- Email: [email protected]
Asthma in Remission
Asthma in Remission* Can Relapse in Early Adulthood Be Predicted at 18 Years of Age? D. Robin Taylor, MD; Jan O. Cowan; Justina M. Greene; Andrew R. Willan, MSc; and Malcolm R. Sears, MB
Study objective: To determine the frequency of relapse of asthma in young adults in remission at 18 years of age, during a follow-up period of 8 years, and to identify possible prognostic markers for relapse. Design: Longitudinal study of birth cohort (n ⴝ 1,037) born in New Zealand in 1972–1973. Setting: University hospital research clinic. Measurements: Participants were assessed at 9, 11, 13, 15, 18, 21, and 26 years of age using a respiratory questionnaire (all ages), spirometry (all ages), bronchodilator response (18 years and 26 years of age), methacholine challenge (9, 11, 13, 15, and 21 years of age), and allergen skin-prick testing (13 years and 21 years of age). Results: Approximately one third of study members (35%) with asthma in remission at 18 years of age relapsed by 21 years or 26 years of age. Atopy and lower FEV1/FVC ratio at 18 years of age were significant independent prognostic factors for relapse in multiple logistic regression analyses. Increased responsiveness to methacholine (provocative concentration < 8 mg/mL) or bronchodilator (improvement in FEV1 > 10%) at 21 years of age were more common among those with relapse, but the positive and negative predictive values for a previous positive methacholine challenge test result at 15 years of age were low. Asthma after relapse was generally mild (mean FEV1 97.1% predicted). Totally new adult asthma developed by 26 years of age in 9% of study members who had no asthma or wheezing at any time up to 18 years of age. Conclusions: Subsequent relapse of previously diagnosed asthma in remission at 18 years of age occurs in one in three young adults. Such relapse is not easily predicted, especially by measurements of airway responsiveness. A history of asthma currently in remission should not be used to prejudice employment opportunities for young adults. (CHEST 2005; 127:845– 850) Key words: airway hyperresponsiveness; asthma; employment; prognosis; remission; relapse Abbreviations: AHR ⫽ airway hyperresponsiveness; CI ⫽ confidence interval; HDM ⫽ house dust mite; OR ⫽ odds ratio; PC20 ⫽ provocative concentration of methacholine resulting in a 20% fall in FEV1
is becoming increasingly common in A sthma Western countries, affecting 15 to 20% of the population.1 In many individuals, the disease is mild, although it may be associated with a significant impact on quality of life and work capacity.2 The natural history is often characterized by periods of remission for a sustained period of time. In a recent *From the Department of Medical and Surgical Sciences (Dr. Taylor and Ms. Cowan), Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Firestone Institute for Respiratory Health (Ms. Greene), McMaster University and St. Joseph’s Healthcare, Hamilton, ON, Canada; and Hospital for Sick Children (Mr. Willan and Dr. Sears), University of Toronto, Toronto, ON, Canada. This study was supported by the Health Research Council of New Zealand, the Otago Medical Research Foundation, the New Zealand Lottery Grants Board, and the Asthma and Respiratory Foundation of New Zealand. www.chestjournal.org
longitudinal study3 of nearly 1,000 New Zealanders, up to 30% of those with “asthma ever” experienced remission for ⱖ 4 years during follow-up to age 26 years. Respiratory and occupational physicians are frequently asked to see young adults with a history of asthma to assess their fitness for certain types of employment. They may have currently active bronchial asthma, or they may be in remission. In the case Manuscript received February 19, 2004; revision accepted September 23, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: D. Robin Taylor, MD, FRCRP, Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand; e-mail: [email protected] CHEST / 127 / 3 / MARCH, 2005
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of the latter, potential employers, notably the armed services, the fire service, and the police force, often seek advice as to the likelihood of future relapse. In most instances, clinicians will rely on the patient’s history and to a lesser extent on the results of objective tests obtained at the time of the consultation in order to make their assessment. In the present study, our aim was to evaluate the frequency as well as the risk factors for relapse of asthma during an 8-year follow-up period in a group of 18-year-old patients with previous asthma but in remission at that age. The secondary aim was to assess the prognostic value of testing for airway hyperresponsiveness (AHR) against a background of previous asthma. Our data were obtained from a large population-based cohort study3 in which the natural history of asthma was evaluated regularly from early childhood to adulthood, including assessments at 15, 18, 21, and 26 years of age. We assessed the relevance of previous asthma, the presence of atopy, measurements of spirometry and AHR, and the advent of tobacco smoking during the 8-year follow-up period in predicting the likelihood of relapse.
Materials and Methods The Dunedin Multidisciplinary Health and Development Study is a longitudinal investigation of health and behavior in a complete birth cohort born in Dunedin, New Zealand in 1972– 1973. Full details regarding the study are available elsewhere.4 Study members enrolled at 3 years of age (n ⫽ 1,037; 91% of those eligible), were assessed every 2 years to 15 years of age, and then at 18, 21, and 26 years of age. The percentages of study members with full respiratory assessment at 15, 18, 21, and 26 years of age were 93.7%, 83.7%, 92.3%, and 92.0% of the living cohort, respectively. Respiratory questionnaires were administered, and lung function tests were performed at 9, 11, 13, 15, 18, 21, and 26 years of age. Predicted lung function values for 18, 21, and 26 years of age were based on a study of New Zealand adults.5 From age 18 years, self-administered questionnaires were added. Atopy was evaluated by skin-prick testing at 13 years and 21 years of age. AHR to methacholine was measured in all consenting study members at 9, 11, 13, 15, and 21 years of age, and deemed to be positive if the provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20) was ⬍ 8 mg/mL. In those with demonstrable airflow obstruction (FEV1/FVC ratio ⬍ 75% at 9 years and 11 years of age; ⬍ 70% at 13 years and 15 years of age), bronchodilator response was tested as an alternative. Bronchodilator responsiveness to salbutamol was measured in all consenting study members at 18 years and 26 years of age, and was defined as positive when there was an increase in FEV1 of ⱖ 10% from baseline. Positive allergen skin test results were defined by wheal ⱖ 2 mm greater than the negative control. Definitions Diagnosed asthma was recorded when the study member (or parent at younger ages) answered the question “Do you have 846
asthma?” affirmatively. Current wheezing reported at any age included all wheezing in the last 12 months, excluding only those with trivial symptoms (episodes occurring only once or twice annually and lasting ⬍ 1 h). Remission at 18 years of age was defined as absence of reported wheezing that had been current at two or more prior assessments. Relapse after 18 years of age was defined as current wheezing at 21 years or 26 years of age, or both. Data were analyzed using statistical software (SAS, version 8.2, SAS Institute; Cary, NC); t tests, 2, and simple and multiple logistic regression analyses were used to determine which factors were predictive of relapse after 18 years of age, and to estimate unadjusted and adjusted odds ratios (ORs), significance, and confidence intervals (CIs) for factors associated with relapse at 21 years and 26 years of age.
Results The analyses presented are of necessity restricted to the 868 study members evaluated at 18 years of age. Of these, 176 patients (20.3%) reported having doctor-diagnosed asthma ever when questioned at 9, 11, 13, or 15 years of age, of whom 68 patients were fully asymptomatic when questioned at 18 years of age. Subsequently, 16 of these 68 patients (24%) reported current wheezing at 21 years of age, which persisted to 26 years of age in 8 patients. Of the 52 patients who remained asymptomatic at 21 years of age, a further 8 patients reported current wheezing at 26 years of age. Thus, overall, 24 of 68 study members (35%) who were in remission at 18 years of age had relapsed by 21 years or 26 years of age, or both. Comparisons between all study members with asthma ever who were and were not in remission at 18 years of age showed significant differences (Table 1). Those in remission at 18 years of age were characterized by significantly greater FEV1 percentage of predicted and FEV1/FVC ratio, approximately half the rates for skin-prick positivity to house dust mite (HDM) and cat allergen at age 13 years, and significantly reduced rates for AHR and/or response to bronchodilator, compared with those not in remission at 18 years of age. Among those in remission at 18 years of age, comparisons were made between those who did and did not relapse subsequently by 26 years of age (Table 2). Those who relapsed were more often atopic and had numerically lower mean FEV1/FVC ratios at age 18 years (84.8 vs 87.3, p ⫽ 0.179), as well as increased frequency of responsiveness to methacholine or bronchodilator at 21 years of age. These differences were not statistically significant. Despite the high prevalence of cigarette smoking at 26 years of age in those who relapsed (45.8%) compared to those who remained in remission Clinical Investigations
Table 1—Comparison of Study Members Who Were or Were Not in Remission*
Variables Demographics Male gender Age of onset, yr Current smoker at age 18 yr Lung function FEV1 % predicted at age 18 FEV1/FVC ratio at age 18 Atopic status HDM wheal ⱖ 2 mm at age 13 yr Cat allergen wheal ⱖ 2 mm at age 13 yr AHR PC20 ⱕ 8 mg/mL at any age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 9 to 15 yr PC20 ⱕ 8 mg/mL at age 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 15 yr Bronchodilator ⱖ 10% at age 18 yr
Persistent Asthma at 18 Years of Age (n ⫽ 108) 58/108 (53.7) 4.7 ⫾ 4.0 35/108 (32.4)
Prior Asthma in Remission at 18 Years of Age (n ⫽ 68)
p Value†
41/68 (60.3) 6.4 ⫾ 4.5 18/68 (26.5)
0.39 0.0106 0.40
90.9 ⫾ 16.3 (n ⫽ 107) 80.9 ⫾ 11.1 (n ⫽ 107)
99.9 ⫾ 11.3 (n ⫽ 65) 86.4 ⫾ 7.4 (n ⫽ 65)
62/86 (72.1) 42/86 (48.8)
21/54 (38.9) 11/54 (20.4)
⬍ 0.0001 0.0007
75/104 (72.1) 79/106 (74.5) 43/92 (46.7) 46/95 (48.4) 33/105 (31.4)
23/66 (34.9) 24/66 (36.4) 6/63 (9.5) 6/63 (9.5) 4/64 (6.3)
⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 0.0001
0.0001 0.0004
*Data are presented as No./total patients (%) or mean ⫾ SD. †Persistent asthma vs prior asthma in remission.
(34.1%), this factor did not appear to have a significant influence at least within the time frame of the study to 26 years of age. Multiple logistic regression analyses involving the 68 study members in remission at 18 years of age who underwent skin-prick testing at 13 years of age
(n ⫽ 52) and spirometry at 18 years of age, with adjustment for sex, identified two independent risk factors that predicted recurrence of asthma by 26 years of age, namely HDM sensitization at 13 years of age (OR, 2.63; 95% CI, 1.23 to 5.61) and a decrease in the FEV1/FVC ratio at 18 years of age
Table 2—Comparison of Study Members Who Did or Did Not Relapse by 26 Years of Age* Variables Demographics Male gender Age of onset, yr Current smoker at age 18 yr Current smoker at age 21 yr Current smoker at age 26 yr Lung function FEV1 % predicted at age 18 yr FEV1 % predicted at age 21 yr FEV1 % predicted at age 26 yr FEV1/FVC ratio at age 18 yr FEV1/FVC ratio at age 21 yr FEV1/FVC ratio at age 26 yr Atopic status HDM wheal ⱖ 2 mm at age 13 yr HDM wheal ⱖ 2 mm at age 21 yr Cat allergen wheal ⱖ 2 mm at age 13 yr Cat allergen wheal ⱖ 2 mm at age 21 yr AHR PC20 ⱕ 8 mg/mL at any age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 15 yr Bronchodilator ⱖ 10% at age 18 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 21 yr
No Relapse (n ⫽ 44) 27/44 (61.4) 6.0 ⫾ 4.6 13/44 (29.5) 14/44 (31.8) 15/44 (34.1)
Relapse (n ⫽ 24)
p Value†
14/24 (58.3) 7.0 ⫾ 4.4 5/24 (20.8) 10/24 (41.7) 11/24 (45.8)
0.81 0.375 0.44 0.42 0.34
99.9 ⫾ 10.6 (n ⫽ 42) 99.3 ⫾ 10.4 (n ⫽ 42) 101.4 ⫾ 11.0 (n ⫽ 44) 87.3 ⫾ 7.0 (n ⫽ 42) 84.0 ⫾ 6.3 (n ⫽ 42) 81.6 ⫾ 5.5 (n ⫽ 44)
100.1 ⫾ 12.8 (n ⫽ 23) 100.1 ⫾ 13.3 (n ⫽ 23) 97.1 ⫾ 18.7 (n ⫽ 22) 84.8 ⫾ 7.8 (n ⫽ 23) 82.5 ⫾ 7.9 (n ⫽ 23) 78.9 ⫾ 9.5 (n ⫽ 22)
0.945 0.79 0.25 0.179 0.38 0.144
11/36 (30.6) 25/38 (65.8) 8/36 (22.2) 10/38 (26.3)
10/18 (55.6) 16/20 (80.0) 3/18 (16.7) 10/20 (50.0)
0.076 0.26 0.63 0.071
11/44 (25.0) 12/44 (27.3) 3/41 (7.3) 1/41 (2.4) 1/37 (2.7)
17/22 (77.3) 12/22 (54.6) 3/22 (13.6) 3/23 (13.0) 6/23 (26.1)
0.018 0.030 0.42 0.093 0.0061
*Data are presented as No./total patients (%) or mean ⫾ SD. †No relapse vs relapse. www.chestjournal.org
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(OR, 0.90 per 1% higher ratio; 95% CI, 0.81 to 0.99). The higher the FEV1/FVC ratio, the lower the likelihood of relapse. In order to evaluate the prognostic significance of a previous positive test result for AHR, comparisons were made between those study members who did or did not have a positive methacholine challenge result at 15 years of age. Only 6 of 193 subjects who had asthma ever to age 15 years had a positive methacholine challenge result at the last measurement at 15 years of age and were asymptomatic at 18 years of age. Of these, three patients subsequently relapsed (50.0%). In contrast, among those who were methacholine negative at 15 years of age, the proportions of patients who relapsed were generally much lower (Table 3). Although numbers are small, they indicate that a positive methacholine challenge result at 15 years of age is more likely to be associated with relapse of asthma by 26 years of age. There was also a strong relationship between a positive response to methacholine at any time between 9 years and 15 years of age and relapse during 18 to 26 years of age (Table 2). However, although highly specific (92.9%), the sensitivity, and positive and negative predictive values of a prior positive methacholine challenge result were low, at 13.6%, 50.0%, and 67.2%, respectively. To put these findings relating to relapse of childhood asthma between 18 years of age and 21 years or 26 years of age in context, we examined the likelihood of new asthma developing by 21 years or 26 years of age in study members with no history of asthma at 18 years of age. This occurred in only 13 of 443 at-risk individuals (2.9%) between 18 years and 21 years of age, 28 of 430 at-risk individuals (6.5%) between 21 years and 26 years of age, or in total 41 of 443 individuals (9.3%) by 26 years of age. To assess the severity of asthma after relapse, characteristics of asthma in study members who relapsed between 18 years of age and either 21 years or 26 years of age (n ⫽ 24) were compared with those of study members with persistent asthma to age 26 years (n ⫽ 81). Overall, there was evidence
Table 3—Methacholine Challenge Results for Study Members at 15 Years of Age* Age at Asthma Diagnosis, yr 21 26 21 or 26 21 and 26
Positive Result at Age 15 Years (n ⫽ 6)
Negative Result at Age 15 Years (n ⫽ 58)
p Value
3/6 (50.0) 3/6 (50.0) 3/6 (50.0) 3/6 (50.0)
11/57 (19.3) 12/58 (20.7) 19/58 (32.8) 4/58 (6.9)
0.085 0.107 0.397 0.0013
*Data are presented as No./total patients (%). 848
that asthma was substantially less severe in the relapsing group than in subjects with persistent asthma, in that they had higher lung function, needed less reliever and controller medication, had fewer days lost from school or work, and had no hospitalizations (Table 4).
Discussion The present analysis was undertaken in response to a frequently posed employment-related question: “If an asymptomatic young adult has a history of asthma, what are the chances of subsequent relapse?” We addressed this issue using data extracted from a longitudinal study3 in which persistence, remissions, and relapse of asthma in a population of nearly 1,000 young adults was studied in detail to 26 years of age. Our results demonstrate that over a follow-up period of 8 years, approximately one third of those with prior asthma who were asymptomatic at 18 years of age experienced relapse by 26 years of age. Earlier studies6,7 have documented relapse rates in subjects with “ex-asthma.” In the Tucson study by Bronnimann and Burrows,6 comprising 2,300 subjects, the overall relapse rate was 38% during a mean follow-up interval of 9.4 years. In the subgroup of young adults recruited between 20 years and 29 years of age, the relapse rate was approximately 30%. The most significant clinical predictor for subsequent relapse was a high frequency of asthma episodes when the asthma was previously deemed to be active. Thereafter, current smoking was a significant risk factor. In the British cohort study,7 at 33 years of age, 27% of a cohort of nearly 6,000 individuals reported wheezing in the previous 12 months, of whom approximately 40% had had symptoms during at 16 to 23 years of age. Atopy and cigarette smoking were the principal risk factors for relapse. The overall picture emerging from our data is broadly similar to those of earlier studies. This suggests, somewhat reassuringly, that although the prevalence of asthma may have increased since these earlier studies were performed, its natural history does not appear to have changed significantly. In our study, the identifiable markers associated with asthma recurrence included prior demonstration of atopy, reduced lung function at age 18 years, and a previous positive methacholine challenge result. We have previously shown,3 and have confirmed again in the present subanalysis, that each of these factors was highly significant in predicting persistence of asthma at 18 years of age (Table 1). These factors also influenced recurrence among those in remission at 18 years of age (Table 2), Clinical Investigations
Table 4 —Comparison of Study Members With Relapse to Those With Persistent Asthma*
Variables
Remission at Age 18 Years and Subsequently Relapsed at Age 21 Years and/or 26 Years of Age (n ⫽ 24)
Persistent Asthma at 26 Years of Age (n ⫽ 81)
p Value†
Mean FEV1 % predicted at age 26 yr Mean FEV1/FVC ratio at age 26 yr, % Bronchodilator ⱖ 10% at age 26 yr Use of controller medication Use of reliever medication Hospitalization between 18 yr and 26 yr of age, No. Absences from work or school at 18 yr to 26 yr of age, d
97.1 78.9 22.7 4/24 (16.7) 13/24 (54.2) 0 0.83 ⫾ 3.19
92.4 75.6 26.7 51/80 (63.8) 76/81 (93.8) 15 in nine study members 3.83 ⫾ 8.98
0.24 0.14 0.71 ⬍ 0.0001 ⬍ 0.0001 0.058 0.014
*Data are presented as mean ⫾ SD or No./total patients (%) unless otherwise indicated. †Relapse vs persistent asthma.
although perhaps because of small numbers, statistical significance was not achieved. Somewhat surprisingly, we failed to confirm that taking up tobacco smoking after 18 years of age was adversely influential during the period of study. This contrasts with the results of Strachan et al.7 The discrepancy may be because of the “healthy smoker effect” or because the effects of smoking take longer to become apparent. In the context of assessing young adults for future employment, some authorities recommend that asymptomatic individuals with a history of asthma should be screened out on the grounds of increased risk. This is particularly so for the armed services,8,9 but also applies to police forces, firefighters, and certain other occupations, eg, aluminum smelting. Such constraints are often applied because of the nature of the work to be undertaken, and to reduce overall risks in the working environment should the affected individual be rendered incapable of performing the work safely or satisfactorily. If relapse does occur and a change of employment becomes necessary, then investment in training is also lost. Against a background of very high rates for asthma in the Western world (approximately 20%), and a significant remission rate (40% at age 18 years in our study), this scenario is likely to be encountered quite frequently. However, our results provide some reassurance. Although asthma recurred in one third of those whose asthma was asymptomatic at age 18 years, its severity was usually mild as judged by relatively normal lung function (mean FEV1 97.1% predicted at age 26 years). For the most part, mild asthma is easily controlled, except perhaps in rare instances when it is “brittle,” ie, symptoms develop precipitously in response to exogenous stimuli. Many clinicians use the results of AHR testing to assess the risk of asthma recurrence in asymptomatic individuals. This approach is based on data from epidemiologic studies10 –12 in subjects with no history of respiratory disease, and suggest that asymptomatic AHR is a risk factor for overt symptomatic asthma to www.chestjournal.org
develop at a later stage. There are also data to indicate that even although subjects with measurable AHR may be asymptomatic, they demonstrate increased airway lability characterized by diurnal variation in peak flow rates and bronchodilator response.13 For this reason, it is suggested that asymptomatic AHR is an intermediate stage between normality and overt clinical disease.14 The clinical application of these data in the current setting in which the population of interest has a history of asthma is uncertain. Among those in our study who experienced relapse, the response to methacholine was positive in only a minority of subjects even at the time of symptom recurrence (26.1% at age 21 years). Similarly, although bronchodilator response (a measure of airway lability) was greater at age 18 years in those who experienced a subsequent recurrence of asthma, it was present at age 18 years in only 13% of those who subsequently relapsed. Thus, the positive and negative predictive values for these tests fall far short of what is necessary to justify using them meaningfully in individual cases, particularly when the career stakes may be high. In conclusion, our study has shown that approximately one in three young adults with a history of childhood asthma who are in remission at 18 years of age will subsequently relapse by 26 years of age. In general, the asthma is mild at the time of relapse. The likelihood of relapse is unpredictable; although it was associated with increased AHR earlier in life, the predictive value of AHR testing is low. Although there may be some high-risk situations that ought to be avoided in patients with previous asthma, eg, occupational exposure to high-molecular-weight allergens, a history of asthma in remission should not be used to prejudice employment opportunities for young adults. References 1 Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The CHEST / 127 / 3 / MARCH, 2005
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2 3 4 5 6 7 8
International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351:1225–1232 Mancuso CA, Rincon M, Charlson ME. Adverse work outcomes and events attributed to asthma. Am J Ind Med 2003; 44:236 –245 Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003; 349:1414 –1422 Silva PA, Stanton WR. From child to adult: the Dunedin Multidisciplinary Health and Development Study. Auckland, New Zealand: Oxford University Press, 1996 Sinclair SW, Avery SF, Brady DM, et al. Prediction formulae for normal pulmonary function values in New Zealand European subjects. N Z Med J 1980; 91:1–5 Bronnimann S, Burrows B. A prospective study of the natural history of asthma: remission and relapse rates. Chest 1986; 90:480 – 484 Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 1996; 312:1195–1199 Dickinson JG. Asthma in the army: a retrospective study and review of the natural history of asthma and its implications for
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recruitment. J R Army Med Corps 1988; 134:65–73 9 Katz I, Moshe S, Sosna J, et al. The occurrence, recrudescence, and worsening of asthma in a population of young adults: impact of varying types of occupation. Chest 1999; 116:614 – 618 10 Rasmussen F, Taylor DR, Flannery EM, et al. Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study. Pediatr Pulmonol 2002; 34:164 –171 11 Zhong NS, Chen RC, Yang MO, et al. Is asymptomatic bronchial hyperresponsiveness an indication of potential asthma? A two-year follow-up of young students with bronchial hyperresponsiveness. Chest 1992; 102:1104 –1109 12 Laprise C, Boulet LP. Asymptomatic airway hyperresponsiveness: a three-year follow-up. Am J Respir Crit Care Med 1997; 156:403– 409 13 Gibson PG, Mattoli S, Sears MR, et al. Increased peak flow variability in children with asymptomatic hyperresponsiveness. Eur Respir J 1995; 8:1731–1735 14 Boulet LP. Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med 2003; 167:371–378
Clinical Investigations
Study objective: To determine the frequency of relapse of asthma in young adults in remission at 18 years of age, during a follow-up period of 8 years, and to identify possible prognostic markers for relapse. Design: Longitudinal study of birth cohort (n ⴝ 1,037) born in New Zealand in 1972–1973. Setting: University hospital research clinic. Measurements: Participants were assessed at 9, 11, 13, 15, 18, 21, and 26 years of age using a respiratory questionnaire (all ages), spirometry (all ages), bronchodilator response (18 years and 26 years of age), methacholine challenge (9, 11, 13, 15, and 21 years of age), and allergen skin-prick testing (13 years and 21 years of age). Results: Approximately one third of study members (35%) with asthma in remission at 18 years of age relapsed by 21 years or 26 years of age. Atopy and lower FEV1/FVC ratio at 18 years of age were significant independent prognostic factors for relapse in multiple logistic regression analyses. Increased responsiveness to methacholine (provocative concentration < 8 mg/mL) or bronchodilator (improvement in FEV1 > 10%) at 21 years of age were more common among those with relapse, but the positive and negative predictive values for a previous positive methacholine challenge test result at 15 years of age were low. Asthma after relapse was generally mild (mean FEV1 97.1% predicted). Totally new adult asthma developed by 26 years of age in 9% of study members who had no asthma or wheezing at any time up to 18 years of age. Conclusions: Subsequent relapse of previously diagnosed asthma in remission at 18 years of age occurs in one in three young adults. Such relapse is not easily predicted, especially by measurements of airway responsiveness. A history of asthma currently in remission should not be used to prejudice employment opportunities for young adults. (CHEST 2005; 127:845– 850) Key words: airway hyperresponsiveness; asthma; employment; prognosis; remission; relapse Abbreviations: AHR ⫽ airway hyperresponsiveness; CI ⫽ confidence interval; HDM ⫽ house dust mite; OR ⫽ odds ratio; PC20 ⫽ provocative concentration of methacholine resulting in a 20% fall in FEV1
is becoming increasingly common in A sthma Western countries, affecting 15 to 20% of the population.1 In many individuals, the disease is mild, although it may be associated with a significant impact on quality of life and work capacity.2 The natural history is often characterized by periods of remission for a sustained period of time. In a recent *From the Department of Medical and Surgical Sciences (Dr. Taylor and Ms. Cowan), Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Firestone Institute for Respiratory Health (Ms. Greene), McMaster University and St. Joseph’s Healthcare, Hamilton, ON, Canada; and Hospital for Sick Children (Mr. Willan and Dr. Sears), University of Toronto, Toronto, ON, Canada. This study was supported by the Health Research Council of New Zealand, the Otago Medical Research Foundation, the New Zealand Lottery Grants Board, and the Asthma and Respiratory Foundation of New Zealand. www.chestjournal.org
longitudinal study3 of nearly 1,000 New Zealanders, up to 30% of those with “asthma ever” experienced remission for ⱖ 4 years during follow-up to age 26 years. Respiratory and occupational physicians are frequently asked to see young adults with a history of asthma to assess their fitness for certain types of employment. They may have currently active bronchial asthma, or they may be in remission. In the case Manuscript received February 19, 2004; revision accepted September 23, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: D. Robin Taylor, MD, FRCRP, Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand; e-mail: [email protected] CHEST / 127 / 3 / MARCH, 2005
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of the latter, potential employers, notably the armed services, the fire service, and the police force, often seek advice as to the likelihood of future relapse. In most instances, clinicians will rely on the patient’s history and to a lesser extent on the results of objective tests obtained at the time of the consultation in order to make their assessment. In the present study, our aim was to evaluate the frequency as well as the risk factors for relapse of asthma during an 8-year follow-up period in a group of 18-year-old patients with previous asthma but in remission at that age. The secondary aim was to assess the prognostic value of testing for airway hyperresponsiveness (AHR) against a background of previous asthma. Our data were obtained from a large population-based cohort study3 in which the natural history of asthma was evaluated regularly from early childhood to adulthood, including assessments at 15, 18, 21, and 26 years of age. We assessed the relevance of previous asthma, the presence of atopy, measurements of spirometry and AHR, and the advent of tobacco smoking during the 8-year follow-up period in predicting the likelihood of relapse.
Materials and Methods The Dunedin Multidisciplinary Health and Development Study is a longitudinal investigation of health and behavior in a complete birth cohort born in Dunedin, New Zealand in 1972– 1973. Full details regarding the study are available elsewhere.4 Study members enrolled at 3 years of age (n ⫽ 1,037; 91% of those eligible), were assessed every 2 years to 15 years of age, and then at 18, 21, and 26 years of age. The percentages of study members with full respiratory assessment at 15, 18, 21, and 26 years of age were 93.7%, 83.7%, 92.3%, and 92.0% of the living cohort, respectively. Respiratory questionnaires were administered, and lung function tests were performed at 9, 11, 13, 15, 18, 21, and 26 years of age. Predicted lung function values for 18, 21, and 26 years of age were based on a study of New Zealand adults.5 From age 18 years, self-administered questionnaires were added. Atopy was evaluated by skin-prick testing at 13 years and 21 years of age. AHR to methacholine was measured in all consenting study members at 9, 11, 13, 15, and 21 years of age, and deemed to be positive if the provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20) was ⬍ 8 mg/mL. In those with demonstrable airflow obstruction (FEV1/FVC ratio ⬍ 75% at 9 years and 11 years of age; ⬍ 70% at 13 years and 15 years of age), bronchodilator response was tested as an alternative. Bronchodilator responsiveness to salbutamol was measured in all consenting study members at 18 years and 26 years of age, and was defined as positive when there was an increase in FEV1 of ⱖ 10% from baseline. Positive allergen skin test results were defined by wheal ⱖ 2 mm greater than the negative control. Definitions Diagnosed asthma was recorded when the study member (or parent at younger ages) answered the question “Do you have 846
asthma?” affirmatively. Current wheezing reported at any age included all wheezing in the last 12 months, excluding only those with trivial symptoms (episodes occurring only once or twice annually and lasting ⬍ 1 h). Remission at 18 years of age was defined as absence of reported wheezing that had been current at two or more prior assessments. Relapse after 18 years of age was defined as current wheezing at 21 years or 26 years of age, or both. Data were analyzed using statistical software (SAS, version 8.2, SAS Institute; Cary, NC); t tests, 2, and simple and multiple logistic regression analyses were used to determine which factors were predictive of relapse after 18 years of age, and to estimate unadjusted and adjusted odds ratios (ORs), significance, and confidence intervals (CIs) for factors associated with relapse at 21 years and 26 years of age.
Results The analyses presented are of necessity restricted to the 868 study members evaluated at 18 years of age. Of these, 176 patients (20.3%) reported having doctor-diagnosed asthma ever when questioned at 9, 11, 13, or 15 years of age, of whom 68 patients were fully asymptomatic when questioned at 18 years of age. Subsequently, 16 of these 68 patients (24%) reported current wheezing at 21 years of age, which persisted to 26 years of age in 8 patients. Of the 52 patients who remained asymptomatic at 21 years of age, a further 8 patients reported current wheezing at 26 years of age. Thus, overall, 24 of 68 study members (35%) who were in remission at 18 years of age had relapsed by 21 years or 26 years of age, or both. Comparisons between all study members with asthma ever who were and were not in remission at 18 years of age showed significant differences (Table 1). Those in remission at 18 years of age were characterized by significantly greater FEV1 percentage of predicted and FEV1/FVC ratio, approximately half the rates for skin-prick positivity to house dust mite (HDM) and cat allergen at age 13 years, and significantly reduced rates for AHR and/or response to bronchodilator, compared with those not in remission at 18 years of age. Among those in remission at 18 years of age, comparisons were made between those who did and did not relapse subsequently by 26 years of age (Table 2). Those who relapsed were more often atopic and had numerically lower mean FEV1/FVC ratios at age 18 years (84.8 vs 87.3, p ⫽ 0.179), as well as increased frequency of responsiveness to methacholine or bronchodilator at 21 years of age. These differences were not statistically significant. Despite the high prevalence of cigarette smoking at 26 years of age in those who relapsed (45.8%) compared to those who remained in remission Clinical Investigations
Table 1—Comparison of Study Members Who Were or Were Not in Remission*
Variables Demographics Male gender Age of onset, yr Current smoker at age 18 yr Lung function FEV1 % predicted at age 18 FEV1/FVC ratio at age 18 Atopic status HDM wheal ⱖ 2 mm at age 13 yr Cat allergen wheal ⱖ 2 mm at age 13 yr AHR PC20 ⱕ 8 mg/mL at any age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 9 to 15 yr PC20 ⱕ 8 mg/mL at age 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 15 yr Bronchodilator ⱖ 10% at age 18 yr
Persistent Asthma at 18 Years of Age (n ⫽ 108) 58/108 (53.7) 4.7 ⫾ 4.0 35/108 (32.4)
Prior Asthma in Remission at 18 Years of Age (n ⫽ 68)
p Value†
41/68 (60.3) 6.4 ⫾ 4.5 18/68 (26.5)
0.39 0.0106 0.40
90.9 ⫾ 16.3 (n ⫽ 107) 80.9 ⫾ 11.1 (n ⫽ 107)
99.9 ⫾ 11.3 (n ⫽ 65) 86.4 ⫾ 7.4 (n ⫽ 65)
62/86 (72.1) 42/86 (48.8)
21/54 (38.9) 11/54 (20.4)
⬍ 0.0001 0.0007
75/104 (72.1) 79/106 (74.5) 43/92 (46.7) 46/95 (48.4) 33/105 (31.4)
23/66 (34.9) 24/66 (36.4) 6/63 (9.5) 6/63 (9.5) 4/64 (6.3)
⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 0.0001
0.0001 0.0004
*Data are presented as No./total patients (%) or mean ⫾ SD. †Persistent asthma vs prior asthma in remission.
(34.1%), this factor did not appear to have a significant influence at least within the time frame of the study to 26 years of age. Multiple logistic regression analyses involving the 68 study members in remission at 18 years of age who underwent skin-prick testing at 13 years of age
(n ⫽ 52) and spirometry at 18 years of age, with adjustment for sex, identified two independent risk factors that predicted recurrence of asthma by 26 years of age, namely HDM sensitization at 13 years of age (OR, 2.63; 95% CI, 1.23 to 5.61) and a decrease in the FEV1/FVC ratio at 18 years of age
Table 2—Comparison of Study Members Who Did or Did Not Relapse by 26 Years of Age* Variables Demographics Male gender Age of onset, yr Current smoker at age 18 yr Current smoker at age 21 yr Current smoker at age 26 yr Lung function FEV1 % predicted at age 18 yr FEV1 % predicted at age 21 yr FEV1 % predicted at age 26 yr FEV1/FVC ratio at age 18 yr FEV1/FVC ratio at age 21 yr FEV1/FVC ratio at age 26 yr Atopic status HDM wheal ⱖ 2 mm at age 13 yr HDM wheal ⱖ 2 mm at age 21 yr Cat allergen wheal ⱖ 2 mm at age 13 yr Cat allergen wheal ⱖ 2 mm at age 21 yr AHR PC20 ⱕ 8 mg/mL at any age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 9 to 15 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 15 yr Bronchodilator ⱖ 10% at age 18 yr PC20 ⱕ 8 mg/mL or bronchodilator ⱖ 10% at age 21 yr
No Relapse (n ⫽ 44) 27/44 (61.4) 6.0 ⫾ 4.6 13/44 (29.5) 14/44 (31.8) 15/44 (34.1)
Relapse (n ⫽ 24)
p Value†
14/24 (58.3) 7.0 ⫾ 4.4 5/24 (20.8) 10/24 (41.7) 11/24 (45.8)
0.81 0.375 0.44 0.42 0.34
99.9 ⫾ 10.6 (n ⫽ 42) 99.3 ⫾ 10.4 (n ⫽ 42) 101.4 ⫾ 11.0 (n ⫽ 44) 87.3 ⫾ 7.0 (n ⫽ 42) 84.0 ⫾ 6.3 (n ⫽ 42) 81.6 ⫾ 5.5 (n ⫽ 44)
100.1 ⫾ 12.8 (n ⫽ 23) 100.1 ⫾ 13.3 (n ⫽ 23) 97.1 ⫾ 18.7 (n ⫽ 22) 84.8 ⫾ 7.8 (n ⫽ 23) 82.5 ⫾ 7.9 (n ⫽ 23) 78.9 ⫾ 9.5 (n ⫽ 22)
0.945 0.79 0.25 0.179 0.38 0.144
11/36 (30.6) 25/38 (65.8) 8/36 (22.2) 10/38 (26.3)
10/18 (55.6) 16/20 (80.0) 3/18 (16.7) 10/20 (50.0)
0.076 0.26 0.63 0.071
11/44 (25.0) 12/44 (27.3) 3/41 (7.3) 1/41 (2.4) 1/37 (2.7)
17/22 (77.3) 12/22 (54.6) 3/22 (13.6) 3/23 (13.0) 6/23 (26.1)
0.018 0.030 0.42 0.093 0.0061
*Data are presented as No./total patients (%) or mean ⫾ SD. †No relapse vs relapse. www.chestjournal.org
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(OR, 0.90 per 1% higher ratio; 95% CI, 0.81 to 0.99). The higher the FEV1/FVC ratio, the lower the likelihood of relapse. In order to evaluate the prognostic significance of a previous positive test result for AHR, comparisons were made between those study members who did or did not have a positive methacholine challenge result at 15 years of age. Only 6 of 193 subjects who had asthma ever to age 15 years had a positive methacholine challenge result at the last measurement at 15 years of age and were asymptomatic at 18 years of age. Of these, three patients subsequently relapsed (50.0%). In contrast, among those who were methacholine negative at 15 years of age, the proportions of patients who relapsed were generally much lower (Table 3). Although numbers are small, they indicate that a positive methacholine challenge result at 15 years of age is more likely to be associated with relapse of asthma by 26 years of age. There was also a strong relationship between a positive response to methacholine at any time between 9 years and 15 years of age and relapse during 18 to 26 years of age (Table 2). However, although highly specific (92.9%), the sensitivity, and positive and negative predictive values of a prior positive methacholine challenge result were low, at 13.6%, 50.0%, and 67.2%, respectively. To put these findings relating to relapse of childhood asthma between 18 years of age and 21 years or 26 years of age in context, we examined the likelihood of new asthma developing by 21 years or 26 years of age in study members with no history of asthma at 18 years of age. This occurred in only 13 of 443 at-risk individuals (2.9%) between 18 years and 21 years of age, 28 of 430 at-risk individuals (6.5%) between 21 years and 26 years of age, or in total 41 of 443 individuals (9.3%) by 26 years of age. To assess the severity of asthma after relapse, characteristics of asthma in study members who relapsed between 18 years of age and either 21 years or 26 years of age (n ⫽ 24) were compared with those of study members with persistent asthma to age 26 years (n ⫽ 81). Overall, there was evidence
Table 3—Methacholine Challenge Results for Study Members at 15 Years of Age* Age at Asthma Diagnosis, yr 21 26 21 or 26 21 and 26
Positive Result at Age 15 Years (n ⫽ 6)
Negative Result at Age 15 Years (n ⫽ 58)
p Value
3/6 (50.0) 3/6 (50.0) 3/6 (50.0) 3/6 (50.0)
11/57 (19.3) 12/58 (20.7) 19/58 (32.8) 4/58 (6.9)
0.085 0.107 0.397 0.0013
*Data are presented as No./total patients (%). 848
that asthma was substantially less severe in the relapsing group than in subjects with persistent asthma, in that they had higher lung function, needed less reliever and controller medication, had fewer days lost from school or work, and had no hospitalizations (Table 4).
Discussion The present analysis was undertaken in response to a frequently posed employment-related question: “If an asymptomatic young adult has a history of asthma, what are the chances of subsequent relapse?” We addressed this issue using data extracted from a longitudinal study3 in which persistence, remissions, and relapse of asthma in a population of nearly 1,000 young adults was studied in detail to 26 years of age. Our results demonstrate that over a follow-up period of 8 years, approximately one third of those with prior asthma who were asymptomatic at 18 years of age experienced relapse by 26 years of age. Earlier studies6,7 have documented relapse rates in subjects with “ex-asthma.” In the Tucson study by Bronnimann and Burrows,6 comprising 2,300 subjects, the overall relapse rate was 38% during a mean follow-up interval of 9.4 years. In the subgroup of young adults recruited between 20 years and 29 years of age, the relapse rate was approximately 30%. The most significant clinical predictor for subsequent relapse was a high frequency of asthma episodes when the asthma was previously deemed to be active. Thereafter, current smoking was a significant risk factor. In the British cohort study,7 at 33 years of age, 27% of a cohort of nearly 6,000 individuals reported wheezing in the previous 12 months, of whom approximately 40% had had symptoms during at 16 to 23 years of age. Atopy and cigarette smoking were the principal risk factors for relapse. The overall picture emerging from our data is broadly similar to those of earlier studies. This suggests, somewhat reassuringly, that although the prevalence of asthma may have increased since these earlier studies were performed, its natural history does not appear to have changed significantly. In our study, the identifiable markers associated with asthma recurrence included prior demonstration of atopy, reduced lung function at age 18 years, and a previous positive methacholine challenge result. We have previously shown,3 and have confirmed again in the present subanalysis, that each of these factors was highly significant in predicting persistence of asthma at 18 years of age (Table 1). These factors also influenced recurrence among those in remission at 18 years of age (Table 2), Clinical Investigations
Table 4 —Comparison of Study Members With Relapse to Those With Persistent Asthma*
Variables
Remission at Age 18 Years and Subsequently Relapsed at Age 21 Years and/or 26 Years of Age (n ⫽ 24)
Persistent Asthma at 26 Years of Age (n ⫽ 81)
p Value†
Mean FEV1 % predicted at age 26 yr Mean FEV1/FVC ratio at age 26 yr, % Bronchodilator ⱖ 10% at age 26 yr Use of controller medication Use of reliever medication Hospitalization between 18 yr and 26 yr of age, No. Absences from work or school at 18 yr to 26 yr of age, d
97.1 78.9 22.7 4/24 (16.7) 13/24 (54.2) 0 0.83 ⫾ 3.19
92.4 75.6 26.7 51/80 (63.8) 76/81 (93.8) 15 in nine study members 3.83 ⫾ 8.98
0.24 0.14 0.71 ⬍ 0.0001 ⬍ 0.0001 0.058 0.014
*Data are presented as mean ⫾ SD or No./total patients (%) unless otherwise indicated. †Relapse vs persistent asthma.
although perhaps because of small numbers, statistical significance was not achieved. Somewhat surprisingly, we failed to confirm that taking up tobacco smoking after 18 years of age was adversely influential during the period of study. This contrasts with the results of Strachan et al.7 The discrepancy may be because of the “healthy smoker effect” or because the effects of smoking take longer to become apparent. In the context of assessing young adults for future employment, some authorities recommend that asymptomatic individuals with a history of asthma should be screened out on the grounds of increased risk. This is particularly so for the armed services,8,9 but also applies to police forces, firefighters, and certain other occupations, eg, aluminum smelting. Such constraints are often applied because of the nature of the work to be undertaken, and to reduce overall risks in the working environment should the affected individual be rendered incapable of performing the work safely or satisfactorily. If relapse does occur and a change of employment becomes necessary, then investment in training is also lost. Against a background of very high rates for asthma in the Western world (approximately 20%), and a significant remission rate (40% at age 18 years in our study), this scenario is likely to be encountered quite frequently. However, our results provide some reassurance. Although asthma recurred in one third of those whose asthma was asymptomatic at age 18 years, its severity was usually mild as judged by relatively normal lung function (mean FEV1 97.1% predicted at age 26 years). For the most part, mild asthma is easily controlled, except perhaps in rare instances when it is “brittle,” ie, symptoms develop precipitously in response to exogenous stimuli. Many clinicians use the results of AHR testing to assess the risk of asthma recurrence in asymptomatic individuals. This approach is based on data from epidemiologic studies10 –12 in subjects with no history of respiratory disease, and suggest that asymptomatic AHR is a risk factor for overt symptomatic asthma to www.chestjournal.org
develop at a later stage. There are also data to indicate that even although subjects with measurable AHR may be asymptomatic, they demonstrate increased airway lability characterized by diurnal variation in peak flow rates and bronchodilator response.13 For this reason, it is suggested that asymptomatic AHR is an intermediate stage between normality and overt clinical disease.14 The clinical application of these data in the current setting in which the population of interest has a history of asthma is uncertain. Among those in our study who experienced relapse, the response to methacholine was positive in only a minority of subjects even at the time of symptom recurrence (26.1% at age 21 years). Similarly, although bronchodilator response (a measure of airway lability) was greater at age 18 years in those who experienced a subsequent recurrence of asthma, it was present at age 18 years in only 13% of those who subsequently relapsed. Thus, the positive and negative predictive values for these tests fall far short of what is necessary to justify using them meaningfully in individual cases, particularly when the career stakes may be high. In conclusion, our study has shown that approximately one in three young adults with a history of childhood asthma who are in remission at 18 years of age will subsequently relapse by 26 years of age. In general, the asthma is mild at the time of relapse. The likelihood of relapse is unpredictable; although it was associated with increased AHR earlier in life, the predictive value of AHR testing is low. Although there may be some high-risk situations that ought to be avoided in patients with previous asthma, eg, occupational exposure to high-molecular-weight allergens, a history of asthma in remission should not be used to prejudice employment opportunities for young adults. References 1 Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The CHEST / 127 / 3 / MARCH, 2005
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2 3 4 5 6 7 8
International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351:1225–1232 Mancuso CA, Rincon M, Charlson ME. Adverse work outcomes and events attributed to asthma. Am J Ind Med 2003; 44:236 –245 Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003; 349:1414 –1422 Silva PA, Stanton WR. From child to adult: the Dunedin Multidisciplinary Health and Development Study. Auckland, New Zealand: Oxford University Press, 1996 Sinclair SW, Avery SF, Brady DM, et al. Prediction formulae for normal pulmonary function values in New Zealand European subjects. N Z Med J 1980; 91:1–5 Bronnimann S, Burrows B. A prospective study of the natural history of asthma: remission and relapse rates. Chest 1986; 90:480 – 484 Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 1996; 312:1195–1199 Dickinson JG. Asthma in the army: a retrospective study and review of the natural history of asthma and its implications for
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recruitment. J R Army Med Corps 1988; 134:65–73 9 Katz I, Moshe S, Sosna J, et al. The occurrence, recrudescence, and worsening of asthma in a population of young adults: impact of varying types of occupation. Chest 1999; 116:614 – 618 10 Rasmussen F, Taylor DR, Flannery EM, et al. Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study. Pediatr Pulmonol 2002; 34:164 –171 11 Zhong NS, Chen RC, Yang MO, et al. Is asymptomatic bronchial hyperresponsiveness an indication of potential asthma? A two-year follow-up of young students with bronchial hyperresponsiveness. Chest 1992; 102:1104 –1109 12 Laprise C, Boulet LP. Asymptomatic airway hyperresponsiveness: a three-year follow-up. Am J Respir Crit Care Med 1997; 156:403– 409 13 Gibson PG, Mattoli S, Sears MR, et al. Increased peak flow variability in children with asymptomatic hyperresponsiveness. Eur Respir J 1995; 8:1731–1735 14 Boulet LP. Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med 2003; 167:371–378
Clinical Investigations