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What Determines the Severity of Asthma?
SESSION
What Determines the Severity of Asthma?* Ann] Woolcock, M.D., F.C.C.P.; K. Yan, F.R.AC.P.; C. M. Salome; C.] Sedgwick; and] Peat
T
his article reviews recent epidemiologic and clinical studies relating to the factors thought to influence the severity of asthma. A patient with severe asthma, whose history and physical findings are presented, posed questions that are answered with particular reference to the factors that appear to cause asthma in the untreated patient. Since the overall aim of treatment is to lessen the severity of the disease, the severity of asthma in the treated patient depends on the success of management. Studies aimed at reducing the degree of BHR in a group of patients with severe asthma are described. The severity of asthma can be defined in terms of symptoms, the level of resting lung function, the degree of bronchial hyperresponsiveness (BHR). For the purposes of diagnosis, prognosis, measurement of prevalence, and monitoring of response to treatment, the degree of BHR is by far the most useful method ofassessing severity. It is recognized, however, that BHR occurs in conditions other than asthma and, for the diagnosis of asthma to be made in the individual or in populations, It is necessary to have symptoms consistent with asthma as well as objective evidence of BHR. PATIENT A highly intelligent engineering student, aged 22 years, presented with symptoms suggesting severe, unstable asthma. He had had no real problems, apart from occasional wheezing and cough in childhood, until the age of 18 years, when, during the winter, he developed an upper respiratory infection and started to wheeze, Since then he had had symptoms almost continuously and had taken a variety of drugs including aerosol bronchodilators, theophylline, and antibiotics. His attacks were precipitated by exposure to house dust, exercise, respiratory infections, and drinking white wine. He hadhad allergic rhinitis all his life, and this had been worse recently. His mother had severe asthma and, when she was later questioned about the patient, confirmed that he had had a very severe episode of bronchitis needing hospital admission at the age of 9 months. Physical examination showed a man of normal stature with a hyperinflated chest and scattered rhonchi in both lungs. The appearance of his nasal mucosa was consistent with allergic rhinitis. Investigations showed mild airway obstruction (FEV, 69% of the predicted value), which improved to 75% after bronchodilator aerosol, increased lung volumes, and strongly positive skin prick tests to common aeroallergens including cats, house dust mites, and pollens. An exercise test revealed severe exercise-induced asthma and a challenge in which he drank white wine resulted in an immediate, but not a late, attack of asthma. He had a number of questions about his asthma. ·From the Department of Medicine, University of Sydney, and the Department of Thoracic Medicine, Royal Prince Alfred Hospital, Sydney, Australia. These studies were supported by the National Health and Medical Research Council of Australia and the Asthma Foundation of N.S.W Reprint requests: Dr: Woolcock, Department ofMedicine, University ofSydney, Sydney, NSW 2027, Australia
5
Queatians 1. How severe is my asthma? 2. What are the risks associated with severe asthma? 3. What caused it to come on only recently? 4. Are allergies the cause of asthma? 5. Did 1 inherit it from my mother? 6. Can asthma be cured? If not, what can be done? These questions are frequently asked by patients with chronic, severe asthma. Most of them cannot be answered precisely. The factors thought to relate to the cause and to the severity of asthma are discussed in relation to each of these questions, and the treatment instituted is described. Questian 1: How severe is my asthma? This question implies that the severity of asthma can be quantitated. It is now recognized that the underlying problem in asthma is manifested as bronchial hyperresposiveness and that the degree of BHR can be measured using inhalation tests with histamine and methacholine. There is good agreement between BHR as measured by inhalation tests and clinical severity of asthma assessed by the treatment required to control symptoms;':" although the range of responses for the amount of treatment required is wide. Furthermore, it is now becoming clear that the resting level of the FEV, and the symptoms reported by the patient are much less accurate methods for assessing severity. Figure 1 shows typical dose response curves to inhaled histamine using the FEV, to measure the airway response in asthmatic patients of different clinical severity. The degree of BHR is measured as the dose of histamine (in jLmol) which causes a 20% fall in the FEV, (PDIIlFEV,). The ranges shown were obtained from subjects with asthma defined in clinical terms as severe (needing steroid therapy), moderately severe (needing daily bronchodilator therapy, but not steroids), mild (needing therapy intermittently in the past 12 months), and intermediate or past (wheezed in the past but not in the past 12months). The dose-response curve for the patient, obtained at the time of the first consultation, is shown as the dotted line, indicating very severe BHR. How applicable is this diagram? Could the dose-response curve from the patient be a chance finding? Does the degree of BHR vary greatly from week to week? Do populations of asthmatic children and adults conform to these ranges?
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CHEST I 87 I 5 I MAY, 1985 I Supplement
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FIGURE 2. The dose-response curves to inhaled histamine of a 38year-old man with severe asthma. The curve shifted to the right 30 minutes after 400 j1.g of salbutamol aerosol (Rr). Four hours after this treatment, the curve had moved toward the control position; all curves are extremely steep. A number of studies have shown that in individual asthmatic patients, the level of BHR remains stable over periods of weeks or months. l3,' Thus, overall, there seems to be little doubt that in patients who present fur treatment of asthma, there is a good correlation between clinical severity and degree of BHR. However, in the community there are children with moderately severe degrees ofBHR who are asymptomatic. M In a study oflo-year-old children in Australia, we found that nearly one third ofchildren with BHR in the mild range (Fig 1)had no symptoms, 20% of children with BHR in the moderate range had no symptoms, but all children with severe BHR had symptoms." On the basis of all the reported studies, there can be little doubt that the response to histamine of this patient indicates that he had severe asthma at the time of presentation. Question 2: This patient has seoere BHR. What is the significance ofthis finding? Based on experience of a large number of patients with severe degrees ofBHR living in Australia, several statements can be made about the risks of severe asthma. First, there is a real risk of death; second, the resting lung function is likely to be abnormal; and third, it will take time, commitment by the patient and physician, and
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FIGURE 3. Dose-response curves tu mhaled histamine in a 55-yearold man on 4 occasions between May 1983 and May 1984 showing progressive improvement. The figures in brackets indicate the FEV, at the beginning of each inhalation test.
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FIGURE 4. The FEVlFVC ratio of the patient measured at yearly intervals between the ages of 12 and 24 years. Lower figure shows height in em, the FVC values are given in brackets. The predicted FEV/FVC ratio shown is fur the age of 12years. The point at which regular treatment started is indicated (Rr). regular medication including corticosteroids to improve the degree of BHR and thus lessen the severity of the asthma. Figure 2 shows dose-response curves to inhaled histamine in a patient admitted to the hospital after having had several respiratory arrests fullowing acute, severe attacks of asthma. The patient had normal resting lung function, with an FEV! of 4.20 L and a FVC of 5.30 L and he had only mild hyperinflation of lung volumes. The curves after treatment with aerosol salbutamol (400 j1.g) indicate temporary improvement in the level ofhyperresponsiveness. However, the curves are extremely steep and, once the airways began to narrow, the next dose caused a large fall in the FEV l . This man was discharged with normal lung function and free of symptoms. He continued to take regular medication, but he had a fatalattack shortly afterward. Figure 3 shows progressive dose-response curves in another patient with somewhat less severe asthma who had had several extremely severe asthma attacks and many hospital admissions. He was treated vigorously with aerosols of salbutamoI, cromoglycate, beclomethasone diproprionate, and ipratropium bromide (an atropine-like agent) regularly at 5 hourly intervals, and the degree of BHR decreased progressively over a period of months. These 2 patients illustrate that any patient with severe BHR, and particularly those with very steep curves, are at risk of severe, lifethreatening attacks. Question 3: What are the factot" which precipitated his severe asthma during his late teenaged yeat"? Figure 4 showshis lung function, measured annually, from the age ofll years, when he was part of a long-term study oflung function in Sydney schoolchildren." He was asymptomatic until the age of 18 years. However, even before he had symptoms, his FEVlFVC ratio was below the predicted value, and it is likely that he had some degree of BHR at that time. It is becoming clear that there are a number of children in the community with undiagnosed asthma"? and it is likely, in view of the history of wheezing in early childhood that he had had unrecognized asthma for many years. The role of bronchitis at the age of 9 months is also of interest in this patient. We have shown in Sydney schoolchildren with asthma, that severe bronchitis before the age of 2 years is an important risk factor fur the later development of asthma. • At the age of 18 years he moved away from home to an apartment close to the university and entered an entirely different life-style and environment. There is no way of determining the influence of this changed environment, but it maywell have precipitated more severe asthma. 27th Annual AspenLung Conterence
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Question 4: 18 there a relationship between seoere atopy and severe asthma? There have been a number of studies which have shown a relationship between allergy and BHR. In the study of Australian children referred to above. we found that 37% ofchildren were atopic (had lor more positive skin reaction to extracts of common allergens) and that 26% of atopic children had asthma (10). Only 12% of the asthmatic children were not allergic. Ninety percent of highly allergic children (more than8 of 13 allergens tested causing positive skin reactions) had asthma. Van Asperen et aI found that 81% of asthmatic children in Sydney were allergic. U Bryant and Burns" also found a relationship between atopic status and asthma in adults. However, the nature of the relationship is not dear. The answer to the question is that there appears to be a strong relationship, but its exact nature is not dear. There is no direct evidence that atopy or allergic reactions are the cause of BHR although they can dearly make existing BHR worse. Question 5: 18 asthma inherited? There seems to be little doubt that there is a genetic factor involved in the development of asthma. First. the disease appears to
be more common in boys than in girls in almost all populations of children.' Secondly, the high prevalence in some isolated communities, such as Tristan De Cunha, 13 appears to have evolved because a majority of the ancestors had the disease. Third, there is a positive family history of asthma in many studies. In our studies of 8- to 10year-old children in Australia, a history of parental asthma was given by 54.1% of the children with asthma, but by only 16.3% of the children without asthma (p
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'!l FIGURE 6. The PD.,FEV, values in a group of 15 subjects (LHS) who took tailor-made therapy regularly to protect their airways and maintain optimal lung function and in a group of 7 subjects (RHS) who took medication only lOrsymptoms. The figures indicate the number of months between measurements. CHEST I 87 I 5 I MAY, 1985 I Supplement
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FIGURE 7. Serial changes in PD.. FEV I (continuous lines) of2 subjects over 12 months with the treatment used. A short-lived exacerbation occurred in the first subject. Dotted line indicates the mean value for the daily air flow meter readings for the month prior to each PD.. FEV, measurement. BHR. Twenty subjects undertook to take aerosol medication on a regular basis, 4 to 5 times a day, for a period ofl to 2 years. The drugs needed to protect the airways were determined for each individual, and each recorded his lung function twice daily. The other 10 subjects took only the medications prescribed at clinic. The method used to design a "tailor-made" drug regimen for each subject was similar to that used in the patient. The patient described above had formal exercise tests done before and immediately after a number of different aerosol drugs to find the combination which completely inhibited his exercise induced asthma. This proved to be 40 mg of cromoglycate and 200 ....g of salbutamol. He was told to keep his environment free ofcats and to treat his bedding regularly to keep
the house dust mites to a minimum. He was given a challenge with white wine, which caused a fall in the FEV" and he was told to avoid this during the period of treatment. He was started on regular treatment with salbutamol, cromoglycate, and beclomethasone diproprionate aerosols, to be taken 5 times a day with extra doses of salbutamol and cromoglycate before exercise. He was instructed to record his own lung function at home using an airflow meter, .. and once his values reached the predicted level to try to maintain them. He was given a supply of oral prednisone and an antibiotic so that he could treat exacerbations promptly. In addition, his allergic rhinitis was treated regularly with beclomethasone diproprionate aerosol to the nose.
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FIGURE 8. A diagram suggesting the factors which may combine to cause asthma. It is postulated that there are 2 closely associated susceptibility genes, 1 for atopy and 1 for BHR. In Australia, about 40% of the population becomes atopic (as judged by skin tests) by the age of 18 years. Most of them remain asymptomatic, while approximately 12%develop allergic rhinitis. About 8% have established asthma by late teenaged years, but only I'll can be classified as having severe asthma. Up to 24% of children between 1and 10 years old have a history of wheezing and may have mild degrees of BHR, but only some continue to have asthma by the age ofl8 years. In the majority, the BHR appears to resolve (although it is possible that some of these people develop asthma in later life). With appropriate treatment, the level ofBHR in asthmatics can be maintained in the mild range.
212S
27th Annual Aspen Lung Confel8nce
The change in his PDlIllFEVt values for histamine on this treatment is shown in Figure 5. There was a progressive improvement in both PDlIllFEV l and in the baseline level ofFEVt • The results ror 22 of the subjects (15 treated and 7 controls) are shown in Figure 6. Many of the subjects have only just started on the project but all have improved. In those who have been treated ror more than 12 months, the PDlIllFEVt values have risen above 1.0 Il-mol, and some have improved to about 4.0 Il-mol. These subjects, although they are not cured, are in a symptom-free state. In general, most subjects reached a "best" value for PDJEV1 after 5 to 12 months and did not improve further. Once this "best" value was reached, it was possible to reduce the amount of medication required to keep the lung function at the optimal value. No change occurred over a similar period in the subjects not given regular medications. Figure 7 shows the serial changes in BHR from 2 of the subjects. Exacerbations occurred in some subjects, in spite of the optimal treatment, but they were short-lived (as shown by subject I), and the PDlIllFEV l values returned to previous levels in days rather than in months. The treatment required varied in different subjects from 1to 4 aerosol drugs. All took a ~2-adrenergic aerosol, usually salbutamol. Most of the severe asthmatics required steroid aerosols and many also had cromoglycate or ipratropium bromide. The answer to the question "Can asthma be cured?" is "No." However, asthma can be treated in such a way that the degree ofBHR can be greatly reduced. The long-term benefits of this improvement in the BHR are related to the reduction of the risks associated with severe BHR which include risk of death, altered life-style, risk of permanent airflow limitation and, in children, chest deformity and abnormal growth. OvERALL CONCEPT
In answer to the patients questions, he did have severe asthma when he presented, but after treatment his asthma could be classified as mild. His asthma did not come out of the blue, but was probably present throughout his childhood in a mild form. The factors which combined to produce the asthma were a genetic predisposition combined with an early episode of respiratory infection. After that, constant mediator release resulting from contact with allergens, from exercise and other provoking situations caused mild but unrecognized asthma. Entry to university, with changed lifestyle (and perhaps also exposure to different allergens), led to more severe BHR and precipitated symptoms. Protection of the airways with aerosol medications resulted in a decrease in the level of BHR and improvement in his asthma. Figure 8 shows a model of how this patient might have developed severe asthma based on what has been reviewed. It is suggested that not only is there a susceptibility gene for atopy, but possibly also one for BHR. It is stressed, however, that at present there is no good evidence that atopy and asthma are inherited separately. However, there is good evidence that not all atopic people develop BHR, and many people with BHR are nonatopic. The percentage figures in Figure 8 are the approximate percentages of young adults in the Australian population that we have found to be atopic, to have allergic rhinitis, to have mild and severe allergic asthma, to have nonallergic asthma, and to be normal, but with a previous history of wheezing (some of these people are atopic). Perhaps many children have a mild degree of BHR which remits spontaneously, unless the airways are exposed to mediators, and it is the severely allergic children whose
airways are continuously exposed to mediators. In spite of this problem it seems likely that with appropriate treatment the degree ofBHR in most young people can be maintained in the mild range. REFERENCES
1 Yan KY, Salome CM, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760-5 2 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and a clinical survey. Clin Allergy 1977; 7:235-43 3 Juniper EF, Firth PA, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978; 38:705-10 4 Shoeffel RE, Anderson SD, Gillam I, Lindsay DA. Multiple exercise and histamine challenge in asthmatic patients. Thorax 1980; 35:164-70 5 Speight ANp, Lee DA, Hey EN. Underdtagnosis and undertreatment of asthma in childhood. Br Med J 1983; 286:1253-6 6 Sears MR, Holdaway MD, Hewitt CJ. Sivla PA. Bronchial hyperreactivity in children without asthma. Aust NZ J Med 1984 (in press) 7 Britton WJ, Woolcock AJ, Sedgwick CJ, Peat JK. Prevalence of bronchial hyperresponsiveness in children: 1. Methodology for field studies. Submitted for publication 8 Leeder SR, Woolcock AJ, Blackburn CRB. Prevalence and natural history of lung disease in New South Wales schoolchildren. Inst J Epidemiol1974; 3:15-23 9 Woolcock AJ, Peat JK, Leeder SR, Blackburn CRB. The development of lung function in Sydney children: effects of respiratory illness and smoking: a ten year study. Eur J Respir Dis 1984 (in press) 10 Britton WJ, Woolcock AJ, Sedgwick CJ, Peat JK, Leeder SR. Prevalence of bronchial hyperresponsiveness in children: 2. Relationship to skin reactivity to allergens in two communities. Submitted ror publication 11 VanAsperen PP, MellisCM, South RT, Simpson SJ. Allergen skin prick testing in asthmatic children. Med J Aust 1980; 2:266-8 12 Bryant DH, Burns ML. The relationship between bronchial histamine reactivity and atopic status. Clin Allergy 1976; 6:373-81 13 Mantle J, Peppy SJ. Asthma amongst Tristan da Cunha Islands. Clin Allergy 1974; 4:161-70 14 Bias WB, Marsh DG. The genetic basis of asthma: Current studies of the genetics of the IgE-mediator imipramine response in man. In: Lichtenstein LM, Austin KF, eds, Asthma. New York: Academic Press, 1977; B:21-34 15 Cockcroft DW, Ruffin R, Dolovich J, Hargreave FE. Allergeninduced increase in non allergic bronchial reactivity. Clin Allergy 1977; 7:503-13 16 Geubelle F, 8orlee-Hermanns G, Leclerq-Focart J. Hyperreactivity of the bronchial tree to histamine in asthmatic children and its variations. Bull Physiopathol Respir 1971; 7:839-40 17 Salome CM, Schoeffel RE, Woolcock AJ. Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects. Thorax 1981; 36:580-4 18 Jenkins CR, Breslin ABX. A long term study of the effect of sodium cromoglycate on airway responsiveness in asthma. 1984; 14 (suppI2):538 19 Juniper EF, Frith PA, Hargreave FE. Long term stability of bronchial responsiveness to histamine. Thorax 1982; 37:288-91 20 Friedman M, Walker S. Assessment of lung function using an airflowmeter. Lancet 1973; 1:310
CHEST I 87 I 5 I MAY, 1985 I Supplement
213S
What Determines the Severity of Asthma?* Ann] Woolcock, M.D., F.C.C.P.; K. Yan, F.R.AC.P.; C. M. Salome; C.] Sedgwick; and] Peat
T
his article reviews recent epidemiologic and clinical studies relating to the factors thought to influence the severity of asthma. A patient with severe asthma, whose history and physical findings are presented, posed questions that are answered with particular reference to the factors that appear to cause asthma in the untreated patient. Since the overall aim of treatment is to lessen the severity of the disease, the severity of asthma in the treated patient depends on the success of management. Studies aimed at reducing the degree of BHR in a group of patients with severe asthma are described. The severity of asthma can be defined in terms of symptoms, the level of resting lung function, the degree of bronchial hyperresponsiveness (BHR). For the purposes of diagnosis, prognosis, measurement of prevalence, and monitoring of response to treatment, the degree of BHR is by far the most useful method ofassessing severity. It is recognized, however, that BHR occurs in conditions other than asthma and, for the diagnosis of asthma to be made in the individual or in populations, It is necessary to have symptoms consistent with asthma as well as objective evidence of BHR. PATIENT A highly intelligent engineering student, aged 22 years, presented with symptoms suggesting severe, unstable asthma. He had had no real problems, apart from occasional wheezing and cough in childhood, until the age of 18 years, when, during the winter, he developed an upper respiratory infection and started to wheeze, Since then he had had symptoms almost continuously and had taken a variety of drugs including aerosol bronchodilators, theophylline, and antibiotics. His attacks were precipitated by exposure to house dust, exercise, respiratory infections, and drinking white wine. He hadhad allergic rhinitis all his life, and this had been worse recently. His mother had severe asthma and, when she was later questioned about the patient, confirmed that he had had a very severe episode of bronchitis needing hospital admission at the age of 9 months. Physical examination showed a man of normal stature with a hyperinflated chest and scattered rhonchi in both lungs. The appearance of his nasal mucosa was consistent with allergic rhinitis. Investigations showed mild airway obstruction (FEV, 69% of the predicted value), which improved to 75% after bronchodilator aerosol, increased lung volumes, and strongly positive skin prick tests to common aeroallergens including cats, house dust mites, and pollens. An exercise test revealed severe exercise-induced asthma and a challenge in which he drank white wine resulted in an immediate, but not a late, attack of asthma. He had a number of questions about his asthma. ·From the Department of Medicine, University of Sydney, and the Department of Thoracic Medicine, Royal Prince Alfred Hospital, Sydney, Australia. These studies were supported by the National Health and Medical Research Council of Australia and the Asthma Foundation of N.S.W Reprint requests: Dr: Woolcock, Department ofMedicine, University ofSydney, Sydney, NSW 2027, Australia
5
Queatians 1. How severe is my asthma? 2. What are the risks associated with severe asthma? 3. What caused it to come on only recently? 4. Are allergies the cause of asthma? 5. Did 1 inherit it from my mother? 6. Can asthma be cured? If not, what can be done? These questions are frequently asked by patients with chronic, severe asthma. Most of them cannot be answered precisely. The factors thought to relate to the cause and to the severity of asthma are discussed in relation to each of these questions, and the treatment instituted is described. Questian 1: How severe is my asthma? This question implies that the severity of asthma can be quantitated. It is now recognized that the underlying problem in asthma is manifested as bronchial hyperresposiveness and that the degree of BHR can be measured using inhalation tests with histamine and methacholine. There is good agreement between BHR as measured by inhalation tests and clinical severity of asthma assessed by the treatment required to control symptoms;':" although the range of responses for the amount of treatment required is wide. Furthermore, it is now becoming clear that the resting level of the FEV, and the symptoms reported by the patient are much less accurate methods for assessing severity. Figure 1 shows typical dose response curves to inhaled histamine using the FEV, to measure the airway response in asthmatic patients of different clinical severity. The degree of BHR is measured as the dose of histamine (in jLmol) which causes a 20% fall in the FEV, (PDIIlFEV,). The ranges shown were obtained from subjects with asthma defined in clinical terms as severe (needing steroid therapy), moderately severe (needing daily bronchodilator therapy, but not steroids), mild (needing therapy intermittently in the past 12 months), and intermediate or past (wheezed in the past but not in the past 12months). The dose-response curve for the patient, obtained at the time of the first consultation, is shown as the dotted line, indicating very severe BHR. How applicable is this diagram? Could the dose-response curve from the patient be a chance finding? Does the degree of BHR vary greatly from week to week? Do populations of asthmatic children and adults conform to these ranges?
60 50
z
.;-
~
40 30
, I
I
•
20
,,• ,,
!
~
10 0
.
0.001
0.01
" .
0.1 1.0 10 DOSE(pnoO FIGURE 1. Typical dose-response curves in which the dose of histamine delivered in jLmolis plotted against the percent change in FEV,. The ranges for asthmatics who have severe, moderate, mild, and intermediate severity of disease are shown. The PDIIlFEV,is the dose of histamine in jLmolwhich causes a 20% fall in FEV,. Dotted line, response.
CHEST I 87 I 5 I MAY, 1985 I Supplement
209S
60
90
50 30 nW1s
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40
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30
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.
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FIGURE 2. The dose-response curves to inhaled histamine of a 38year-old man with severe asthma. The curve shifted to the right 30 minutes after 400 j1.g of salbutamol aerosol (Rr). Four hours after this treatment, the curve had moved toward the control position; all curves are extremely steep. A number of studies have shown that in individual asthmatic patients, the level of BHR remains stable over periods of weeks or months. l3,' Thus, overall, there seems to be little doubt that in patients who present fur treatment of asthma, there is a good correlation between clinical severity and degree of BHR. However, in the community there are children with moderately severe degrees ofBHR who are asymptomatic. M In a study oflo-year-old children in Australia, we found that nearly one third ofchildren with BHR in the mild range (Fig 1)had no symptoms, 20% of children with BHR in the moderate range had no symptoms, but all children with severe BHR had symptoms." On the basis of all the reported studies, there can be little doubt that the response to histamine of this patient indicates that he had severe asthma at the time of presentation. Question 2: This patient has seoere BHR. What is the significance ofthis finding? Based on experience of a large number of patients with severe degrees ofBHR living in Australia, several statements can be made about the risks of severe asthma. First, there is a real risk of death; second, the resting lung function is likely to be abnormal; and third, it will take time, commitment by the patient and physician, and
60 50 40
l >" ~
! I
30 20
~
10 0 ,
0.001
0.01
0.1
, . 1.0 10
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FIGURE 3. Dose-response curves tu mhaled histamine in a 55-yearold man on 4 occasions between May 1983 and May 1984 showing progressive improvement. The figures in brackets indicate the FEV, at the beginning of each inhalation test.
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I
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FIGURE 4. The FEVlFVC ratio of the patient measured at yearly intervals between the ages of 12 and 24 years. Lower figure shows height in em, the FVC values are given in brackets. The predicted FEV/FVC ratio shown is fur the age of 12years. The point at which regular treatment started is indicated (Rr). regular medication including corticosteroids to improve the degree of BHR and thus lessen the severity of the asthma. Figure 2 shows dose-response curves to inhaled histamine in a patient admitted to the hospital after having had several respiratory arrests fullowing acute, severe attacks of asthma. The patient had normal resting lung function, with an FEV! of 4.20 L and a FVC of 5.30 L and he had only mild hyperinflation of lung volumes. The curves after treatment with aerosol salbutamol (400 j1.g) indicate temporary improvement in the level ofhyperresponsiveness. However, the curves are extremely steep and, once the airways began to narrow, the next dose caused a large fall in the FEV l . This man was discharged with normal lung function and free of symptoms. He continued to take regular medication, but he had a fatalattack shortly afterward. Figure 3 shows progressive dose-response curves in another patient with somewhat less severe asthma who had had several extremely severe asthma attacks and many hospital admissions. He was treated vigorously with aerosols of salbutamoI, cromoglycate, beclomethasone diproprionate, and ipratropium bromide (an atropine-like agent) regularly at 5 hourly intervals, and the degree of BHR decreased progressively over a period of months. These 2 patients illustrate that any patient with severe BHR, and particularly those with very steep curves, are at risk of severe, lifethreatening attacks. Question 3: What are the factot" which precipitated his severe asthma during his late teenaged yeat"? Figure 4 showshis lung function, measured annually, from the age ofll years, when he was part of a long-term study oflung function in Sydney schoolchildren." He was asymptomatic until the age of 18 years. However, even before he had symptoms, his FEVlFVC ratio was below the predicted value, and it is likely that he had some degree of BHR at that time. It is becoming clear that there are a number of children in the community with undiagnosed asthma"? and it is likely, in view of the history of wheezing in early childhood that he had had unrecognized asthma for many years. The role of bronchitis at the age of 9 months is also of interest in this patient. We have shown in Sydney schoolchildren with asthma, that severe bronchitis before the age of 2 years is an important risk factor fur the later development of asthma. • At the age of 18 years he moved away from home to an apartment close to the university and entered an entirely different life-style and environment. There is no way of determining the influence of this changed environment, but it maywell have precipitated more severe asthma. 27th Annual AspenLung Conterence
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Question 4: 18 there a relationship between seoere atopy and severe asthma? There have been a number of studies which have shown a relationship between allergy and BHR. In the study of Australian children referred to above. we found that 37% ofchildren were atopic (had lor more positive skin reaction to extracts of common allergens) and that 26% of atopic children had asthma (10). Only 12% of the asthmatic children were not allergic. Ninety percent of highly allergic children (more than8 of 13 allergens tested causing positive skin reactions) had asthma. Van Asperen et aI found that 81% of asthmatic children in Sydney were allergic. U Bryant and Burns" also found a relationship between atopic status and asthma in adults. However, the nature of the relationship is not dear. The answer to the question is that there appears to be a strong relationship, but its exact nature is not dear. There is no direct evidence that atopy or allergic reactions are the cause of BHR although they can dearly make existing BHR worse. Question 5: 18 asthma inherited? There seems to be little doubt that there is a genetic factor involved in the development of asthma. First. the disease appears to
be more common in boys than in girls in almost all populations of children.' Secondly, the high prevalence in some isolated communities, such as Tristan De Cunha, 13 appears to have evolved because a majority of the ancestors had the disease. Third, there is a positive family history of asthma in many studies. In our studies of 8- to 10year-old children in Australia, a history of parental asthma was given by 54.1% of the children with asthma, but by only 16.3% of the children without asthma (p
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'!l FIGURE 6. The PD.,FEV, values in a group of 15 subjects (LHS) who took tailor-made therapy regularly to protect their airways and maintain optimal lung function and in a group of 7 subjects (RHS) who took medication only lOrsymptoms. The figures indicate the number of months between measurements. CHEST I 87 I 5 I MAY, 1985 I Supplement
2118
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FIGURE 7. Serial changes in PD.. FEV I (continuous lines) of2 subjects over 12 months with the treatment used. A short-lived exacerbation occurred in the first subject. Dotted line indicates the mean value for the daily air flow meter readings for the month prior to each PD.. FEV, measurement. BHR. Twenty subjects undertook to take aerosol medication on a regular basis, 4 to 5 times a day, for a period ofl to 2 years. The drugs needed to protect the airways were determined for each individual, and each recorded his lung function twice daily. The other 10 subjects took only the medications prescribed at clinic. The method used to design a "tailor-made" drug regimen for each subject was similar to that used in the patient. The patient described above had formal exercise tests done before and immediately after a number of different aerosol drugs to find the combination which completely inhibited his exercise induced asthma. This proved to be 40 mg of cromoglycate and 200 ....g of salbutamol. He was told to keep his environment free ofcats and to treat his bedding regularly to keep
the house dust mites to a minimum. He was given a challenge with white wine, which caused a fall in the FEV" and he was told to avoid this during the period of treatment. He was started on regular treatment with salbutamol, cromoglycate, and beclomethasone diproprionate aerosols, to be taken 5 times a day with extra doses of salbutamol and cromoglycate before exercise. He was instructed to record his own lung function at home using an airflow meter, .. and once his values reached the predicted level to try to maintain them. He was given a supply of oral prednisone and an antibiotic so that he could treat exacerbations promptly. In addition, his allergic rhinitis was treated regularly with beclomethasone diproprionate aerosol to the nose.
ENVIRONMENT AL ALLERGENS (HOM & POLLENS)
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7 Yrs
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SEVERE BHR 1%
NON ALLERGIC ASTHMA 2%
(RESOLVES~)
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20Yrs
FIGURE 8. A diagram suggesting the factors which may combine to cause asthma. It is postulated that there are 2 closely associated susceptibility genes, 1 for atopy and 1 for BHR. In Australia, about 40% of the population becomes atopic (as judged by skin tests) by the age of 18 years. Most of them remain asymptomatic, while approximately 12%develop allergic rhinitis. About 8% have established asthma by late teenaged years, but only I'll can be classified as having severe asthma. Up to 24% of children between 1and 10 years old have a history of wheezing and may have mild degrees of BHR, but only some continue to have asthma by the age ofl8 years. In the majority, the BHR appears to resolve (although it is possible that some of these people develop asthma in later life). With appropriate treatment, the level ofBHR in asthmatics can be maintained in the mild range.
212S
27th Annual Aspen Lung Confel8nce
The change in his PDlIllFEVt values for histamine on this treatment is shown in Figure 5. There was a progressive improvement in both PDlIllFEV l and in the baseline level ofFEVt • The results ror 22 of the subjects (15 treated and 7 controls) are shown in Figure 6. Many of the subjects have only just started on the project but all have improved. In those who have been treated ror more than 12 months, the PDlIllFEVt values have risen above 1.0 Il-mol, and some have improved to about 4.0 Il-mol. These subjects, although they are not cured, are in a symptom-free state. In general, most subjects reached a "best" value for PDJEV1 after 5 to 12 months and did not improve further. Once this "best" value was reached, it was possible to reduce the amount of medication required to keep the lung function at the optimal value. No change occurred over a similar period in the subjects not given regular medications. Figure 7 shows the serial changes in BHR from 2 of the subjects. Exacerbations occurred in some subjects, in spite of the optimal treatment, but they were short-lived (as shown by subject I), and the PDlIllFEV l values returned to previous levels in days rather than in months. The treatment required varied in different subjects from 1to 4 aerosol drugs. All took a ~2-adrenergic aerosol, usually salbutamol. Most of the severe asthmatics required steroid aerosols and many also had cromoglycate or ipratropium bromide. The answer to the question "Can asthma be cured?" is "No." However, asthma can be treated in such a way that the degree ofBHR can be greatly reduced. The long-term benefits of this improvement in the BHR are related to the reduction of the risks associated with severe BHR which include risk of death, altered life-style, risk of permanent airflow limitation and, in children, chest deformity and abnormal growth. OvERALL CONCEPT
In answer to the patients questions, he did have severe asthma when he presented, but after treatment his asthma could be classified as mild. His asthma did not come out of the blue, but was probably present throughout his childhood in a mild form. The factors which combined to produce the asthma were a genetic predisposition combined with an early episode of respiratory infection. After that, constant mediator release resulting from contact with allergens, from exercise and other provoking situations caused mild but unrecognized asthma. Entry to university, with changed lifestyle (and perhaps also exposure to different allergens), led to more severe BHR and precipitated symptoms. Protection of the airways with aerosol medications resulted in a decrease in the level of BHR and improvement in his asthma. Figure 8 shows a model of how this patient might have developed severe asthma based on what has been reviewed. It is suggested that not only is there a susceptibility gene for atopy, but possibly also one for BHR. It is stressed, however, that at present there is no good evidence that atopy and asthma are inherited separately. However, there is good evidence that not all atopic people develop BHR, and many people with BHR are nonatopic. The percentage figures in Figure 8 are the approximate percentages of young adults in the Australian population that we have found to be atopic, to have allergic rhinitis, to have mild and severe allergic asthma, to have nonallergic asthma, and to be normal, but with a previous history of wheezing (some of these people are atopic). Perhaps many children have a mild degree of BHR which remits spontaneously, unless the airways are exposed to mediators, and it is the severely allergic children whose
airways are continuously exposed to mediators. In spite of this problem it seems likely that with appropriate treatment the degree ofBHR in most young people can be maintained in the mild range. REFERENCES
1 Yan KY, Salome CM, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760-5 2 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and a clinical survey. Clin Allergy 1977; 7:235-43 3 Juniper EF, Firth PA, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978; 38:705-10 4 Shoeffel RE, Anderson SD, Gillam I, Lindsay DA. Multiple exercise and histamine challenge in asthmatic patients. Thorax 1980; 35:164-70 5 Speight ANp, Lee DA, Hey EN. Underdtagnosis and undertreatment of asthma in childhood. Br Med J 1983; 286:1253-6 6 Sears MR, Holdaway MD, Hewitt CJ. Sivla PA. Bronchial hyperreactivity in children without asthma. Aust NZ J Med 1984 (in press) 7 Britton WJ, Woolcock AJ, Sedgwick CJ, Peat JK. Prevalence of bronchial hyperresponsiveness in children: 1. Methodology for field studies. Submitted for publication 8 Leeder SR, Woolcock AJ, Blackburn CRB. Prevalence and natural history of lung disease in New South Wales schoolchildren. Inst J Epidemiol1974; 3:15-23 9 Woolcock AJ, Peat JK, Leeder SR, Blackburn CRB. The development of lung function in Sydney children: effects of respiratory illness and smoking: a ten year study. Eur J Respir Dis 1984 (in press) 10 Britton WJ, Woolcock AJ, Sedgwick CJ, Peat JK, Leeder SR. Prevalence of bronchial hyperresponsiveness in children: 2. Relationship to skin reactivity to allergens in two communities. Submitted ror publication 11 VanAsperen PP, MellisCM, South RT, Simpson SJ. Allergen skin prick testing in asthmatic children. Med J Aust 1980; 2:266-8 12 Bryant DH, Burns ML. The relationship between bronchial histamine reactivity and atopic status. Clin Allergy 1976; 6:373-81 13 Mantle J, Peppy SJ. Asthma amongst Tristan da Cunha Islands. Clin Allergy 1974; 4:161-70 14 Bias WB, Marsh DG. The genetic basis of asthma: Current studies of the genetics of the IgE-mediator imipramine response in man. In: Lichtenstein LM, Austin KF, eds, Asthma. New York: Academic Press, 1977; B:21-34 15 Cockcroft DW, Ruffin R, Dolovich J, Hargreave FE. Allergeninduced increase in non allergic bronchial reactivity. Clin Allergy 1977; 7:503-13 16 Geubelle F, 8orlee-Hermanns G, Leclerq-Focart J. Hyperreactivity of the bronchial tree to histamine in asthmatic children and its variations. Bull Physiopathol Respir 1971; 7:839-40 17 Salome CM, Schoeffel RE, Woolcock AJ. Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects. Thorax 1981; 36:580-4 18 Jenkins CR, Breslin ABX. A long term study of the effect of sodium cromoglycate on airway responsiveness in asthma. 1984; 14 (suppI2):538 19 Juniper EF, Frith PA, Hargreave FE. Long term stability of bronchial responsiveness to histamine. Thorax 1982; 37:288-91 20 Friedman M, Walker S. Assessment of lung function using an airflowmeter. Lancet 1973; 1:310
CHEST I 87 I 5 I MAY, 1985 I Supplement
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