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A Prospective Study of the Natural History of Asthma
A Prospective Study of the Natural History of Asthma* Remission and Relapse Rates Scott Bronnimann, M.D.,
F:C.C.~;t
and Benjamin Burrows, M.D.,
In this longitudinal study of a general population sample, remissions of asthma were common only during the second decade of life and were especially unusual in subjects ages 30 to 60 yean on enrollment. Asthmatic subjects with severe symptoms, with reduced ventilatory function, or with a concomitant diagnosis of chronic bronchitis or emphysema on entry to the study were very unlikely to be in remission
studies have added a great deal to our EPidemiologic understanding of the natural history of asthma.
1-5
In particular; prospective studies on populations of communities have avoided potential biases of clinical series by examining asthma in its full spectrum of severity;6-13 however, our knowledge of the natural history of asthma is incomplete, particularly in terms of the factors which influence the persistence, cessation, or recurrence of the disease. A recent review of the epidemiology of asthma by Gregg! addresses the difficulty in finding a precise definition of asthma. The role that bronchial hyperreactivity, as measured by bronchoprovocation testing, ultimately will have as a criterion of asthma is not established. In terms of data from respiratory questionnaires, Dodge and Burrows" reported from a cross-sectional survey that more than 30 percent of the subjects admitted to some form ofwheezing, but only 6 to 7 percent felt that they had asthma. Our criterion for asthma follows the convention of other epidemiologic studies by relying on the subjects' perception of whether or not they have the disease. The presence of recent symptoms and the use of antiasthmatic therapy are considered indicators of the activity of the disease. Using these criteria, we have determined rates of remission and relapse of asthma in a sample from a community over a nine-year period and have examined the characteristics of subjects at the start of the study which relate to the subsequent occurrence of remissions or relapses of the disease. *From the Division of Respiratory Sciences (Westend Research Laboratories), University of Arizona College o(Medicine, Tucson. Supported by Specialized Center of Research grant HL-I4136 from the National Heart, Lung, and Blood Institute. t American Thoracic Socie9'1American Lung Association Research 1bining Fellowship awardee at the time of the study. Manuscript received March 22, 1985; revision accepted April 22,
1986
Rsprint re~: Dr. Burrows, Dioiaion of Respiratory Sciences, Arizona Health Sciences Cente~ 7bc8on 85724
480
F:C.C.~
nine years later. Relapses of disease were common in subjects with a past history of asthma who were considered to be quiescient on enrollment to the study. Relapse rates tended to increase with age, at least up to the age of 70. Relapses were especially frequent among those "ex-asthmatics" who had persisting respiratory symptomatology on entry to the study.
MATERIALS AND METHODS
The population under study is a random stratified cluster sample of non-Mexican white American households in Tucson, Ariz. Details of the selection of the population and general methods have been published." Initial self-completion questionnaires were obtained from 3,454 subjects. The present study examined only those who completed questionnaires in the first (1972to 1973)and seventh (1981 to 1983) surveys. Because the surveys take slightly longer than one year, the mean follow-up was 9.4 years, with a minimum ofB.5 years. Two thousand three hundred subjects (74.9 percent of known survivors) completed the seventh survey questionnaire. A total of 382 subjects died prior to the seventh survey. For subjects aged six years or older, maximum expiratory flowvolume curves were obtained in both surveys on a specially designed pneumotachygraphic apparatus," which was calibrated against a Stead-Wells spirometer. Predicted values and normal limits for spirometric variables were calculated from asymptomatic nonsmokers in the population." In addition to maximum expiratory flow-volume curves, a battery of aeroallergen prick tests using local aeroallergens was administered to subjects aged three years and above to assess their atopic status. In all, 91.6 percent of the eligible subjects received cutaneous tests, and an index of overall reactivity on allergy skin tests was calculated as previously described. 18 Samples of serum were also drawn from subjects over five years of age. The percentage of blood eosinophils on a blood smear was determined in 69.8 percent of the eligible population, and the serum IgE level was measured in 82.7 percent. The presence of asthma in a subject entering the study was defined as a "yes" response to the simple question, "Have you ever had asthma?" The asthma was considered active if at least one of the following criteria were met: (1)a "yes" response to the question, "Are you presently taking medication or treatment for your asthma?", (2)a response of at least Ie one attack" to the question, "During the past year, how many attacks of asthma have you had?"; or (3)on a scale ofl (rarely) to 5 (very often), a frequency of at least 3 (frequent) to the question, "How often are you bothered by attacks of shortness of breath with wheezing?" It seemed reasonable to accept relatively frequent attacks of shortness of breath with wheezing as indicative of active disease in someone with a known history of asthma. The presence of other wheezing complaints were not used as a criterion for defining the activity of the disease. Asthma was considered to be inactive (ex-asthma) if the subject denied medications, asthmatic attacks, and "frequent" attacks of shortness of breath with wheezing during the preceding year. NaturalHistoryof Asthma (Bronn/mann, Burrows)
Rates of remission and relapse were determined by comparison of responses to the questionnaires in the first and seventh surveys. Subjects were considered to have had a remission if they fulfilled the criteria for active asthma in the first survey and the criteria for exasthma in the seventh survey. Similarly, subjects were categorized as a relapse if they met the criteria for ex-asthma in the first survey and for active asthma in the seventh survey. The 2,300 subjects who completed the seventh survey were different from the 1,154 subjects who did not only in terms of rates of active asthma. Their rate of active asthma on enrollment (5.9 percent) was significantly lower (p<0.01) thanthat of subjects failing to complete the seventh survey (9.2 percent). Most but not all of this difference is accounted for by a Significantly higher mortality in subjects with active asthma. The mortality over nine years in those with active asthma in the first survey was 17 percent (421242), compared to a mortality over nine years of 11 percent (331/3, (66) in the nonasthmatic subjects (p<0.01). The sample followed was representative of the initial total population in all other respects. Most of the excess deaths in asthmatic subjects occurred in older age groups, and, except in one instance, the cause of death was not ascribed to asthma itself on the death certificate. The questionnaire also asked about diagnoses ofchronic bronchitis and of emphysema and about symptoms of cough, phlegm, and wheeze. The term, "chronic productive cough," is used to refer to a "yes" response to two questions: the first asked if one usually coughed; and the second asked if one usually brought up phlegm, sputum, or mucus on most days for at least three months of the year. Statistical analyses employed standard programs in the SPSS library, using the University of Arizona (DEC 10-Cyber) computer system. RESULTS
Remission of Asthma
Of the 2,300 subjects in the study, 136 had active asthma in the first survey. In the seventh survey, 30 of these 136 subjects were in remission, a 22 percent remission rate. Figure 1 shows the rate of remission of active asthma by the age of the subjects at entry into the study. The 80
Remission Of Current Asthma
-
60
c: 0
-Ui en
-e Q)
a:
40
0~
20
-
-
-
-
n
~
-
Age at Entry <10 10-19 20-29 30-39 40·49 SO·59 60-69 70·79 (N) at Risk (17) (20) (21) (14) (17) (18) (21) (8)
FIGURE 1. Rate of remission of asthma by decade of age in 136 asthmatic subjects followed for mean of 9.4 years. Numbers in parentheses indicate number of subjects in each decade of age.
TableI-Factors ABsociated with &mission Probability of Remission*
Initial Symptoms Wheeze on most days Yes No Frequent asthmatic attacks (>12lyr) Yes No Very frequent attacks of breath with wheeze (grades 4-5) Yes No Chronic productive cough Yes No Percent of predicted FEV1 Normal Abnormal Coexisting diagnosis of chronic bronchitis or emphysema Yes No
p Value
4/34 (12) 34/98 (35)
p <0.05
2/28 (7) 36/106 (34)
P <0.02
1/36 (3) 37/98 (38)
p
6/43 (14) 32/91 (35)
p<0.02
25/59 (42) 6/39 (15)
p
2/31 (7) 22/76 (29)
p
*Numbers within parentheses are percents.
total number at risk for a remission in each decade of age is indicated at the bottom of Figure 1. The remission rate was highest in the group aged 10 to 19 years, with 65 percent (13/20) having a remission, and was lowest in the subjects aged 40 to 49 years, with 6 percent (lJl7) having a remission. The overall variation of the remission rate with the decade of age was highly significant (p<.001) by Xi analysis. The graph shows a high remission rate in adolescence, a relatively low rate of remission in middle age, and then an increase in the rate after the age of 60 years. When the data collected in the initial survey were analyzed, the factors shown in Table1were found to be significantly related to a remission at follow-up, The presence of wheeze on most days was associated with a 12 percent (4/34) remission rate, compared to 35 percent (34/98) ifwheeze was less frequent. Asthmatic subjects who initially had asthmatic attacks with a frequency of more than 12 attacks per year had a 7 percent remission rate (2/28) vs a 34 percent rate (36/106) in those with less frequent asthmatic attacks. Similarly, only 3 percent (1/36) of subjects with very frequent (grades 4 to 5) attacks of shortness of breath with wheezing had a remission, compared with 38 percent (37/98) if such attacks were absent or less frequent. Of all variables analyzed, very frequent attacks of shortness of breath with wheeze was the one most adversely affecting the remission rate. The presence of chronic productive cough made remission significantly less likely (14 percent [6/43] vs 35 percent [32191]; p<0.02), as did a coexisting diagnosis of chronic bronchitis or emphysema (6 percent [2/31] vs 29 percent [22176]; p<0.05)_ CHEST I 90 I 4 I OClOBER. 1986
481
Table I-MetJn S1cin Tat lnda in Continuing and BetnitIitag AatlatntJ*
Age, yr
<15 15-34
35-54 55-74
Subjects with Active Asthma on Both Surveys (N)
4.22±3.53 (9) 8.95±6.42 (22) 9.17±5.35 (24) 2.64±4.06 (25)
Subjects with Asthma in Remission in Last Survey (N)
2.88±3.14 8.23±5.29 3.33±3.06 6.55±5.92
(8) (13) (3) (9)t
·18ble values are mean skin test index (± SD); numbers within parentheses are numbers of subjects. tp
A normal initial value for the percent predicted forced expiratory volume in one second (FEVJ was associated with a remission rate of 42 percent (25/59), which was significantly higher than the 15 percent (6139) remission rate in those with an abnormal percent predicted FEV!. Other than an age at entry between 10 and 20 years, a normal percent predicted FEV! proved to be the factor most favorably affecting the remission rate. The percent predicted FEV! from the first survey of subjects whose asthma remained active in both surveys averaged 78.7 ± 22.0 percent. The percent predicted FEV! in subjects who had a remission averaged 88.8 ± 12.7 percent (p<0.02). In the seventh survey, spirometric data were also collected from most subjects, and those whose asthma remained active had an average percent predicted FEVl of 75.7 ± 25.7 percent. This compares to an average percent predicted FEV! of 95. 7 ± 16.0 percent in those who had a remission (p<0.005). The relationship of reactivity on allergy skin tests to remission of asthma in different age groups is shown in 'Iable 2. Reactivity tended to be less in subjects less than the age of 55 years who had remission, but skin test reactivity was significantly higher in subjects over the age of 55 years who had a remission.
Relapses of Asthma Ninety-nine subjects were identified as having exasthma in the first survey. By the seventh survey, 38 of these 99 had a relapse, a 38 percent relapse rate. Figure 2 shows the rate with which these exasthmatic subjects had a relapse by their age at entry into the study. The total number at risk for a relapse in each decade of age is indicated at the bottom of Figure 2. Relapses were not rare at any age and became more frequent with increasing age, reaching 67 percent (8112) in subjects aged 60 to 69 years. Table 3 indicates which factors related to a relapse of asthma. In the ex-asthmatic subjects aged less than 55 years who answered "yes" to having wheeze of any extent in the first survey, 53 percent (23143) met the criteria for active disease by the seventh survey. Ifthey totally denied wheeze, only 7 percent (2129) of exasthmatic subjects had a relapse (p
Relapse Of Ex-Asthma
80
-
60 Q)
UJ
....-
c-
as
......
Cii40
a: cfl
....-
.....-
..-
..-
20
Age at Entry <10 10·19 20-29 30·39 40-49 50-59 60-69 70·79 (N) at Risk (4) (11) (31) (13) (8) (13) (12) (4) FIGURE 2. Rate of relapse of asthma by decade of age in 99 fonnerly asthmatic subjects followed for mean of 9.4 years. Numbers in parentheses indicate number of subjects in each decade of age.
aged 15 to 54 years, 86 percent (6m with chronic productive cough had a relapse, compared to 28 percent (15/54) of those without chronic productive cough (p
Relapse Rates·
p Value
23/43 (54) 2/29 (7)
p
617 (86) 15154 (28)
p
11132 (34) 6/58 (10)
p
·Numbers within parentheses are percents. NaturalHistoryof Asthma (Bronn/mann, Burrows)
Table 4-Effect ofSmoldrag on Bemiaion and Bslapae of AathmtJ* Age>15 yr
Probability of Remission
Probability
Continuing smoker Ex-smoker Never smoked
3124 (13) 8/39 (28) 14147 (30)
15131 (48) 9/24 (38) 8/24 (33)
of Relapse
*Numbers within parentheses are percents.
Several factors were unrelated to either relapse or remission of asthma. They were serum IgE level, symptoms of rhinitis, and gender Blood eosinophil counts did not relate significantly to relapse but tended to be lower in those over the age of 15 years who had a remission. Although trends did not reach significance, smoking appeared to have an adverse effect on asthma. Current smokers had the lowest remission rate and the highest relapse rate, while those who never smoked had the highest remission rate and lowest relapse rate (Table 4). DISCUSSION
In this study, a high remission rate (65 percent; 13/20) was noted only in the group aged 10 to 19 years. Previous studies have also shown this decade to be characterized by frequent remissions. Williams and McNicol and associates'?' prospectively studied 331 children from 7 to 21 years old who had asthma or wheezy bronchitis when enrolled. Remissions of at least one-year duration were noted in 70 to 75 percent of these children at the age of 14 years, and 55 percent of those who had a remission remained free of wheezing to the age of21 years. In a clinic-based group of 449 children with asthma, Rackemann and Edwards" found a remission rate of 52 percent after 20 years of followup. In a four-year study of a community, Broder et al' recorded an average remission rate of only 18 percent in the 56 asthmatic subjects less than 16 years of age. This report provides one of the first descriptions of rates of relapse and remission in adults. As compared to children and adolescents, adults with asthma have lower remission rates, and they reacquire active symptoms (relapse) more frequently. In this study, adults between the ages of 30 and 60 years with active asthmatic symptoms average only about a 10 percent chance of losing those symptoms over a nine-year period. After the age of 60 years, the remission rate appears to increase somewhat. Comparable data from the four-year study by Broder et al" showed average remission rates of 16.7 percent between the ages of 16 and 44 years and 21.0 percent in subjects aged 45 years and oven Due to the variability of the symptoms associated with asthma, diagnosis of a meaningful remission requires a long period without active symptoms or the
need for medication. The choice of a one-year period for determining activity of the disease in the present study was completely arbitrary. The very high relapse rates observed suggest that a longer period may be required to identify subjects whose disease has truly gone into remission, rather than being in a temporarily quiescent phase. Relapses of asthma were not rare in any age group. After the age of 20 years, relapses became more frequent with increasing age. As described in methods, the relapses were not dependent on just the symptom of wheeze, which may result from a variety of nonasthmatic conditions. These relapses are presumed to be part of the long-term natural history of asthma present earlier in life. Persistent asthma has been incriminated as a cause of irreversible obstruction of the airways. In a six-year respiratory study of a community, Schachter et ale found that adults with asthma had a significantly greater average decline in the forced expiratory flow at 50 percent of total lung capacity (Vmax50%) than nonasthmatic subjects, with a trend also seen for excessive decline of FEV}. Martin et al1l found significantly lower mean values of FEV} in 21-year-olds with relatively persistent asthmatic symptoms as compared to controls. Our data show significantly lower mean values for percent predicted FEV1 in both surveys in persons whose asthma persisted throughout the study vs those who had a remission. The lower average value for percent predicted FEV} in subjects with more severe asthma does not necessarily imply irreversible airflow obstruction. More complete evaluation of pulmonary function and response to a maximum medical regimen would be needed to determine to what extent the disease of the airways is potentially reversible. In addition, our inability to relate changes in symptoms to specific therapy, to characterize more completely the factors provoking the disease in individual subjects, or to date more precisely the ages of onset and remission of illness also represent important limitations in the type of study being reported. Most respiratory symptoms were correlated with persistence of asthma. It is not surprising that the more severe or frequent the symptoms of asthma, the less likely there is to be a remission; however, the striking finding is the strength of this correlation, particularly for the symptom of attacks of shortness of breath with wheezing. H such attacks were initially very frequent (grade 4 or 5), there was almost no chance of a remission by nine years of follow-up. Other studies have also noted that greater respiratory symptoms predict a less favorable long-term outlook. 4.6 Atopy, symptoms of rhinitis, and blood eosinophil counts were not closely correlated with remissions or relapses in our population. Schachter et al6 also noted few associations between severity of asthma and hisCHEST I 90 I 4 I OClOBER, 1988
483
tory of allergy. In summary, after the second decade, asthmatic subjects show a relatively low rate of remission. The presence of severe respiratory symptoms greatly reduces the likelihood that asthma will remit. Exasthmatic adults have an appreciable risk of future active asthma, especially if they have any persisting respiratory symptoms. Abnormal values for the percent predicted FEV l were significantlymore common in subjects with unremitting asthma, as compared to subjects with remissions. Except in subjects over the age of 55 years, atopy was not useful in predicting remissions or relapses. REFERENCES 1 Gregg I. Epidemiological aspects. In: Clark TjH, Godfrey S, eds. Asthma. Philadelphia: WB Saunders Co, 1983 . 2 Reed CEo Epidemiology and natural history. In: Stein M, ed. New directions in asthma. Park Ridge, Ill: American College of Chest Physicians, 1975 3 Johnstone DE. Some aspects of the natural history of asthma. Ann Allergy 1982; 49:257-64 4 Broder I, Higgins M~ MathewsK~ Keller JB. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan: 4. natural history. J Allergy Clin Immunol 1974; 54:100-10 5 Rackemann FM, Edwards MC. Asthma in children. N Eng} J Med 1952; 246:815-23 6 Schachter EN, Doyle CA, Beck GJ. A prospective study of asthma in a rural community. Chest 1984; 85:623-30
7 Williams HB, McNicol KN. Prevalence, natural history, and relationship of wheezy bronchitis and asthma in children. Br Med J 1969; 4:321-25 8 McNicol KN, Williams HB. Spectrum of asthma in children: 1. clinical and physiological components. Br Med J 1973; 4:7-11 9 McNicol KN, Williams HB. Spectrum of asthma in children: 2. allergic components. Br Med J 1973; 4:12-6 10 McNicol KN, Williams HB, Allan J, McAndrew I. Spectrum of asthma in children: 3. psychological and social components. Br Med J 1973; 4:16-20 11 Martin AJ, McLennan LA, Landau LI, Phelan PD. The natural history of childhood asthma to adult life. Br Med J 1980; 2:1397-400 12 Martin AJ, Landau LI, Phelan PD. Lung function in young adults who had asthma in childhood. Am Rev Respir Dis 1980; 122:609-16 13 Martin AJ, Landau LI, Phelan PD. Asthma from childhood at age 21: the patient and his disease. Br Med J 1982; 1:380-82 14 Dodge RR, Burrows B. The prevalence and incidence of asthma and asthma-like symptoms in a general population sample. Am Rev Respir Dis 1980; 122:567-75 15 Lebowitz MD, Knudson RJ, Burrows B. Tucson epidemiologic study of obstructive lung diseases: 1. methodology and prevalence of disease. Am J Epidemioll975; 102:137-52 16 Nelson DC, Burrows B, Knudson RJ. A device for recording flow and volume data in population surveys. J Appl Physiol 1973; 35:304-06 17 Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximal expiratory flow volume curve. Am Rev Respir Dis 1976; 113:587-600 18 Barbee RA, Lebowitz MD, Thompson HC, Burrows B. Immediate skin test reactivity in a general population sample. Ann Intern Med 1976; 84:129-33
Natural History of Asthma (Bronn/mann, Bunows)
F:C.C.~;t
and Benjamin Burrows, M.D.,
In this longitudinal study of a general population sample, remissions of asthma were common only during the second decade of life and were especially unusual in subjects ages 30 to 60 yean on enrollment. Asthmatic subjects with severe symptoms, with reduced ventilatory function, or with a concomitant diagnosis of chronic bronchitis or emphysema on entry to the study were very unlikely to be in remission
studies have added a great deal to our EPidemiologic understanding of the natural history of asthma.
1-5
In particular; prospective studies on populations of communities have avoided potential biases of clinical series by examining asthma in its full spectrum of severity;6-13 however, our knowledge of the natural history of asthma is incomplete, particularly in terms of the factors which influence the persistence, cessation, or recurrence of the disease. A recent review of the epidemiology of asthma by Gregg! addresses the difficulty in finding a precise definition of asthma. The role that bronchial hyperreactivity, as measured by bronchoprovocation testing, ultimately will have as a criterion of asthma is not established. In terms of data from respiratory questionnaires, Dodge and Burrows" reported from a cross-sectional survey that more than 30 percent of the subjects admitted to some form ofwheezing, but only 6 to 7 percent felt that they had asthma. Our criterion for asthma follows the convention of other epidemiologic studies by relying on the subjects' perception of whether or not they have the disease. The presence of recent symptoms and the use of antiasthmatic therapy are considered indicators of the activity of the disease. Using these criteria, we have determined rates of remission and relapse of asthma in a sample from a community over a nine-year period and have examined the characteristics of subjects at the start of the study which relate to the subsequent occurrence of remissions or relapses of the disease. *From the Division of Respiratory Sciences (Westend Research Laboratories), University of Arizona College o(Medicine, Tucson. Supported by Specialized Center of Research grant HL-I4136 from the National Heart, Lung, and Blood Institute. t American Thoracic Socie9'1American Lung Association Research 1bining Fellowship awardee at the time of the study. Manuscript received March 22, 1985; revision accepted April 22,
1986
Rsprint re~: Dr. Burrows, Dioiaion of Respiratory Sciences, Arizona Health Sciences Cente~ 7bc8on 85724
480
F:C.C.~
nine years later. Relapses of disease were common in subjects with a past history of asthma who were considered to be quiescient on enrollment to the study. Relapse rates tended to increase with age, at least up to the age of 70. Relapses were especially frequent among those "ex-asthmatics" who had persisting respiratory symptomatology on entry to the study.
MATERIALS AND METHODS
The population under study is a random stratified cluster sample of non-Mexican white American households in Tucson, Ariz. Details of the selection of the population and general methods have been published." Initial self-completion questionnaires were obtained from 3,454 subjects. The present study examined only those who completed questionnaires in the first (1972to 1973)and seventh (1981 to 1983) surveys. Because the surveys take slightly longer than one year, the mean follow-up was 9.4 years, with a minimum ofB.5 years. Two thousand three hundred subjects (74.9 percent of known survivors) completed the seventh survey questionnaire. A total of 382 subjects died prior to the seventh survey. For subjects aged six years or older, maximum expiratory flowvolume curves were obtained in both surveys on a specially designed pneumotachygraphic apparatus," which was calibrated against a Stead-Wells spirometer. Predicted values and normal limits for spirometric variables were calculated from asymptomatic nonsmokers in the population." In addition to maximum expiratory flow-volume curves, a battery of aeroallergen prick tests using local aeroallergens was administered to subjects aged three years and above to assess their atopic status. In all, 91.6 percent of the eligible subjects received cutaneous tests, and an index of overall reactivity on allergy skin tests was calculated as previously described. 18 Samples of serum were also drawn from subjects over five years of age. The percentage of blood eosinophils on a blood smear was determined in 69.8 percent of the eligible population, and the serum IgE level was measured in 82.7 percent. The presence of asthma in a subject entering the study was defined as a "yes" response to the simple question, "Have you ever had asthma?" The asthma was considered active if at least one of the following criteria were met: (1)a "yes" response to the question, "Are you presently taking medication or treatment for your asthma?", (2)a response of at least Ie one attack" to the question, "During the past year, how many attacks of asthma have you had?"; or (3)on a scale ofl (rarely) to 5 (very often), a frequency of at least 3 (frequent) to the question, "How often are you bothered by attacks of shortness of breath with wheezing?" It seemed reasonable to accept relatively frequent attacks of shortness of breath with wheezing as indicative of active disease in someone with a known history of asthma. The presence of other wheezing complaints were not used as a criterion for defining the activity of the disease. Asthma was considered to be inactive (ex-asthma) if the subject denied medications, asthmatic attacks, and "frequent" attacks of shortness of breath with wheezing during the preceding year. NaturalHistoryof Asthma (Bronn/mann, Burrows)
Rates of remission and relapse were determined by comparison of responses to the questionnaires in the first and seventh surveys. Subjects were considered to have had a remission if they fulfilled the criteria for active asthma in the first survey and the criteria for exasthma in the seventh survey. Similarly, subjects were categorized as a relapse if they met the criteria for ex-asthma in the first survey and for active asthma in the seventh survey. The 2,300 subjects who completed the seventh survey were different from the 1,154 subjects who did not only in terms of rates of active asthma. Their rate of active asthma on enrollment (5.9 percent) was significantly lower (p<0.01) thanthat of subjects failing to complete the seventh survey (9.2 percent). Most but not all of this difference is accounted for by a Significantly higher mortality in subjects with active asthma. The mortality over nine years in those with active asthma in the first survey was 17 percent (421242), compared to a mortality over nine years of 11 percent (331/3, (66) in the nonasthmatic subjects (p<0.01). The sample followed was representative of the initial total population in all other respects. Most of the excess deaths in asthmatic subjects occurred in older age groups, and, except in one instance, the cause of death was not ascribed to asthma itself on the death certificate. The questionnaire also asked about diagnoses ofchronic bronchitis and of emphysema and about symptoms of cough, phlegm, and wheeze. The term, "chronic productive cough," is used to refer to a "yes" response to two questions: the first asked if one usually coughed; and the second asked if one usually brought up phlegm, sputum, or mucus on most days for at least three months of the year. Statistical analyses employed standard programs in the SPSS library, using the University of Arizona (DEC 10-Cyber) computer system. RESULTS
Remission of Asthma
Of the 2,300 subjects in the study, 136 had active asthma in the first survey. In the seventh survey, 30 of these 136 subjects were in remission, a 22 percent remission rate. Figure 1 shows the rate of remission of active asthma by the age of the subjects at entry into the study. The 80
Remission Of Current Asthma
-
60
c: 0
-Ui en
-e Q)
a:
40
0~
20
-
-
-
-
n
~
-
Age at Entry <10 10-19 20-29 30-39 40·49 SO·59 60-69 70·79 (N) at Risk (17) (20) (21) (14) (17) (18) (21) (8)
FIGURE 1. Rate of remission of asthma by decade of age in 136 asthmatic subjects followed for mean of 9.4 years. Numbers in parentheses indicate number of subjects in each decade of age.
TableI-Factors ABsociated with &mission Probability of Remission*
Initial Symptoms Wheeze on most days Yes No Frequent asthmatic attacks (>12lyr) Yes No Very frequent attacks of breath with wheeze (grades 4-5) Yes No Chronic productive cough Yes No Percent of predicted FEV1 Normal Abnormal Coexisting diagnosis of chronic bronchitis or emphysema Yes No
p Value
4/34 (12) 34/98 (35)
p <0.05
2/28 (7) 36/106 (34)
P <0.02
1/36 (3) 37/98 (38)
p
6/43 (14) 32/91 (35)
p<0.02
25/59 (42) 6/39 (15)
p
2/31 (7) 22/76 (29)
p
*Numbers within parentheses are percents.
total number at risk for a remission in each decade of age is indicated at the bottom of Figure 1. The remission rate was highest in the group aged 10 to 19 years, with 65 percent (13/20) having a remission, and was lowest in the subjects aged 40 to 49 years, with 6 percent (lJl7) having a remission. The overall variation of the remission rate with the decade of age was highly significant (p<.001) by Xi analysis. The graph shows a high remission rate in adolescence, a relatively low rate of remission in middle age, and then an increase in the rate after the age of 60 years. When the data collected in the initial survey were analyzed, the factors shown in Table1were found to be significantly related to a remission at follow-up, The presence of wheeze on most days was associated with a 12 percent (4/34) remission rate, compared to 35 percent (34/98) ifwheeze was less frequent. Asthmatic subjects who initially had asthmatic attacks with a frequency of more than 12 attacks per year had a 7 percent remission rate (2/28) vs a 34 percent rate (36/106) in those with less frequent asthmatic attacks. Similarly, only 3 percent (1/36) of subjects with very frequent (grades 4 to 5) attacks of shortness of breath with wheezing had a remission, compared with 38 percent (37/98) if such attacks were absent or less frequent. Of all variables analyzed, very frequent attacks of shortness of breath with wheeze was the one most adversely affecting the remission rate. The presence of chronic productive cough made remission significantly less likely (14 percent [6/43] vs 35 percent [32191]; p<0.02), as did a coexisting diagnosis of chronic bronchitis or emphysema (6 percent [2/31] vs 29 percent [22176]; p<0.05)_ CHEST I 90 I 4 I OClOBER. 1986
481
Table I-MetJn S1cin Tat lnda in Continuing and BetnitIitag AatlatntJ*
Age, yr
<15 15-34
35-54 55-74
Subjects with Active Asthma on Both Surveys (N)
4.22±3.53 (9) 8.95±6.42 (22) 9.17±5.35 (24) 2.64±4.06 (25)
Subjects with Asthma in Remission in Last Survey (N)
2.88±3.14 8.23±5.29 3.33±3.06 6.55±5.92
(8) (13) (3) (9)t
·18ble values are mean skin test index (± SD); numbers within parentheses are numbers of subjects. tp
A normal initial value for the percent predicted forced expiratory volume in one second (FEVJ was associated with a remission rate of 42 percent (25/59), which was significantly higher than the 15 percent (6139) remission rate in those with an abnormal percent predicted FEV!. Other than an age at entry between 10 and 20 years, a normal percent predicted FEV! proved to be the factor most favorably affecting the remission rate. The percent predicted FEV! from the first survey of subjects whose asthma remained active in both surveys averaged 78.7 ± 22.0 percent. The percent predicted FEV! in subjects who had a remission averaged 88.8 ± 12.7 percent (p<0.02). In the seventh survey, spirometric data were also collected from most subjects, and those whose asthma remained active had an average percent predicted FEVl of 75.7 ± 25.7 percent. This compares to an average percent predicted FEV! of 95. 7 ± 16.0 percent in those who had a remission (p<0.005). The relationship of reactivity on allergy skin tests to remission of asthma in different age groups is shown in 'Iable 2. Reactivity tended to be less in subjects less than the age of 55 years who had remission, but skin test reactivity was significantly higher in subjects over the age of 55 years who had a remission.
Relapses of Asthma Ninety-nine subjects were identified as having exasthma in the first survey. By the seventh survey, 38 of these 99 had a relapse, a 38 percent relapse rate. Figure 2 shows the rate with which these exasthmatic subjects had a relapse by their age at entry into the study. The total number at risk for a relapse in each decade of age is indicated at the bottom of Figure 2. Relapses were not rare at any age and became more frequent with increasing age, reaching 67 percent (8112) in subjects aged 60 to 69 years. Table 3 indicates which factors related to a relapse of asthma. In the ex-asthmatic subjects aged less than 55 years who answered "yes" to having wheeze of any extent in the first survey, 53 percent (23143) met the criteria for active disease by the seventh survey. Ifthey totally denied wheeze, only 7 percent (2129) of exasthmatic subjects had a relapse (p
Relapse Of Ex-Asthma
80
-
60 Q)
UJ
....-
c-
as
......
Cii40
a: cfl
....-
.....-
..-
..-
20
Age at Entry <10 10·19 20-29 30·39 40-49 50-59 60-69 70·79 (N) at Risk (4) (11) (31) (13) (8) (13) (12) (4) FIGURE 2. Rate of relapse of asthma by decade of age in 99 fonnerly asthmatic subjects followed for mean of 9.4 years. Numbers in parentheses indicate number of subjects in each decade of age.
aged 15 to 54 years, 86 percent (6m with chronic productive cough had a relapse, compared to 28 percent (15/54) of those without chronic productive cough (p
Relapse Rates·
p Value
23/43 (54) 2/29 (7)
p
617 (86) 15154 (28)
p
11132 (34) 6/58 (10)
p
·Numbers within parentheses are percents. NaturalHistoryof Asthma (Bronn/mann, Burrows)
Table 4-Effect ofSmoldrag on Bemiaion and Bslapae of AathmtJ* Age>15 yr
Probability of Remission
Probability
Continuing smoker Ex-smoker Never smoked
3124 (13) 8/39 (28) 14147 (30)
15131 (48) 9/24 (38) 8/24 (33)
of Relapse
*Numbers within parentheses are percents.
Several factors were unrelated to either relapse or remission of asthma. They were serum IgE level, symptoms of rhinitis, and gender Blood eosinophil counts did not relate significantly to relapse but tended to be lower in those over the age of 15 years who had a remission. Although trends did not reach significance, smoking appeared to have an adverse effect on asthma. Current smokers had the lowest remission rate and the highest relapse rate, while those who never smoked had the highest remission rate and lowest relapse rate (Table 4). DISCUSSION
In this study, a high remission rate (65 percent; 13/20) was noted only in the group aged 10 to 19 years. Previous studies have also shown this decade to be characterized by frequent remissions. Williams and McNicol and associates'?' prospectively studied 331 children from 7 to 21 years old who had asthma or wheezy bronchitis when enrolled. Remissions of at least one-year duration were noted in 70 to 75 percent of these children at the age of 14 years, and 55 percent of those who had a remission remained free of wheezing to the age of21 years. In a clinic-based group of 449 children with asthma, Rackemann and Edwards" found a remission rate of 52 percent after 20 years of followup. In a four-year study of a community, Broder et al' recorded an average remission rate of only 18 percent in the 56 asthmatic subjects less than 16 years of age. This report provides one of the first descriptions of rates of relapse and remission in adults. As compared to children and adolescents, adults with asthma have lower remission rates, and they reacquire active symptoms (relapse) more frequently. In this study, adults between the ages of 30 and 60 years with active asthmatic symptoms average only about a 10 percent chance of losing those symptoms over a nine-year period. After the age of 60 years, the remission rate appears to increase somewhat. Comparable data from the four-year study by Broder et al" showed average remission rates of 16.7 percent between the ages of 16 and 44 years and 21.0 percent in subjects aged 45 years and oven Due to the variability of the symptoms associated with asthma, diagnosis of a meaningful remission requires a long period without active symptoms or the
need for medication. The choice of a one-year period for determining activity of the disease in the present study was completely arbitrary. The very high relapse rates observed suggest that a longer period may be required to identify subjects whose disease has truly gone into remission, rather than being in a temporarily quiescent phase. Relapses of asthma were not rare in any age group. After the age of 20 years, relapses became more frequent with increasing age. As described in methods, the relapses were not dependent on just the symptom of wheeze, which may result from a variety of nonasthmatic conditions. These relapses are presumed to be part of the long-term natural history of asthma present earlier in life. Persistent asthma has been incriminated as a cause of irreversible obstruction of the airways. In a six-year respiratory study of a community, Schachter et ale found that adults with asthma had a significantly greater average decline in the forced expiratory flow at 50 percent of total lung capacity (Vmax50%) than nonasthmatic subjects, with a trend also seen for excessive decline of FEV}. Martin et al1l found significantly lower mean values of FEV} in 21-year-olds with relatively persistent asthmatic symptoms as compared to controls. Our data show significantly lower mean values for percent predicted FEV1 in both surveys in persons whose asthma persisted throughout the study vs those who had a remission. The lower average value for percent predicted FEV} in subjects with more severe asthma does not necessarily imply irreversible airflow obstruction. More complete evaluation of pulmonary function and response to a maximum medical regimen would be needed to determine to what extent the disease of the airways is potentially reversible. In addition, our inability to relate changes in symptoms to specific therapy, to characterize more completely the factors provoking the disease in individual subjects, or to date more precisely the ages of onset and remission of illness also represent important limitations in the type of study being reported. Most respiratory symptoms were correlated with persistence of asthma. It is not surprising that the more severe or frequent the symptoms of asthma, the less likely there is to be a remission; however, the striking finding is the strength of this correlation, particularly for the symptom of attacks of shortness of breath with wheezing. H such attacks were initially very frequent (grade 4 or 5), there was almost no chance of a remission by nine years of follow-up. Other studies have also noted that greater respiratory symptoms predict a less favorable long-term outlook. 4.6 Atopy, symptoms of rhinitis, and blood eosinophil counts were not closely correlated with remissions or relapses in our population. Schachter et al6 also noted few associations between severity of asthma and hisCHEST I 90 I 4 I OClOBER, 1988
483
tory of allergy. In summary, after the second decade, asthmatic subjects show a relatively low rate of remission. The presence of severe respiratory symptoms greatly reduces the likelihood that asthma will remit. Exasthmatic adults have an appreciable risk of future active asthma, especially if they have any persisting respiratory symptoms. Abnormal values for the percent predicted FEV l were significantlymore common in subjects with unremitting asthma, as compared to subjects with remissions. Except in subjects over the age of 55 years, atopy was not useful in predicting remissions or relapses. REFERENCES 1 Gregg I. Epidemiological aspects. In: Clark TjH, Godfrey S, eds. Asthma. Philadelphia: WB Saunders Co, 1983 . 2 Reed CEo Epidemiology and natural history. In: Stein M, ed. New directions in asthma. Park Ridge, Ill: American College of Chest Physicians, 1975 3 Johnstone DE. Some aspects of the natural history of asthma. Ann Allergy 1982; 49:257-64 4 Broder I, Higgins M~ MathewsK~ Keller JB. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan: 4. natural history. J Allergy Clin Immunol 1974; 54:100-10 5 Rackemann FM, Edwards MC. Asthma in children. N Eng} J Med 1952; 246:815-23 6 Schachter EN, Doyle CA, Beck GJ. A prospective study of asthma in a rural community. Chest 1984; 85:623-30
7 Williams HB, McNicol KN. Prevalence, natural history, and relationship of wheezy bronchitis and asthma in children. Br Med J 1969; 4:321-25 8 McNicol KN, Williams HB. Spectrum of asthma in children: 1. clinical and physiological components. Br Med J 1973; 4:7-11 9 McNicol KN, Williams HB. Spectrum of asthma in children: 2. allergic components. Br Med J 1973; 4:12-6 10 McNicol KN, Williams HB, Allan J, McAndrew I. Spectrum of asthma in children: 3. psychological and social components. Br Med J 1973; 4:16-20 11 Martin AJ, McLennan LA, Landau LI, Phelan PD. The natural history of childhood asthma to adult life. Br Med J 1980; 2:1397-400 12 Martin AJ, Landau LI, Phelan PD. Lung function in young adults who had asthma in childhood. Am Rev Respir Dis 1980; 122:609-16 13 Martin AJ, Landau LI, Phelan PD. Asthma from childhood at age 21: the patient and his disease. Br Med J 1982; 1:380-82 14 Dodge RR, Burrows B. The prevalence and incidence of asthma and asthma-like symptoms in a general population sample. Am Rev Respir Dis 1980; 122:567-75 15 Lebowitz MD, Knudson RJ, Burrows B. Tucson epidemiologic study of obstructive lung diseases: 1. methodology and prevalence of disease. Am J Epidemioll975; 102:137-52 16 Nelson DC, Burrows B, Knudson RJ. A device for recording flow and volume data in population surveys. J Appl Physiol 1973; 35:304-06 17 Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximal expiratory flow volume curve. Am Rev Respir Dis 1976; 113:587-600 18 Barbee RA, Lebowitz MD, Thompson HC, Burrows B. Immediate skin test reactivity in a general population sample. Ann Intern Med 1976; 84:129-33
Natural History of Asthma (Bronn/mann, Bunows)