Introduction

Hyperactive airway disease or most commonly called as Reactive Airway Disease (RAD) is
used to describe a family of diseases that shares an airway sensitivity to physical, chemical, and
pharmacologic stimuli. This sensitivity results in a bronchoconstrictor response and is seen in
patients with asthma, chronic obstructive pulmonary disease (COPD), emphysema, viral upper
respiratory illness and other disorders. (Packer, 2011)

Hyperactive airway disease is a hallmark of asthma across asthma phenotypes (Hvidtfeldt,

2003). Hyperactive airway, defined as increased bronchoconstriction (constriction of airways) in
response to an inhaled agonist (Hargreave, 1986) is characteristic of asthma, and is often
accompanied by other exaggerated airway responses including cough, mucus production, and
increased microvascular leakage. Hyperactive airway is seen in any animal models of asthma
and asthma exacerbation, including antigen sensitization and challenge, exposure to ozone or
to organophosphate pesticides, virus infection, and obesity. In all these animal models airway
hyperresponsiveness is mediated, in whole or part, by changes in neural control of the airways.

Consideration of the origin of hyperactive airway appears central to understanding the origin of
asthma. Subjects with and without asthma differ both in the ease with which airway narrowing is
produced by inhalation of histamine or methacholine and in the ability to demonstrate a maximal
response to these agents. The latter appears, on present evidence, to be due to an added
mechanism in asthma rather than the absence of a potent inhibitory process. Hyperactive
airway is probably acquired during life as a result of airway reactions to various stimuli, although
genetic factors such as atopy are likely to predispose the person to develop
hyperresponsiveness. Environmental stimuli include inhaled allergens, chemical sensitizers,
airway infections, immunization, and ozone. Allergen-induced hyperactive airway occurs in
association with late-phase asthmatic responses. This and ozone-induced hyperresponsiveness
have been demonstrated to be associated with release of chemical mediators and the cellular
phase of inflammation. Their effect does not appear to be accounted for by increase in airway
epithelial permeability, decrease in airway caliber, reflex bronchoconstriction, or ß-adrenoceptor
blockade. The mechanism(s) responsible for the induced hyperresponsiveness are unknown but
may involve airway epithelial damage, edema in and around the airway walls, stimulation of the
noncholinergic excitatory or inhibition of the nonadrenergic inhibitory systems, or a change in
function of airway smooth muscle. Hyperactive airway can be transient or persistent. Transient
increases in responsiveness are almost certainly associated with mediator release and
injlammation. It is not known whether persistent hyperresponsiveness is due to the same
process, fired, for example, by leaky mediator-releasing cells andlor to some persisting change
in neurogenic or smooth muscle function. (Hargreave, 1986)

Hyperactive airway to nonspecific external stimuli is a common feature of asthma and is

responsible for most of the clinical features of this disease (National Asthma Education and
Prevention Program, 2002). Exaggerated airway responses to bronchoconstrictors can also be
detected in a significant proportion of individuals with no history of respiratory diseasesor
complaints of respiratory symptoms (Boulet, 2003). The clinical significance of this phenomenon
is still a matter of debate. Asymptomatic hyperactive could precede the occurrence of asthma
(Laprise, 1997) , perhaps representing a condition of transition from the lack of symptoms to the
asthmatic phenotype. In addition, longitudinal studies have demonstrated that increased airway
responsiveness is associated with an accelerated decline in lung function (Boulet, 2003), not
only in asthmatic subjects but also in individuals with no respiratory symptoms. Therefore, the
assessment of the severity of airway responsiveness could provide valuable information
regarding the natural course of respiratory diseases. It should be emphasised, however, that
this phenomenon has been evaluated mainly among adolescents or young adult individuals,
and little information is available for populations of more advanced age. (Scichilone, 2005)

Hyperactive airway is an almost universal feature of current symptomatic asthma. Its severity
correlates closely with the severity of variable airflow obstruction, which is how asthma is
currently defined. Consideration of its origin therefore appears central to understanding the
origin of asthma. Postulated hypotheses for the origin have included genetic or acquired in
response to exposure to environmental stimuli such as allergens, infection, or pollutants. These
stimuli have been found to cause an inflammatory reaction, and mediators released in the
inflammatory process appear to be related to the increase in responsiveness. The actual
mechanism of the increased responsiveness of the airway smooth muscle remains poorly
understood. Before discussing possible mechanisms, it is necessary to review what is meant by
airway responsiveness and how it is measured. (Hargreave, 1986)

One of the most important aspects of the mucosal immune system in clinical medicine is its role
in the development of obstructive airway disease. Although the mucosal immune system is
undoubtedly crucial to the survival of humans, certain illnesses are probably a result of an
inability to regulate selected components of the immune response occurring at mucosal sites,
particularly in the airway. In contrast to recurrent bacterial pneumonia and repeated infections of
the sinuses and middle ear cavities, which occur in individuals with immunologic deficits
expressed at mucosal sites, wheezing and hyperactive airway induced by viral infections occur
in individuals who are unable to regulate certain immune pathways but are otherwise
immunologically intact. (Garofalo, 2005)

Neural changes underlying hyperresponsiveness could include changes in 1) afferent (sensory)

nerves, 2) neurons within the central nervous system, and 3) efferent nerves, including
parasympathetic cholinergic nerves and nitrergic bronchodilatory nerves. Although sympathetic
nerves are present in lungs, they do not significantly affect airway tone in humans. (Canning,
2001)
Statistics and Incidences

Viral airway infections can cause hyperactive airway in normal individuals and can exacerbate
asthma (Busse et al., 1997; Johnston et al., 1995). It is estimated that viral infections are
associated with as many as 50% of wheezing illnesses and asthma exacerbations in children
and as many as 20% of those in adults (Johnston et al., 1995; Pattemore et al., 1992). Mild viral
respiratory tract infections seldom cause wheezing in normal individuals, but they frequently
exacerbate symptoms in asthmatics, and severe infections can cause life-threatening asthma
attacks (Ferreira et al., 2002).

Wheezing induced by infectious agents occurs with a frequency of 11 cases per 100 children in
the first year of life, 6 cases per 100 children in the second year, and 1.3 cases per 100 children
in the third year (Denny and Clyde, 1986). The most severe forms of illness are observed in
infants between 2 and 3 months of age (Brandt et al., 1973). Respiratory syncytial virus (RSV),
the parainfluenza viruses, and influenza viruses are probably the most important causes of
infectious asthma in infancy, whereas rhinoviruses predominate as a cause of milder outpatient
wheezing in older children. Similar studies have been completed in adults. In a study of 138
asthmatic adults, 89% (223/250) of colds were associated with exacerbations of asthma
(Nicholson et al., 1993). In 115 laboratory-confirmed cases of viral or chlamydial infection, 28
(24%) episodes occurred in which peak expiratory flows fell by 50 ml/min or greater.
Rhinoviruses are presumed to be the most important etiologic agents in adults.

Two studies have confirmed that hyperactive airway is far more common amongst the elderly
than previously recognized studied by Horsley, et al and Choy et al at 1993 and 2002,
respectively that shows prevalence rates ranging 29–43%.

Airway hyperresponsiveness increases with ageing

One of the first studies aimed at addressing the relationship between age and hyperactive
airway was published in 1985 by HOPP et al., this cross-sectional study was carried out on a
sample of 148 nonsmoking healthy subjects, with age ranging 5–86 yrs and 11 (7.4%) subjects
aged >67 yrs. These individuals formed part of a larger study of the natural history of asthma
conducted during 1972–1983. In this population, exaggerated bronchoconstrictive responses to
spasmogen, expressed as the area under the dose–response curve, were found to be more
prevalent in the youngest and oldest study groups, as opposed to the intermediate age groups.
This finding was put forward as suggesting that age has a significant influence on the
occurrence of hyperactive airway, independent of respiratory symptoms.

As stated above, assessment of the relationship between hyperactive airway and age should
ideally be performed in a longitudinal study setting. The influence of age on airway
responsiveness has been widely investigated in the Normative Aging Study, a longitudinal study
of ageing established by the Veterans Administration in 1961. To this end, a total of 914 male
volunteers, aged 41–86 yrs, were enrolled, with a relatively large number of older individuals
represented (110 (12%) subjects aged of 70 yrs). The study clearly indicated that airway
responsiveness increases with advancing age among former smokers and, to a lesser extent,
among subjects who have never smoked. The lack of a significant relationship in the current
smokers is presumably due to the low number of smoker subjects recruited. Interestingly, these
relationships held after adjustment for pre-challenge FEV1, suggesting that the impact of age on
responsiveness is not mediated by an effect on airway geometry. Since this study was carried
out on a male population, some concerns about the influence of sex on the prevalence of airway
hyperresponsiveness in the general population are raised; in this respect, females have been
shown to exhibit a higher degree of airway responsiveness by Cerveri et al in 1988 because of
greater susceptibility to smoking or lower baseline lung function, although other studies have
failed to demonstrate a role of sex as a determinant of airway responsiveness in the general
population according to Hopp et al in 1985 and Renwick et al in 1999. In another study
conducted on the Normative Aging Study population, 435 healthy middle-aged and older males
(mean age 60.3¡7.26 yrs) underwent methacholine bronchoprovocation challenge on an annual
basis over a 3-yr follow-up interval. Most (92%) subjects who did not show an airway response
to methacholine at the beginning of the study remained normoresponsive at the follow-up test,
whereas 8% of normoresponsive subjects developed a mild response to the
bronchoprovocation challenge after 3 yrs. In contrast, most subjects who reported a greater fall
in FEV1 at the first bronchoprovocation examination showed large variability in response at
follow-up (concordance 45%). A significant increment in the dose–response slope was
described with advancing age in the hyperreactive individuals. Interestingly, this change was
related to increasing blood basophil count, suggesting a role of the time course of the underlying
inflammatory mechanisms related to ageing. In this longitudinal analysis, smoking cessation
was found to predict a decrease in airway hyperresponsiveness, indirectly suggesting that
smoking habit may be a factor affecting increased airway responsiveness. The level of
respiratory function, expressed as FEV1 (percentage of the predicted value), did not influence
the rate of increasing airway responsiveness, perhaps due to the small changes in FEV1 during
the 3-yr follow-up period.

The largest cross-sectional study addressing the prevalence of airway hyperresponsiveness in a

general population was conducted in the Chinese city of Anqing (Xu, 2001). A total of 10,284
subjects underwent methacholine challenge during 1995–1998. The subjects were divided into
four groups according to age (,15 yrs, 15–29 yrs, 30–44 yrs and .45 yrs). The airway response
rate was found to be highest in children and older adults. This is in agreement with the study of
HOPP et al., and suggests that increased airway responsiveness has a bimodal distribution
across the ages (Rijcken, 1993).

In another study, in which methacholine challenge was performed in a total of 208 individuals
aged 45–86 yrs and living in central Manchester, a high prevalence (34.1% of participants) of
airway hyperresponsiveness was reported (Renwick, 1999). The study showed a weak
independent positive association between age and airway responsiveness. Most importantly,
this relationship was shown to depend on the different parameters used to describe airway
calibre in the regression analysis (FEV1, FEV1/forced vital capacity (FVC) and FVC). Indeed,
the study seems to indicate that the influence of age on airway responsiveness is mediated by
an effect on baseline airway calibre.

Taken together, these observations pose the important question as to whether baseline lung
function is the main determinant of the effect of age on airway responsiveness. This issue was
addressed by Rijcken et al. (Rijcken, 1987). In a random population of 1,905 subjects, selected
from a large-scale population study conducted in the Netherlands, airway hyperresponsiveness,
assessed using the histamine challenge test, was detected in 24.5% of the sample, increasing
from 13.8% in subjects aged 14–24 yrs to 40.5% in those aged 55–64 yrs. In the 15 subjects
aged .64 yrs, the percentage of positive histamine test results was 33.3. This trend was
significant (x2 = 73.8 (four degrees of freedom); p,0.0001; b = 6.9%?yr -1). The independent role
of age was confirmed by logistic regression analysis. In order to investigate the effect of lung
function on the relationship between age and airway responsiveness, the analysis was repeated
with separate adjustment for FEV1, FEV1/height2 , FEV1/vital capacity and FEV1 (% pred), and
yielded similar results. The same authors later confirmed the strong association of age with
airway responsiveness by examining a sample of 2,216 subjects aged 15–72 yrs. (Rijcken,
1993). The results of the regression analysis between age and hyperresponsiveness remained
unchanged when subjects with respiratory symptoms were excluded. In conclusion, older age
was associated with higher airway hyperresponsiveness, independently of the level of
respiratory function and/or symptoms. These results were confirmed when the responsiveness
was analysed as a binary variable. Similar findings were found by O’connor et al. who reported
a positive association between age and airway hyperresponsiveness, independently of FEV1 in
a cohort of 778 middle-aged and elderly males (age 41–86 yrs). Paoletti et al. obtained
methacholine bronchoprovocation challenge results from 1,558 subjects, aged 8–73 yrs, who
participated in the Po River Delta Epidemiological Study, a prospective longitudinal study on the
natural history of chronic obstructive pulmonary disease. In agreement with previous
observations, airway responsiveness was higher in older ages, when the population was
analysed cross-sectionally, and remained unchanged when subjects with respiratory symptoms
were removed.

In a randomly selected population consisting of 511 individuals, aged 18–64 yrs, from two areas
in the south of England, Burney et al. confirmed that age was independently associated with the
response to histamine bronchoprovocation; the authors described the distribution of airway
hyperresponsiveness as a U-shaped curve by age: the prevalence of airway
hyperresponsiveness was high in the 18–24-yr study group, fell to 10% in those aged 35–44 yrs
and then rose again to 24% in those aged 55–64 yrs. The inclusion of baseline lung function in
the multiple regression analysis did not alter the estimates of the regression coefficients.
Conversely, smoking was the most important factor affecting hyperresponsiveness in the older
subjects.

Airway hyperresponsiveness is not influenced by ageing

As previously mentioned, some studies do not confirm the positive correlation between airway
hyperresponsiveness and ageing. In this context, two studies deserve some attention (Bakke,
1991; Britton, 1994). Although showing a positive relationship between ageing and airway
responsiveness, after adjustment for airway caliber (in terms of pre-test FEV1), increasing age
was associated with a decreased, rather than increased, risk of hyperresponsiveness. Bakke et
al. analysed a Norwegian population consisting of 490 subjects, with an age range of 18–73 yrs.
Interestingly, the authors predicted that, for every 10-yr increase in age, the adjusted odds ratio
for a PC20 to methacholine of , <32 mgmL-1 decreased by two. Britton et al. measured airway
responsiveness in a population of 2,415 adults aged 18–70 yrs. Before adjustment for FEV1,
the independent odds ratio for older age groups was 2.05, whereas, after adjustment for FEV1,
the relationship between age and airway responsiveness reversed, such that increased age was
associated with lower airway responsiveness. The implication of these observations is that
normally sized airways in older individuals would be relatively unlikely to be hyperreactive. The
most important findings against an effect of age on airway responsiveness are provided by the
Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA), a multicentric study
designed to examine potential associations between air pollution and lung diseases in adults
(Schwartz, 2002). A total of 7,126 subjects aged 18–60 yrs underwent bronchoprovocation
challenge with methacholine. Although the study did not include subjects aged .60 yrs, thus
limiting comparison with other studies, airway responsiveness was found to decline with
increasing age. In particular, the decline was markedly affected by atopic status and smoking
habit; indeed, the reduction in airway responsiveness was smaller in the nonatopic categories
and increased with the number of cigarettes smoked daily. Similar results were obtained when
the analysis was corrected for respiratory symptoms and level of lung function

Woolcock et al. assessed airway responsiveness to histamine in a rural Australian population

consisting of 876 subjects (aged 18–78 yrs), and concluded that age did not affect airway
hyperresponsiveness. Similarly, Malo et al. and cerveri et al. did not find any relationship
between age and airway hyperresponsiveness. In particular, the study performed by Malo et al.
included a sample of 100 nonsmoking individuals, ranging 20–60 yrs of age, with no respiratory
symptoms, atopic history or familial history of asthma. This study showed that age did not
induce changes in airway responsiveness, whereas baseline airway caliber appeared to be the
major determinant of airway hyperresponsiveness. The study by Cerveri et al. included 654
subjects from a small town in northern Italy, whose age ranged 15–64 yrs. The provocative dose
of methacholine causing a 15% fall in FEV1, chosen to detect airway hyperresponsiveness, did
not correlate with age. However, both studies suffer from the lack of subjects aged 65 yrs.

Trigg et al. investigated the role of age in airway responsiveness in a general practice
population of 318 subjects (aged 18–75 yrs); again, airway hyperresponsiveness was not
associated with increasing age, although it could be argued that the proportion of subjects
showing airway hyperresponsiveness was higher in the oldest group (.30% in those aged 65–75
yrs versus <25% in the other study groups). The study also showed a strong negative
association between airway hyperresponsiveness and baseline lung function

In a total of 202 subjects, age ranging 18–65 yrs, randomly selected from an area in eastern
England, Higgins et al. were able to demonstrate that age does not have a significant impact on
airway responsiveness, although an interaction with smoking and atopy is reported. In other
words, the influence of smoking and atopy on airway responsiveness could be mediated by an
effect of ageing on the former. Indeed, the effects of smoking habit and atopy diminish with
ageing.

Discussion
The findings of the present review seem to suggest that, overall, the prevalence of airway
hyperresponsiveness increases with age. It should be noted that the studies that negate the
increase in airway hyperresponsiveness with ageing fail to include subjects aged >65 yrs;
indeed, in four out of eight studies that were included, the analysis is limited to subjects aged
<65 yrs, and in none of the studies are subjects aged >80 yrs included. Conversely, with the
exception of one study (Burney, 1987), all investigations showing a positive correlation between
age and airway hyperresponsiveness recruited subjects aged >65 yrs. Together with data
provided by studies on children or adolescents (which are not shown in the present review),
these observations raise the hypothesis of a U-shaped distribution of airway responsiveness,
which appears to be highest in the early and late phases of life.

There is no doubt that some factors, such as the pre-test lung function state, atopic condition
and smoking habit, profoundly affect the hyperresponsive condition. As a consequence, their
role cannot be ignored when airway hyperresponsiveness is assessed in those of older age.
Other mechanisms (e.g. inflammatory and neuronal) or technical aspects also need to be taken
into account.

Lung function
Ageing per se is associated with important structural and physiological changes. The senile lung
is characterised by an exaggerated but homogeneous enlargement of airspaces (Verbeken,
1992; Saetta, 1985; Lang, 1994). The age-dependent alterations that occur in the connective
tissue of the lungs exert physiological changes in respiratory function, mainly with a reduction in
the elastic recoil pressure (Janssens, 1999; Verbeken, 1992; Permutt, 1960) since elastic recoil
is considered a limiting factor for the maximum decrease in airway caliber during
bronchoconstriction (Ding, 1987), these alterations in lung elasticity could result in enhanced
bronchoconstriction. Indeed, the reduction in the elastic recoil of the lung reduces the radial
traction that is applied to the airway walls, allowing for the loss of supporting tissue from
peripheral airways with ease of airway closure (Cheung, 1997), depicting a functional lung
pattern that stanescu (Stanescu, 1999) described as ‘‘small airways obstruction syndrome’’. As
a consequence, increasing age results in a reduction in maximal expiratory flow rates and may
lead to increased residual volume (RV). A condition of air trapping, expressed in an increased
RV/total lung capacity ratio, has been demonstrated to be the best predictor of a positive
methacholine bronchoprovocation result, even in subjects with normal FEV1/FVC (Stranbrook,
1995). This could explain the increased likelihood of airway hyperresponsiveness in the elderly.
On this basis, it is conceivable to hypothesise that the relationship between age and increasing
airway responsiveness is simply mediated by geometric factors related to changes in lung
volumes and, in turn, airway calibre. Since the resistance of a tube is inversely related to its
radius to the fourth power, a given degree of airway smooth muscle shortening causes a greater
narrowing if the airway calibre is smaller (Moreno, 1986). This mechanism, rather than being
considered an intrinsic difference in airway responsiveness between young and elderly subjects,
could be promoted as a major reason for the increased airway responsiveness that is
associated with ageing. The present authors envisage that the phenomenon of increased airway
hyperresponsiveness with ageing is a result of the decline in lung function associated with age-
related abnormalities of the lung.

Another aspect of the association between lung mechanics and age is worth addressing,
namely the effect of deep inspiration on airway calibre. Lung inflations have been demonstrated
to have beneficial effects on the airways of healthy subjects (Wheatley, 1989; Brusasco, 1999;
Kapsali, 2000; Scichilone, 2000; Brown, 2001) Impairment of these respiratory functions is
associated. with the occurrence of airway hyperresponsiveness and respiratory symptoms
(Kapsali, 2000; Scichilone, 2002). It has been demonstrated that the bronchodilatory effect of
deep inspiration diminishes with ageing (Scichilon, 2004) It has been hypothesised that deep
inspirations induce bronchodilation by stretching the airways because of the forces of
interdependence between airways and parenchyma (Moreno, 1986; Mead, 1970). Therefore,
any factor affecting this relationship leads to impairment of the bronchodilatory ability of deep
inspirations. A condition of reduced elastic recoil, such as that documented in the elderly, could
reasonably account for the attenuation of deep-inspiration-induced bronchodilation. The
attenuation of the ability of the respiratory system to reinstate airway patency could contribute to
the occurrence of airway hyperresponsiveness with ageing, perhaps playing a central role in the
development of lower respiratory symptoms in the elderly.

The question remains as to whether the smooth muscle of aged airways shows altered
contractility. To the present authors’ knowledge, this has not been addressed. The present
original contribution to this topic is based on findings from a study that shows that the airway
response to inhaled methacholine, when the deep inspiration effect is removed, does not
appear to be strongly influenced by age (data not shown). Although the outcome of in vivo
administration of a direct bronchoconstrictive stimulus is probably dependent on several factors,
it is not unreasonable to argue that, when the lung inflation effect is removed, such as in the
protocol that involves single doses of methacholine (Scichilone, 2001), the primary factor
affecting the outcome of a bronchial challenge with a direct stimulus is smooth muscle reactivity.
Based on this observation, the previously described changes in airway responsiveness
associated with ageing cannot be attributed to alterations in the contractile state of airway
smooth muscle, but might be, at least in part, related to changes in the beneficial effects of lung
inflation

Smoking
Asymptomatic smokers show increased airway responsiveness compared to nonsmokers
(Jensen, 1998). This difference becomes more evident in elderly populations, in whom the
duration of exposure to cigarette smoking is longer. Many factors have been advocated to
explain the effect of smoking on airway responsiveness. These can be grouped into two main
mechanisms. On the one hand, smoking can cause chronic airway inflammation and damage to
the epithelium, thus leading to the development of airway hyperresponsiveness; in this context,
a dose-dependent relationship between the number of cigarettes smoked and the degree of
hyperresponsiveness has been demonstrated (Gerrard, 1980). On the other hand, the
increased responsiveness that is observed in current or former smokers of advanced age could
occur through an effect on airway calibre. Therefore, adjustment for FEV1 is advocated when
the association between cigarette smoking and airway hyperresponsiveness is to be assessed.
However, after controlling for baseline lung function, the effect of smoking on airway
responsiveness appears to remain, supporting the hypothesis of a direct effect of smoking on
responsiveness. In support of a direct effect is the observation that increased airway
responsiveness is also detected after relatively short exposure to smoking, when significant
changes in lung function are not expected. Finally, an acceleration of the normal ageing
processes after tobacco exposure, through mechanisms that are not clear, cannot be excluded.
Smoking exposure could induce a low grade of inflammation of the airways that alters the
responsiveness to stimuli through the release of mediators acting on airway smooth muscle.

A selection bias in the inclusion of smoking habit could explain some discrepancies between
studies when assessing the effect of age on airway hyperresponsiveness. The lack of a
significant association between cigarette smoking and airways hyperresponsiveness that has
been observed in some studies could depend on the fact that hyperresponsive individuals tend
to quit smoking. Conversely, subjects who show some degree of airway hyperresponsiveness
because of exposure to passive smoking in a work environment could become
normoresponsive after retirement. To the present authors’ knowledge, this has not been
specifically addressed.

In conclusion, cigarette smoking can be reasonably considered to be one of the main factors
affecting the relationship between airway responsiveness and ageing, primarily because of the
length of exposure.

Sex
Several studies have demonstrated the role of female sex as a risk factor associated with
airway hyperresponsiveness (Cerveri, 1988; Paoletti, 1995; Britton, 1994). It has been
suggested that the higher prevalence of airway hyperresponsiveness in females could be
attributable to their smaller lung volumes. Leynaert et al. have confirmed the independent role of
female sex in the occurrence of airway hyperresponsiveness after adjusting for height and body
mass index in order to exclude the effect of anthropometric difference, and after adjusting for
various spirometric parameters (FEV1, FEV1 (% pred), FVC and FEV1/FVC) in order to abolish
the effect of different airway calibre. Perhaps females are more susceptible than males to other
environmental factors. In this respect, it should be noted that the use of gas for cooking is
associated with a higher risk of respiratory symptoms and impaired lung function in females
than in males (Jarvis, 1998). Greater cholinergic reactivity has been observed in females
(Tashkin, 1992), and hormonal differences related to sex might explain the age and sex
differences in airway responsiveness. Finally, some authors have reported an association
between airway hyperresponsiveness and smoking in females but not in males (Paoletti. 1995;
Tashkin; 1992), suggesting that females are more susceptible than males to the effect of
smoking, thus developing airway hyperresponsiveness to a greater degree. Longitudinal
confirmation of these findings would clarify the above-mentioned issues.

Atopy
Atopic status is one of the major factors associated with the phenomenon of airway
hyperresponsiveness in the general population (Crockcroft, 1984; Clough, 1991; Witt, 1986).
However, the role of atopy in the occurrence of airway hyperresponsiveness in the elderly is not
clear. At more advanced age, atopic status appears to markedly influence development of
asthma. In this respect, Burrows et al. have demonstrated that the level of serum
immunoglobulin (Ig) E is a strong predictor of new-onset asthma in a population aged .60 yrs.
With respect to airway hyperresponsiveness, Renwick and Connolly, in a study performed on a
random population sample of adults, have shown that the relationship between airway
hyperresponsiveness and measures of atopy (IgE score and eosinophil count) becomes
significant only at more advanced age (>65 yrs). This raises the hypothesis that discrepancies
among studies could depend upon the different methods, such as skin-prick testing or total
serum IgE level, that have been used to define the atopic condition. Although IgE levels and
skin-prick testing are positively associated, it is not uncommon to find subjects with low levels of
IgE and strong reactions to prick tests (Holford-Strevens, 1984). Some studies have found that
the hyperresponsive state increases with ageing, especially among atopic subjects (Clough,
1991; Witt, 1986, Renwick, 1997). In addition, eosinophil numbers in the blood have been
demonstrated to increase with ageing (Rijcken, 1993). Taken together, these observations
further support the concept that atopy can be considered an additional factor that contributes to
increase the occurrence of hyperresponsiveness in individuals of this age range
References:

Bakke PS, Baste V, Gulsvik A. Bronchial responsiveness in a Norwegian community. Am Rev

Respir Dis 1991; 143: 317–322.

Boulet LP. Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent

asthma? Am J Respir Crit Care Med 2003; 167: 371–378.

Brandt, C. D., Kim, H. W., Arrobio, J. O., Jeffries, B. C., Wood, S. C.,Chanock, R. M. and
Parrott, R. H. (1973). Epidemiology of respiratory syncytial virus infection in Washington,
D.C. III. Composite analysis of eleven consecutive yearly epidemics. AmerJ. Epidemiol.
95, 355–364.

Britton J, Pavord I, Richards K, et al. Factors influencing the occurrence of airway

hyperreactivity in the general population: the importance of atopy and airway calibre. Eur
Respir J 1994; 7: 881–887

Brown RH, Scichilone N, Mudge B, Diemer FB, Permutt S, Togias A. High-resolution computed
tomographic evaluation of airway distensibility and the effects of lung inflation on airway
caliber in healthy subjects and individuals with asthma. Am J Respir Crit Care Med
2001; 163: 994–1001.

Brusasco V, Crimi E, Barisione G, Spanevello A, Rodarte J, Pellegrino R. Airway

responsiveness to methacholine: effects of deep inhalations and airway inflammation. J
Appl Physiol 1999; 87: 567–573.

Burney PGJ, Britton JR, Chinn S. Descriptive epidemiology of bronchial reactivity in an adult
population: results from a community study. Thorax 1987; 42: 38–44.

Busse, W. W. (1995). Viral-infections in humans. Am. J. Respir. Crit. Care Med. 151, 1675–
1677.

Canning B., A. Fischer, Neural regulation of airway smooth muscle tone, Respir. Physiol. 125
(2001) 113–127

Cerveri I, Bruschi C, Zoia MC, et al. Distribution of bronchial nonspecific reactivity in the general
population. Chest 1988; 93: 26–30
Cheung D, Schot R, Zwinderman A, Zagers H, Dijkman J, Sterk P. Relationship between loss in
parenchymal elastic recoil pressure and maximal airway narrowing in subjects with al-
antitrypsin deficiency. Am J Respir Crit Care Med 1997; 155: 135–140

Choy DK, Hui DS, Li ST, et al. Prevalence of wheeze, bronchial hyper-responsiveness and
asthma in the elderly Chinese. Clin Exp Allergy 2002; 32: 702–707.

Clough JB, Williams JD, Holgate ST. Effect of atopy on the natural history of symptoms, peak
expiratory flow, and bronchial responsiveness in 7- and 8-year-old children with cough
and wheeze. A 12-month longitudinal study. Am Rev Respir Dis 1991; 143: 755–760.

Crockcroft DW, Murdock KY, Berscheid BA. Relationship between atopy and bronchial
responsiveness to histamine in a random population. Ann Allergy 1984; 53: 26–29.

Denny, F. W. and Clyde, W. A., Jr. (1986). Acute lower respiratory tract infections in
nonhospitalized children. J. Pediatr. 108, 635–646.

Ding D, Martin J, Macklem P. Effects of lung volume on maximal methacholine-induced

bronchoconstriction in normal humans. J Appl Physiol 1987; 62: 1324–1330.

Ferreira, A., Williams, Z., Donninger, H., van Schalkwyk, E. M., and Bardin, P. G. (2002).
Rhinovirus is associated with severe asthma exacerbations and raised nasal interleukin-
12. Respiration 69, 136–142.

Garofalo R., Welliver R., Ogra P. Mucosal Immunology (Third Edition). Chapter 83, Pages 1433-
1450. 2005

Gerrard JW, Cockcroft DW, Mink JT, Cotton DJ, Poonawala R, Dosman JA. Increased
nonspecific bronchial reactivity in cigarette smokers with normal lung function. Am Rev
Respir Dis 1980; 122: 577–581.

Hargreave F, J. Dolovich, P.M. O’Byrne, E.H. Ramsdale, E.E. Daniel, The origin of airway
hyperresponsiveness, J. Allergy Clin. Immunol. 78 (1986) 825–832,

Higgins BG, Britton JR, Chinn S, Lai KK, Burney PG, Tattersfield AE. Factors affecting peak
expiratory flow variability and bronchial reactivity in a random population sample. Thorax
1993; 48: 899–905.

Hopp RJ, Bewtra A, Nair NM. The effect of age on methacholine response. J Allergy Clin
Immunol 1985; 76: 609–613

Horsley JR, Sterling IJ, Waters WE, Howell JB. How common is increased airway reactivity
amongst the elderly? Gerontology 1993; 39: 38–48
Hvidtfeldt M. et al. Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell
involvement across asthma phenotypes 2003
Jarvis D, Chinn S, Sterne J, Luczynska C, Burney P, on behalf of the European Community
Respiratory Health Survey. The association of respiratory symptoms and lung function
with the use of gas for cooking. Eur Respir J 1998; 11: 651–658.

Johnston, S. L., Pattemore, P. K., Sanderson, G., Smith, S., Lampe, F., Josephs, L.,
Symington, P., Otoole, S., Myint, S. H., Tyrrell, D. A. J., and Holgate, S. T. (1995).
Community study of role of viral-infections in exacerbations of asthma in 9-11 year-old
children. BMJ 310, 1225–1229.

Kapsali T, Permutt S, Laube B, Scichilone N, Togias A. Potent bronchoprotective effect of deep

inspiration and its absence in asthma. J Appl Physiol 2000; 89: 711–720.

Laprise C, Boulet LP. Asymptomatic airway hyperresponsivness: a three-year follow-up. Am J

Respir Crit Care Med 1997; 156: 403–409

Malo JL, Pineau L, Cartier A, Martin RR. Reference values of the provocative concentrations of
methacholine that cause 6% and 20% changes in forced expiratory volume in one
second in a normal population. Am Rev Respir Dis 1983; 128: 8–11.

Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J

Appl Physiol 1970; 28: 596–608.

Moreno RH, Hogg JC, Pare PD. Mechanics of airway narrowing. Am Rev Respir Dis 1986; 133:
1171–1180.

National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the
Diagnosis and Management of Asthma. Update on Selected Topics – 2002. J Allergy
Clin Immunol 2002; 110: Suppl. 5, S141–S219.

Nicholson, K. G., Kent, J. and Ireland, D. C. (1993). Respiratory viruses and exacerbations of
asthma in adults. BMJ 307, 982–986.

O’Connor GT, Sparrow D, Segal MR, Weiss ST. Smoking, atopy, and methacholine airway
responsiveness among middle-aged and elderly men. The Normative Aging Study. Am
Rev Respir Dis 1989; 140: 1520–1526.

Packer M. Anesthesia Secrets (Fourth Edition). Chapter 38 – Reactive Airway Disease. 2011

Paoletti P, Carrozzi L, Viegi G, et al. Distribution of bronchial responsiveness in a general

population: effect of sex, age, smoking, and level of pulmonary function. Am J Respir
Crit Care Med 1995; 151: 1770–1777.
Pattemore, P. K., Johnston, S. L., and Bardin, P. G. (1992). Viruses as precipitants of asthma
symptoms. I. Epidemiology. Clin. Exp. Allergy 22, 325–336.

Permutt S, Martin HB. Static pressure-volume characteristics of lungs in normal males. J Appl
Physiol 1960; 15: 819–825.

Renwick DS, Connolly MJ. The relationship between age and bronchial responsiveness:
evidence from a population survey. Chest 1999; 115: 660–665.

Rijcken B, Schouten JP, Mensinga TT, Weiss ST, De Vries K, Van der Lende R. Factors
associated with bronchial responsiveness to histamine in a population sample of adults.
Am Rev Respir Dis 1993; 147: 1447–1453.

Schwartz J, Schindler C, Zemp E, et al. Predictors of methacholine responsiveness in a general

population. Chest 2002; 122: 812–820.

Scichilone N, Kapsali T, Permutt S, Togias A. Deep inspiration-induced bronchoprotection is

stronger than bronchodilation. Am J Respir Crit Care Med 2000; 162: 910–916.

Scichilone N, Marchese R, Catalano F, Togias A, Vignola AM, Bellia V. The bronchodilatory

effect of deep inspiration diminishes with aging. Respir Med 2004; 98: 838–843.

Scichilone N., Messina M., Battaglia, S. Catalano and V. Bellia. Airway hyperresponsiveness in
the elderly: prevalence and clinical implications. 2005

Sparrow D, O’Connor GT, Rosner B, Segal MR, Weiss ST. The influence of age and level of
pulmonary function on nonspecific airway responsiveness. The Normative Aging Study.
Am Rev Respir Dis 1991; 143: 978–982.

Sparrow D, O’Connor GT, Rosner B, Weiss ST. Predictors of longitudinal change in

methacholine airway responsiveness among middle-aged and older men: the Normative
Aging Study. Am J Respir Crit Care Med 1994; 149: 376–381.

Stanbrook MB, Chapman KR, Kesten S. Gas trapping as a predictor of positive methacholine
challenge in patients with normal spirometry results. Chest 1995; 107: 992–995.

Stanescu D. Small airways obstruction syndrome. Chest 1999; 116: 231–233

Tashkin DP, Altose MD, Bleecker ER, et al. The Lung Health Study: airway responsiveness to
inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung
Health Study Research Group. Am Rev Respir Dis 1992; 145: 301–310.
Trigg CJ, Bennett JB, Tooley M, Sibbald B, D’Souza MF, Davies RJ. A general practice based
survey of bronchial hyperresponsiveness and its relation to symptoms, sex, age, atopy,
and smoking. Thorax 1990; 45: 866–872.
Verbeken EK, Cauberghs M, Mertens I, Clement J, Lauweryns JM, Van de Woestijne KP. The
senile lung. Comparison with normal and emphysematous lungs. 2. Functional aspects.
Chest 1992; 101: 800–809.

Wheatley J, Pare P, Engel L. Reversibility of induced bronchoconstriction by deep inspiration in

normal and asthmatic subjects. Eur Respir J 1989; 2: 331–339.

Witt C, Stuckey MS, Woolcock AJ, Dawkins RL. Positive allergy prick tests associated with
bronchial histamine responsiveness in an unselected population. J Allergy Clin Immunol
1986; 77: 698–702

Xu X, Niu T, Chen C, et al. Association of airway responsiveness with asthma and persistent
wheeze in a Chinese population. Chest 2001; 119: 691–700.

Zamel N. Threshold of airway response to inhaled methacholine in healthy men and women. J
Appl Physiol 1984; 56: 129–132

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