Characteristics of Bronchial Hyperresponsiveness in Chronic Obstructive Pulmonary Disease and in Asthma 1 , 2 ANN J. WOOLCOCK, SANDRA D. ANDERSON, JENNIFER K. PEAT, JACQUI.I. DU TOIT, YU GUANG ZHANG, CHRISTINE M. SMITH, and CHERYL M. SALOME
Introduction Why Are We Interested in Comparing Asthma and COPD? As respiratory scientists our aim is to understand and eventually to prevent respiratory diseases. To date we have been unsuccessful in understanding and preventing both asthma and chronic obstructive pulmonary disease (COPO) despite the known association of the latter with cigarette smoking. Research has been hampered by difficulties in defining the underlying abnormalities present in these diseases, and discussions oftheir similarities and differences may lead to useful insights into their causes and natural history. It could be argued that the aims and methods of treatment are similar for both diseases, making further studies unnecessary. However, there are important reasons for continuing to study them. Methods to distinguish the diseases are needed for prognosis and treatment. To prevent them it is necessary to understand their natural history and to determine which allergic persons are likely to get asthma and which smokers are likely to get COPO.
What Are the Known Differences and Similarities? In white societies, asthma usually starts in childhood and is associated with allergy, whereas COPO is a disease of late adult life associated with cigarette smoking. The pathologic changes in the airways are different in nature and site (1). In terms of the present discussion, the presence of eosinophils, the involvement of both large and small airways, and the inflammation and thickening on both sides of the muscle layer are important features of asthma. In addition, the responses to therapy are different in the two diseases. The similarities between the diseases include the presence ofairflow limitation, which is the main lung function abnormality in both diseases, and breathlessness, which occurs when the airflow limitation is severe. In addition, predisposing factors are present in both diseases, so that only some of those at risk (i.e., some allergic persons and some cigarette smokers) develop abnormalities that cause symptoms. In order to explain the fact that only some smokers and some allergic persons develop disease, Orie and coworkers (2) postulated a "host" factor in subjects with these diseases and suggested that this factor might be the reactivity of the airways. This proposal was called the Dutch Hypothesis by Fletcher and colleagues (3). This proposal continues to be 1438
discussed, and therefore it is important to study the characteristics of bronchial hyperresponsiveness (BHR) in these two diseases.
Definitions In this article the following definitions are used. 1. Asthma is a disease characterized by increased responsiveness of the airways to various stimuli and manifested by widespread narrowing of the airways that changes spontaneously or in response to treatment over short periods of time (4). 2. capo is characterized by irreversible reduct jon in expiratory flow rates, with the FEY I less than 80ll/a of the predicted value or the FEY,/FYC ratio less than 75ll/o. In ad-> dition, during periods of disease stability, the FEY, improves by less than 15ll/a in response to acute bronchodilator therapy. In some of the studies referred to in this review, the term chronic airflow limitation (CAL) is used to describe those subjects who frequently have several different pathologic processes present such as bronchitis, bronchiolitis, and emphysema. For this reason, the characteristics of BHR in subjects with COPD are unlikely to conform to a single pattern. Because both asthma and COPD are relatively common and because some asthmatics smoke, there is no reason why the two diseases cannot exist in the same person. Furthermore, there are a number of patients, usually women, who have never smoked, never lived with a smoker, are not atopic, have no history suggesting asthma and yet have severe COPO. The pathology and natural history of this disease has not yet been described. 3. BHR is the ability of the airways to narrow too much or too easily to provoking stimuli. In asthma, the airways are byperresponsive to many different provoking stimuli. In subjects with mild COPD {challenge studies are not safe in the presence of severe CaPO), the airways narrow too easily, they may narrow too much, and they respond to only some provoking stimuli. 4. Normal lung function was defined as values within 20ll/o of the values reported by Morris and coworkers (5).
Characteristics of Bronchial Hyperresponsiveness The characteristics of BHR are discussed under eight headings. Data are presented from a number of sources including some ongoing studies, previously reported studies from our group, and published studies of other groups.
Subjects In order to contrast the characteristics of BHR in the two diseases, we studied dearly defined subjects conforming to the above definitions. The "asthma" results are all from adult subjects who fulfilled the above definition. They had never smoked, most were younger than 40 yr of age, and most were atopic. The details of some of the asthmatic subjects whose results are reported have been published (6-7). The "capo" results are all from smokers in whom asthma had never been diagnosed or who had never used antiasthma drugs. In the present study, smokers were recruited by advertising. Ten subjects who had smoked for more than 20 pack-years, had abnormal lung function, and were not being treated for asthma were included. All but two were men (table 1). Data from two previous studies (7, 10) are reported in this review. In one (9), the subjects were specifically chosen because they were asymptomatic despite having mild COPO. In another (6), they were part of a population study. In both studies, the same definition of COPD applied.
Methods Dose-Response Curves In the present studies, the method ofYan and coworkers (6) with methacholine was used to define the characteristics of the dose-response curves. Other provoking agents, including histamine and propranolol, were used in specific tests employing the Yan method. From the resulting dose-response curves, the position of the curves, expressed as micromoles of agonists, and the shape, expressed in terms of slope and the presence of a plateau, were documented.
Provocation with Osmotic Stimuli The method described by Smith and Anderson (11) was used. The subject inhaled either 4.5ll/o saline or distilled water from an ultrasonic nebulizer until the FEV, decreased by 20ll/o. The tests were stopped when 30 ml of
1 From the Department of Medicine, University of Sydney, and the Department of Thoracic Medicine, Institute of Respiratory Medicine, Royal Prince Alfred Hospital. Sydney, Australia. 2 Correspondence and requests for reprints shouldbe addressed \0 ProfessorAnn J. Woolcock, Institute of Respiratory Medicine, Department of Thoracic Medicine, Royal Prince Alfred Hospital, Missenden Road, Carnperdown, Sydney, Australia 2050.
AM REV RESPlfl DIS 1991; 143:1438-1443
BRONCHIAL HYPERRESPONSIVENESS IN COPD AND IN ASTHMA
1439 TABLE 1 DETAILS OF SUBJECTS
Subject No. 1 2 3 4 5 6 7 8 9 10
Age (yr)
Sex
62 51 56 63 45 63 56 48 63 56
M F M M M M M M F M
Atopy
Pack-Years
FEV, (% pred)
FEV,/FVC (%)
N
68 42 39 113 45 59 26 45 43 51
56 93 65 74 79 67 81 79 61 93
70 73 57 60 72 69 55 68 76 63
V N N N
V N N
V N
PO,. (M)
Plateau (M)
AF Variability (%)
0.82 3 > 50 28 2.8 0.85 6.2 > 149 1.3 76
N N
14 11 9 8 6 9 5 5 12 5
PO,.' (H)
>
> >
2.4 2.2 7.8 1.0 3.7 1.7 5.9 7.8 0.5 7.8
V V N N N
V N
V
DefinitiOn of abbreviations: H = histamine; M = methacholine; AF = airflow meter; Y = yes; N = no. • Mean values from three histamine challenges.
saline of water had been delivered, of which almost 100/0 is predicted to deposit in the lower airway.
Airflow Meter Variability Subjects weregiven an airflow meter (12), and they recorded flow-meter values in the mornings on waking and in the evenings. Most of the subjects with asthma recorded flow rates each day using the same instrument. In this report, only the values recorded before bronchodilator aerosol were used to calculate the variability of readings. Variability was calculated for each day as the range of readings divided by the highest and expressed as a percent. A mean value for sevento 10 daily values, close to the time of the methacholine challenge, was calculated. Symptoms A questionnaire was used to record information about smoking habits and symptoms; all subjects were questioned about symptoms during the provocations, and the results were recorded. Treatment Many of the asthmatic subjects whose data are presented and some of the subjects with COPD received inhaled beclomethasone dipropionate for varying periods of time. Individual asthmatics received varied doses, whereas the subjects with mild COPD were given400 ug a day as part of a trial of the drug.
tomatic COPD previously reported (10), we found a similar range of values for PD.o to methacholine. In general, subjects with COPD are as sensitiveto methacholine as subjects with mild or moderately severe asthma.
stopped after a comparatively low dose had been given. In our previous study (10) of asymptomatic smokers, most subjects had a plateau to methacholine but not to histamine.
Reactivity This term describes the shape of the doseresponse curves. This small group of subjects with mild COPD (figure 1) had high doses of methacholine given in order to examine the shape of the curve. There was a wide range of slopes, and in four a plateau was demonstrated. Plateaus were not demonstrated with histamine although the challenges were
Relative Responses to Histamine and Methacholine The PD.o values to histamine compared with methacholine for the 24 subjects from the present and previous study (10) are shown in figure 2. Almost all subjects weremore sensitiveto histamine. Our recent study (9)in which 14subjects with COPD, including some previously studied (10), had methacholine and histamine challenges, confirmed this differ-
Asthmatic (n=9)
se
co '"
J!
~30
i5" u,
20
.
to
~~~~~~ ~~~~
Fig. 1. Dose-response curves of 10subjects with capo to histamine compared with curves to methacholine and responses in a group of nine asthmatic and two normal subjects to histamine.
'.1
I.'
'"
30
20
--
to
100
1,0
•• 1
Histcmlne dose" (}Jmol)
J
10
'00
Histamine dose (umol)
COPO (n=10)
COPO (n=10)
co'"
:E
1I1 30
~:n~nn 0.1
Results Sensitivity The position of the dose-response curves describes the sensitivity of the airways to the provoking substance. In figure 1, curves can be seen from 10 subjects with COPD for methacholine and histamine, and compared with curves in response to inhaled histamine for a group of nine asthmatics and two normal nonatopic subjects. The PD.o values for methacholine ranged from 1.0 to 10 umol, and those for histamine from 0.5 to 5.9 umol; table 1 gives the details of the results from these subjects. They had several inhalation tests, and the values in the table are expressed as a mean value. In the subjects with asymp-
Normal (n=2)
so
1.0
10
20
- - - - - - - - --
10
100
0.1
Histamine dose (,umol)
1.0
10
100
Methacholine dose ()Lmol)
100,0 . +J ..0 0 "i:: 0
>
I
......
Introduction Why Are We Interested in Comparing Asthma and COPD? As respiratory scientists our aim is to understand and eventually to prevent respiratory diseases. To date we have been unsuccessful in understanding and preventing both asthma and chronic obstructive pulmonary disease (COPO) despite the known association of the latter with cigarette smoking. Research has been hampered by difficulties in defining the underlying abnormalities present in these diseases, and discussions oftheir similarities and differences may lead to useful insights into their causes and natural history. It could be argued that the aims and methods of treatment are similar for both diseases, making further studies unnecessary. However, there are important reasons for continuing to study them. Methods to distinguish the diseases are needed for prognosis and treatment. To prevent them it is necessary to understand their natural history and to determine which allergic persons are likely to get asthma and which smokers are likely to get COPO.
What Are the Known Differences and Similarities? In white societies, asthma usually starts in childhood and is associated with allergy, whereas COPO is a disease of late adult life associated with cigarette smoking. The pathologic changes in the airways are different in nature and site (1). In terms of the present discussion, the presence of eosinophils, the involvement of both large and small airways, and the inflammation and thickening on both sides of the muscle layer are important features of asthma. In addition, the responses to therapy are different in the two diseases. The similarities between the diseases include the presence ofairflow limitation, which is the main lung function abnormality in both diseases, and breathlessness, which occurs when the airflow limitation is severe. In addition, predisposing factors are present in both diseases, so that only some of those at risk (i.e., some allergic persons and some cigarette smokers) develop abnormalities that cause symptoms. In order to explain the fact that only some smokers and some allergic persons develop disease, Orie and coworkers (2) postulated a "host" factor in subjects with these diseases and suggested that this factor might be the reactivity of the airways. This proposal was called the Dutch Hypothesis by Fletcher and colleagues (3). This proposal continues to be 1438
discussed, and therefore it is important to study the characteristics of bronchial hyperresponsiveness (BHR) in these two diseases.
Definitions In this article the following definitions are used. 1. Asthma is a disease characterized by increased responsiveness of the airways to various stimuli and manifested by widespread narrowing of the airways that changes spontaneously or in response to treatment over short periods of time (4). 2. capo is characterized by irreversible reduct jon in expiratory flow rates, with the FEY I less than 80ll/a of the predicted value or the FEY,/FYC ratio less than 75ll/o. In ad-> dition, during periods of disease stability, the FEY, improves by less than 15ll/a in response to acute bronchodilator therapy. In some of the studies referred to in this review, the term chronic airflow limitation (CAL) is used to describe those subjects who frequently have several different pathologic processes present such as bronchitis, bronchiolitis, and emphysema. For this reason, the characteristics of BHR in subjects with COPD are unlikely to conform to a single pattern. Because both asthma and COPD are relatively common and because some asthmatics smoke, there is no reason why the two diseases cannot exist in the same person. Furthermore, there are a number of patients, usually women, who have never smoked, never lived with a smoker, are not atopic, have no history suggesting asthma and yet have severe COPO. The pathology and natural history of this disease has not yet been described. 3. BHR is the ability of the airways to narrow too much or too easily to provoking stimuli. In asthma, the airways are byperresponsive to many different provoking stimuli. In subjects with mild COPD {challenge studies are not safe in the presence of severe CaPO), the airways narrow too easily, they may narrow too much, and they respond to only some provoking stimuli. 4. Normal lung function was defined as values within 20ll/o of the values reported by Morris and coworkers (5).
Characteristics of Bronchial Hyperresponsiveness The characteristics of BHR are discussed under eight headings. Data are presented from a number of sources including some ongoing studies, previously reported studies from our group, and published studies of other groups.
Subjects In order to contrast the characteristics of BHR in the two diseases, we studied dearly defined subjects conforming to the above definitions. The "asthma" results are all from adult subjects who fulfilled the above definition. They had never smoked, most were younger than 40 yr of age, and most were atopic. The details of some of the asthmatic subjects whose results are reported have been published (6-7). The "capo" results are all from smokers in whom asthma had never been diagnosed or who had never used antiasthma drugs. In the present study, smokers were recruited by advertising. Ten subjects who had smoked for more than 20 pack-years, had abnormal lung function, and were not being treated for asthma were included. All but two were men (table 1). Data from two previous studies (7, 10) are reported in this review. In one (9), the subjects were specifically chosen because they were asymptomatic despite having mild COPO. In another (6), they were part of a population study. In both studies, the same definition of COPD applied.
Methods Dose-Response Curves In the present studies, the method ofYan and coworkers (6) with methacholine was used to define the characteristics of the dose-response curves. Other provoking agents, including histamine and propranolol, were used in specific tests employing the Yan method. From the resulting dose-response curves, the position of the curves, expressed as micromoles of agonists, and the shape, expressed in terms of slope and the presence of a plateau, were documented.
Provocation with Osmotic Stimuli The method described by Smith and Anderson (11) was used. The subject inhaled either 4.5ll/o saline or distilled water from an ultrasonic nebulizer until the FEV, decreased by 20ll/o. The tests were stopped when 30 ml of
1 From the Department of Medicine, University of Sydney, and the Department of Thoracic Medicine, Institute of Respiratory Medicine, Royal Prince Alfred Hospital. Sydney, Australia. 2 Correspondence and requests for reprints shouldbe addressed \0 ProfessorAnn J. Woolcock, Institute of Respiratory Medicine, Department of Thoracic Medicine, Royal Prince Alfred Hospital, Missenden Road, Carnperdown, Sydney, Australia 2050.
AM REV RESPlfl DIS 1991; 143:1438-1443
BRONCHIAL HYPERRESPONSIVENESS IN COPD AND IN ASTHMA
1439 TABLE 1 DETAILS OF SUBJECTS
Subject No. 1 2 3 4 5 6 7 8 9 10
Age (yr)
Sex
62 51 56 63 45 63 56 48 63 56
M F M M M M M M F M
Atopy
Pack-Years
FEV, (% pred)
FEV,/FVC (%)
N
68 42 39 113 45 59 26 45 43 51
56 93 65 74 79 67 81 79 61 93
70 73 57 60 72 69 55 68 76 63
V N N N
V N N
V N
PO,. (M)
Plateau (M)
AF Variability (%)
0.82 3 > 50 28 2.8 0.85 6.2 > 149 1.3 76
N N
14 11 9 8 6 9 5 5 12 5
PO,.' (H)
>
> >
2.4 2.2 7.8 1.0 3.7 1.7 5.9 7.8 0.5 7.8
V V N N N
V N
V
DefinitiOn of abbreviations: H = histamine; M = methacholine; AF = airflow meter; Y = yes; N = no. • Mean values from three histamine challenges.
saline of water had been delivered, of which almost 100/0 is predicted to deposit in the lower airway.
Airflow Meter Variability Subjects weregiven an airflow meter (12), and they recorded flow-meter values in the mornings on waking and in the evenings. Most of the subjects with asthma recorded flow rates each day using the same instrument. In this report, only the values recorded before bronchodilator aerosol were used to calculate the variability of readings. Variability was calculated for each day as the range of readings divided by the highest and expressed as a percent. A mean value for sevento 10 daily values, close to the time of the methacholine challenge, was calculated. Symptoms A questionnaire was used to record information about smoking habits and symptoms; all subjects were questioned about symptoms during the provocations, and the results were recorded. Treatment Many of the asthmatic subjects whose data are presented and some of the subjects with COPD received inhaled beclomethasone dipropionate for varying periods of time. Individual asthmatics received varied doses, whereas the subjects with mild COPD were given400 ug a day as part of a trial of the drug.
tomatic COPD previously reported (10), we found a similar range of values for PD.o to methacholine. In general, subjects with COPD are as sensitiveto methacholine as subjects with mild or moderately severe asthma.
stopped after a comparatively low dose had been given. In our previous study (10) of asymptomatic smokers, most subjects had a plateau to methacholine but not to histamine.
Reactivity This term describes the shape of the doseresponse curves. This small group of subjects with mild COPD (figure 1) had high doses of methacholine given in order to examine the shape of the curve. There was a wide range of slopes, and in four a plateau was demonstrated. Plateaus were not demonstrated with histamine although the challenges were
Relative Responses to Histamine and Methacholine The PD.o values to histamine compared with methacholine for the 24 subjects from the present and previous study (10) are shown in figure 2. Almost all subjects weremore sensitiveto histamine. Our recent study (9)in which 14subjects with COPD, including some previously studied (10), had methacholine and histamine challenges, confirmed this differ-
Asthmatic (n=9)
se
co '"
J!
~30
i5" u,
20
.
to
~~~~~~ ~~~~
Fig. 1. Dose-response curves of 10subjects with capo to histamine compared with curves to methacholine and responses in a group of nine asthmatic and two normal subjects to histamine.
'.1
I.'
'"
30
20
--
to
100
1,0
•• 1
Histcmlne dose" (}Jmol)
J
10
'00
Histamine dose (umol)
COPO (n=10)
COPO (n=10)
co'"
:E
1I1 30
~:n~nn 0.1
Results Sensitivity The position of the dose-response curves describes the sensitivity of the airways to the provoking substance. In figure 1, curves can be seen from 10 subjects with COPD for methacholine and histamine, and compared with curves in response to inhaled histamine for a group of nine asthmatics and two normal nonatopic subjects. The PD.o values for methacholine ranged from 1.0 to 10 umol, and those for histamine from 0.5 to 5.9 umol; table 1 gives the details of the results from these subjects. They had several inhalation tests, and the values in the table are expressed as a mean value. In the subjects with asymp-
Normal (n=2)
so
1.0
10
20
- - - - - - - - --
10
100
0.1
Histamine dose (,umol)
1.0
10
100
Methacholine dose ()Lmol)
100,0 . +J ..0 0 "i:: 0
>
I
......
