rapid decline in pulmonary function applies to asymptomatic AHR, and in those cases it may be associated with an increased risk of developing asthma in the near future (37). In children, one study has shown that both AHR and previous wheezing were associated with lower increase in airway caliber (38). Sears and coworkers have demonstrated that lower levels of lung function are associated with a higher prevalence of airway responsiveness in the presence of atopy, whereas in subjects without atopy only those with the most impaired lung function showed any significant AHR (39).

We now have substantial evidence that asymptomatic AHR often precedes the development of symptomatic asthma and can be considered a risk factor for the disease. Indeed, 14 to 58% of subjects with asymptomatic AHR may develop symptomatic asthma during the few years after this observation (4042). In occupational asthma, as Gautrin and coworkers have also shown that in those individuals exposed to a sensitizing agent at their workplace, having a measurable PC20 (≤ 32 mg/ml) was a determinant for the development of this type of asthma (43).

In children, although some reports did not support this possibility (44, 45), others provided evidence that asymptomatic AHR often precedes asthma and that it is a risk factor for the disease (4649). De Gooijer and associates reported that childhood atopy was a risk factor for respiratory symptoms in young adulthood but mild childhood AHR was not a risk factor (44). In a longitudinal population study, the combination of sensitization to house dust mite and asymptomatic AHR was an important predictor for the development of asthma (47). Another study suggested that children with symptoms of asthma who are hyperresponsive to an exercise bronchoprovocation test were reported to be at increased risk of developing new symptoms such as wheezing (48).The individual predictive value of exercise testing, however, was low. Rasmussen and coworkers recently reported on the clinical outcome of asymptomatic AHR in their birth cohort of 1,037 children followed to age 26 years (49). Compared with children without symptoms of asthma and without AHR, those with asymptomatic AHR at age 9 years were more likely to report asthma and wheeze at any subsequent assessment, have high IgE levels and blood eosinophils at ages 11 and 21, and more often showed positive responses to skin allergen testing at ages 13 and 21 years. Children without symptoms of asthma and with AHR were therefore more likely to develop asthma and atopy later in life compared with children without symptoms of asthma and without AHR. These studies suggest that asmptomatic AHR is a risk factor of asthma, although associated factors such as atopy may contribute to this relationship.

Not only is there an increased prevalence of symptomatic asthma in the years after the identification of asymptomatic AHR, the opposite is also true. Some patients with asthma evolve toward asymptomatic AHR or in some cases even normalize airway responsiveness (15, 16, 50). Many subjects with asthma considered to be in “remission” of their asthma have persisting airway responsiveness and inflammation, although they report having no or only mild persistent symptoms related to asthma (15, 50). In occupational asthma, the reduction or complete withdrawal from exposure to sensitizing agents, AHR to nonspecific agents disappears in about 25% of workers (33); the longer the length of time they had been exposed to the sensitizing agent, the less AHR is reversible after withdrawal from work.

Genetic Influences and Atopy

The genetic determinants of asthma are usually associated with a genetic predisposition to develop atopy (51). However, it is possible that even if asthma and AHR are closely related to atopy, AHR may have per se a genetic component that could be dissociated from atopy (Figure 1)

. Indeed, it has been shown that AHR has a unimodal distribution in the general population but a bimodal distribution in members of families with asthma and without atopy (52, 53). The fact that subjects with atopy may not have AHR and that subjects with AHR may not be atopic suggests that they have at least partly independent genetic determinants, although this remains to be further studied (51).

Studies of family patterns have shown that there is a higher prevalence of AHR among relatives of subjects with asthma when compared with those of subjects without asthma (52, 53). We previously documented a surprisingly high prevalence (41.3%) of asymptomatic AHR in families of subjects with asthma compared with families without asthma (26.7%) (31). Subjects with asymptomatic AHR coming from families with asthma had higher atopic scores and IgE levels than with those from families without asthma. In children without symptoms of asthma, AHR to cold air was associated with a positive family history of asthma (54).

Most subjects with AHR who will eventually develop respiratory symptoms have a personal or family history of atopy (38, 47, 53). Atopy may predispose to an airway inflammatory process that could in itself lead to symptomatic or asymptomatic AHR (18). Cockcroft and coworkers reported that 9.2% of young adult subjects with atopy and without asthma had AHR (32), whereas Braman and associates found AHR in 40% of patients aged 12 to 54 who had rhinitis (55). In an interesting study by Sears and coworkers, even in children who had been asymptomatic throughout their lives and had no history of atopic disease, AHR appeared to be closely linked to an allergic diathesis, as reflected by the total serum IgE level (56).

Eosinophilia and skin test positivity have been significantly associated with AHR (14, 57). In a general adult population, eosinophilia was associated with AHR in both persons with and without symptoms of asthma, whereas positive skin-test responses were associated with AHR only in subjects with symptoms of asthma (57). Whether atopy and asymptomatic AHR are independent risk factors for asthma remains, however, to be further studied.

We reported previously that 15% of subjects with asymptomatic AHR (mean age of 31.6 years) developed symptoms of asthma over a 3-year period (37). These individuals have been exposed to indoor allergens to which they were sensitized and had at least one first-degree relative with asthma; those who became asthmatic over time had more marked baseline AHR, and it increased with the onset of asthma symptoms.


Although an increased prevalence of AHR has been reported in females, the relationship between sex and AHR seems independent of the presence or absence of symptoms (3). We also found that in a genetically predisposed population, asymptomatic AHR was more prevalent in women than in men (31).

Respiratory Infections

Although respiratory viral infections may influence airway function, there are few data regarding their role in asymptomatic AHR. In a population of 551 subjects aged 10 to 23 (58), Kolnaar and coworkers found that in adolescents and young children, asymptomatic AHR was not related to lower respiratory infections that had occurred in early childhood. In that study, subjects with asymptomatic AHR had similar characteristics than those without AHR.

Other Factors

Asymptomatic AHR seems also to be more prevalent in smokers or in individuals with second-hand smoke exposure (59). The association of AHR with a family history of asthma appears stronger in asymptomatic AHR, whereas atopy and parental smoking seem stronger in subjects with symptoms of asthma. AHR may be found in other conditions such as chronic obstructive pulmonary disease, but the pathogenetic mechanisms may be quite different from those in asthma. It seems to be also commonly found in subjects without asthma who have food allergy (60).

Overall, asymptomatic AHR is associated with genetic determinants, atopy, and smoking exposure, and it seems to be more prevalent in women.

There are many possible explanations for the apparent absence of symptoms in patients with abnormal airway responsiveness (Table 1)

TABLE 1. Mechanisms involved in asymptomatic airway hyperresponsiveness

Cutoff for AHR too high
Intermittent AHR
Poor perception of symptoms
Nonrecognition of symptoms by patient or children's parents
Physiologic abnormality without clinical consequence
Too little inflammation/remodeling
Airway obstruction of small magnitude
Weak diurnal variation in expiratory flows
Insufficient “triggers” of bronchoconstriction

Definition of abbreviation: AHR = airway hyperresponsiveness.

. It is possible that asymptomatic AHR represents a normal distribution of responsiveness in the general population without clinical consequences. It is also possible that AHR may be asymptomatic because the PC20 cutoff is too high with regard to the provocation method and that it does not reflect an abnormal airway status. Furthermore, the criterion for determining if airway responsiveness is increased varies among authors. The American Thoracic Society guidelines mention that a “negative” methacholine challenge result is commonly defined as a nonresponse to the highest concentration (a PC20 > 8–25 mg/ml), with a “positive” test often defined as a PC20 < 8 or < 16 mg/ml. When using ROC analysis, the best PC20 cutoff point that separates patients with asthma from those without asthma is in the range of 8–16 mg/ml. (61). The cutoff points used to define AHR vary according to the method applied for the calculation of airway response and may influence the data on prevalence of asymptomatic AHR (62, 63). With the “concentration method,” a PC20 FEV1 of 8, 16, or 25 mg/ml has been used, whereas with the “dose method,” it has been either a PD20 of 3.9 or 7.8 μmol, or 1 to 2 mg. Beyond these methodologic concerns, however, several investigators have found asymptomatic AHR even when the threshold for cutoff point and method of measurement was low (3). Furthermore, children without symptoms of asthma and adults with AHR may have mild variable airway obstruction, suggesting abnormal airway behavior (62, 64).

It is also conceivable that subjects have an increased response to a “direct” challenge such as obtained with methacholine but not to an “indirect” stimulus such as exercise or cold air. Indirect stimuli may be better to assess airway responsiveness as they are more specific to asthma (65); they, however, are quite insensitive for mild symptomatic but clinically relevant AHR, and it is likely that they would perform poorly in identifying those with asymptomatic AHR. In one study, an increased response to adenosine monophosphate, another indirect stimulus, was associated with allergic rhinitis, allergic asthma, atopy, and blood eosinophilia (66). Subjects without symptoms of asthma may possibly show an increased response to any of those indirect stimuli, but the prevalence of positive tests to those last in the absence of symptoms is uncertain for most of them.

Intermittent AHR

AHR may be intermittent such as seen after exposure to sensitizing agents, like common airborne allergens or other substances found at the workplace, or after respiratory infections. Airway responsiveness may have been abnormal at the time of exposure but no symptoms remain at the assessment, or it may still be reduced so that symptoms are absent or minimal. If symptoms were present in the past, then recollection by the subject may also influence the report.

Poor Perception or Nonrecognition of Respiratory Symptoms?

Because the perception of symptoms associated with airway obstruction follows a normal unimodal distribution in the population with asthma, subjects with marked reductions in expiratory flows can sometimes be asymptomatic or have minimal symptoms (67). Asymptomatic AHR may sometimes be related to a defective perception by the patient of his or her airway obstruction. In this context, Brand found that subjects with asymptomatic AHR were less likely to report an increase in the perception score during histamine provocation than those who had symptomatic AHR (68). However, the only symptom quantified was dyspnea, and the degree of induced airway obstruction was sometimes small. Other reports have shown that children and adults with asymptomatic AHR were quite able to perceive airflow limitation (38, 62, 69). In general, however, a reduction in perception may contribute to the nonrecognition of respiratory symptoms.

On the other hand, nonrecognition of symptoms by subjects who have no impaired perception of airway obstruction may be even more widespread than poor perception. In a study reported by Gautrin and coworkers, only 2 of 12 asymptomatic AHR children were reported to have previously experienced symptoms similar to those observed during a methacholine test (70). It is nevertheless possible that parents will deny the presence of symptoms because of the social and psychological impact of admitting that their child has asthma, or they may simply not be aware of the symptomatic status of their child. This possibility however, does not provide a good explanation for the majority of asymptomatic AHR patients' cases. It is finally possible that some patients perceive bronchoconstriction well, but it is associated with a nociceptive sensation that is insufficient to lead the patient to report his or her symptoms. However, this situation is probably uncommon (71).

Physiologic Abnormality Without Clinical Expression

The sensation of respiratory symptoms has to exceed a certain threshold before a nociceptive stimulus is perceived. It is conceivable that the more responsive the subject's airways are, the easier it is to induce symptoms. Indeed, asymptomatic AHR is mostly found when AHR is mild, although surprisingly, some patients with marked AHR are also asymptomatic.

The lack of symptoms in association with AHR may be due to a low degree of variability of airway obstruction. Although these changes may be of the same magnitude as they are in subjects with asthma (62), some researchers have found that children with asymptomatic AHR were less likely to develop airway obstruction in response to such stimuli such as isocapnic hyperventilation of cold air (69). This may relate to the relative insensitivity of some indirect stimuli to detect AHR.

One can hypothesize that the absence of symptoms can be due to the degree of underlying airway inflammation/remodeling that is insufficient to cause symptoms or airway obstruction. In this context, we and others have found that inflammation and remodeling features such as subepithelial fibrosis were less pronounced in asymptomatic AHR than in asthma (42, 72). We also found that the development of symptoms was associated with an increase in airway inflammation and remodeling, which paralleled a further increase in AHR (42). Finally, the absence of symptoms may be due to insufficient triggers, such as lack of exercise in sedentary people or absence of exposure to relevant allergens or respiratory irritants.

Until recently, it was unclear whether subjects with asymptomatic AHR had airway inflammation similar to what is seen in asthma. It has now been documented that they can have evidences of peripheral (blood) or airway inflammation, as shown by an increased number of eosinophils, and even airway remodeling (e.g., subepithelial collagen deposition), particularly if they are atopic. The severity of these features is usually intermediate between what is found in normal individuals and subjects with asthma (42, 72, 73). The histologic features observed in subjects with asymptomatic AHR are similar to those previously described in subjects without asthma, with atopy, and without AHR, or with “borderline AHR,” but they are less intense than those observed in subjects with asthma. However, Pin and coworkers observed fewer inflammatory cells in the airways of children with asymptomatic hyperresponsiveness than in those of children with symptomatic AHR, although the numbers were similar to those of asymptomatic normoresponsive children (69). By comparing subjects with asymptomatic AHR, chronic obstructive pulmonary disease, and subjects who were not affected, Betz and coworkers found that polymorphonuclear cells were increased in the first two groups when compared with control subjects; eosinophil counts in individuals with asymptomatic AHR were slightly increased compared with control subjects. These findings support the hypothesis that asymptomatic AHR is associated with airway inflammation that may ultimately predispose to development of asthma and perhaps of chronic obstructive pulmonary disease (74).

We compared 2-year changes in clinical and bronchial immunohistologic parameters such as epithelial desquamation and subepithelial fibrosis, in a cohort of consecutive subjects with asymptomatic AHR recruited from epidemiologic studies on the prevalence of AHR, to subjects with asthma and control subjects without asthma matched for age and sex (42). Baseline eosinophil count, total serum IgE level, number of positive allergy responses, baseline FEV1, and the degree of bronchial epithelial desquamation found in subjects with asymptomatic AHR were similar to those of subjects with asthma. The mucosal CD3-, CD4-, CD25-, EG1-, and EG2-positive cell counts were intermediate between that of control subjects and those values found in subjects with asthma. Subjects with asymptomatic AHR had focal bronchial subepithelial fibrosis rather than the more regular pattern observed in subjects with asthma. After 2 years, repeated bronchial biopsies showed that 4 of 10 previously biopsied subjects who had in the meantime developed asthma symptoms had increases both in the extent of subepithelial fibrosis and the number of CD25- and CD4-positive cells. These data suggest that asymptomatic AHR is associated with an accelerated increase in AHR over time. The observed increase in airway inflammation and subepithelial fibrosis may explain the later development of symptoms in some of these subjects. These observations are parallel to those of Niimi and coworkers, who found bronchial subepithelial layer thickening in patients with asthma compared with control subjects, this thickening being greater in individuals with the “classical” form of asthma than in those with cough-variant asthma (75).

It is therefore possible that in subjects with genetic predispositions, persistent exposure to indoor allergens, or intercurrent respiratory viral infections may lead to an increase of the underlying inflammatory process, which could over time lead to structural changes enhancing AHR. This inflammatory process may become self-perpetuating, either because of a change in inflammatory or structural cell “programming,” a change in the epithelial mesenchymal unit behavior, or another type of response to structural alterations (20, 21). The fact that inflammation and remodeling can be observed in lower airways of subjects without asthma and with atopy exposed to relevant allergens and in subjects in whom mild asthma was recently diagnosed support this hypothesis, although long-term consequences of these processes may differ from one individual to another (76, 77).

It is important to stress that asymptomatic AHR must be distinguished from the more common situation where symptoms associated with mild forms of asthma are unrecognized. Once this is clarified, one still does not know if he should treat asymptomatic AHR, the major impetus for treatment being to try to prevent future development of asthma. The key difference between patients with asthma and those with asymptomatic AHR is that the former do not usually know that they have the condition and therefore do not seek medical attention; even physicians are not aware of the abnormality. We should nevertheless make an effort to identify these subjects to prevent future asthma. This can be done for instance in measuring AHR in subjects with severe atopy and allergic rhinoconjunctivitis, particularly if they come from families with asthma and have significant exposure to indoor allergens (e.g., domestic animals).

An important finding that has perhaps not been sufficiently emphasized is that, by the time asthma is diagnosed, structural and functional changes are often irreversible (77). It is thus appropriate to hypothesize that the best treatment for asthma could be its prevention, and that monitoring AHR could provide some insight as to the risk of developing asthma in the future. Unfortunately, the best way to monitor AHR regarding stimuli (direct versus indirect) and optimal time-intervals, is unknown.

Another important question is how to try to prevent the development of asthma in individuals with asymptomatic hyperresponsiveness. One possible way would be to recommend the avoidance of exposure to environmental inducers, particularly indoor allergens. Another way could be to improve or prevent further increase in AHR with inhaled corticosteroids or other agents. Unfortunately, the changes observed with inhaled corticosteroids are usually modest, and when the drugs are stopped, AHR tends to come back to the baseline (17). In mild asthma, airway responsiveness may revert to normal and symptoms may disappear on withdrawal from exposure to a sensitizing substance or with inhaled corticosteroids use (17, 78). Inhaled corticosteroids use may be associated with a reduction in airway inflammation (79), but their capacity to influence airway remodeling seems limited (80, 81). The same effect could be expected in asymptomatic AHR, therefore helping to prevent or delay the onset of symptoms. Unfortunately, it is often difficult to persuade patients, even when symptomatic, to regularly receive preventative medications, unless our arguments are very convincing and the possible benefits are supported by evidence.

One is then faced with the task of identifying high-risk individuals who would benefit the most from these interventions and determining whether such interventions are cost-effective and associated with a sufficient degree of success to justify their application. It is possible that in the future, we will be able to prevent asthma, and subjects with asymptomatic AHR are probably candidates “of choice” for such interventions. Any such intervention should, however, be based on data reflecting the long-term natural history of AHR and its consequence on clinical outcomes. Hopefully, this type of data will become available in the future.

It is possible that we will identify still unrecognized clinical consequences in patients without symptoms of asthma and with AHR. An intriguing recent study has shown for instance that subjects with atopy and asymptomatic AHR may be more susceptible to effects of diving on pulmonary function (82). It is clear that we need more information on the natural history of asymptomatic AHR, particularly as it relates to the development of asthma. We also need to further investigate why AHR is often unassociated with respiratory symptoms. In looking at and comparing clinical studies, attention should be paid as to which criteria were used to define asymptomatic AHR because these may differ from one study to another.

Because the significance of asymptomatic AHR may be different depending on age, family history of asthma and atopy, sex, atopic status, associated conditions, or environmental exposures, the impact of these factors on the clinical outcomes should be further explored. The possible role of nonpharmacologic and pharmacologic measures on the prevention of asthma in specific subgroups of subjects with asymptomatic AHR should be also investigated. Not only will these studies help us understand the significance and consequences of asymptomatic asthma but they will also contribute to a better understanding of asthma.

In summary, asymptomatic AHR is a common phenomenon, and it should be differentiated from the situation where symptoms attributable to mild asthma are unrecognized. Asymptomatic AHR is more frequently observed in subjects with atopy, in members of families with asthma, in those individuals exposed to tobacco smoke, and in women. The variability observed in the prevalence of AHR is likely related to methodologic differences between investigations, to the terminology used to define AHR, to the techniques of measurement, and to the populations studied. Asymptomatic AHR is associated with airway inflammation and remodeling, although these features are not as severe as observed in asthma. Asymptomatic AHR is associated with an increased risk for later development of asthma, suggesting that it is a marker of a pathologic process that could lead to asthma. However, more studies must be done so that one can define the population in which symptomatic AHR may be clinically relevant and whether those people could benefit from preventative environmental or pharmacologic measures to reduce the risk of developing symptomatic asthma.

The author is grateful to Ms. Sylvie Carette and Lori Schubert for their help in the preparation of this manuscript and to Drs. Jean Deslauriers, François Maltais, Donald W. Cockcroft, and the reviewers of this manuscript for their most useful comments.

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Correspondence and requests for reprints should be addressed to Dr. Louis-Philippe Boulet, M.D., Hôpital Laval, 2725 Chemin Sainte-Foy, Sainte-Foy, QC, Canada G1V 4G5. E-mail:


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