A Comparison of the Clinical Characteristics of Children and Adults With Severe Asthma

A Comparison of the Clinical Characteristics of Children and Adults With Severe Asthma* Henry A. Jenkins, MD; Reubin Cherniack, MD; Stanley J. Szefler, MD; Ronina Covar, MD; Erwin W. Gelfand, MD; and Joseph D. Spahn, MD

Objectives: This study sought to better define the clinical characteristics of severe asthma in both children and adults, and to evaluate the effect of asthma duration on multiple parameters of disease severity. Design: Retrospective analysis of prospectively collected data on 275 patients (125 children) with severe asthma who were admitted to a tertiary asthma referral center. Methods: Demographics, lung function (ie, spirometry and body box plethysmography), glucocorticoid (GC) pharmacokinetic studies, and lymphocyte stimulation assays were performed on all patients. Results: Children were as likely to require therapy with high-dose inhaled GCs and long-term therapy with oral GCs, and to have had a prior intubation, yet they had significantly less airflow limitation (mean [ⴞ SEM] FEV1, 74.0 ⴞ 2.1% predicted vs 57.1 ⴞ 1.8% predicted, respectively; p < 0.0001), less resistance to airflow (mean airway resistance, 140.3 ⴞ 8.5% predicted vs 311 ⴞ 18% predicted, respectively; p < 0.0001), and larger lung volumes (mean total lung capacity, 116.4 ⴞ 1.6% predicted vs 105.3 ⴞ 1.8% predicted, respectively; p < 0.0001) compared to adults. Children were more likely to be male and to display greater responsiveness to GCs in vitro. Lung function impairment was associated with asthma duration in children and in adults with onset of asthma in childhood, while there was no relationship between disease severity and asthma duration among those with adult-onset asthma. Despite significant differences in disease duration, patients with adult-onset asthma had equally compromised lung function compared to adults with long-standing asthma. Conclusions: Children with severe asthma tended to be male, to have less severe airflow obstruction, and to display greater responsiveness to GCs in vitro compared to adults. Symptoms and episodic acute declines in lung function may precede chronic airflow limitation in this group of children. As such, it may be more relevant to follow the deterioration in lung function over time in children. Finally, disease severity in children and adults whose onset of asthma occurred in childhood was related to disease duration, but not in patients with onset of asthma in adulthood. (CHEST 2003; 124:1318 –1324) Key words: adult-onset asthma; childhood-onset asthma; glucocorticoids; National Heart, Lung, and Blood Institute guidelines; severe asthma Abbreviations: GC ⫽ glucocorticoid; IC50 ⫽ inhibitory concentration that results in 50% suppression of lymphocyte activation; NHLBI ⫽ National Heart, Lung, and Blood Institute; PBMC ⫽ peripheral blood mononuclear cell; Raw ⫽ airway resistance; RV ⫽ residual volume; sGaw ⫽ specific airway conductance; TLC ⫽ total lung capacity

is a significant and global health-care A sthma concern affecting an estimated 8% of the adult population and possibly up to 20% of children.1,2 Although most persons with asthma have mild-tomoderate disease, ⱕ 10% have severe disease that is recalcitrant to the available treatment modalities.1

Severe asthma accounts for a significant proportion of the health-care costs associated with asthma. In addition, those persons with severe asthma are likely to experience the greatest morbidity, not only from their disease, but also from the medications used to treat their disease.

*From the Divisions of Clinical Pharmacology (Drs. Jenkins, Szefler, Covar, and Spahn) and Allergy-Clinical Immunology (Dr. Gelfand), the Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, and the Department of Medicine (Dr. Cherniack), National Jewish Medical and Research Center and, University of Colorado Health Sciences Center, Denver, CO.

Manuscript received January 9, 2003; revision accepted April 16, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Joseph D. Spahn, MD, National Jewish Medical & Research Center, 1400 Jackson St (K-926), Denver, CO 80206

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There are large gaps in our knowledge pertaining to the clinical characteristics and natural history of severe asthma, as outlined in a National Heart, Lung, and Blood Institute (NHLBI) workshop.1 The areas called on for further investigation by this panel included questions of whether the clinical characteristics of children with severe asthma differ from those of adults with severe asthma, and whether they differ between adults with severe asthma the onset of which occurred in childhood and those with asthma onset that occurred in adulthood. The purpose of this report was to describe the differences in the clinical characteristics of children vs adults with severe asthma. In addition, we determined whether there were differences in the clinical characteristics of adults with severe asthma with onset of asthma occurring in childhood vs those with onset occurring in adulthood. Materials and Methods This retrospective cross-sectional study was carried out in 275 patients who had been referred for evaluation of difficult-tocontrol asthma in the pediatric or adult units at the National Jewish Medical and Research Center between 1997 and 2001. Patients included in this analysis had severe asthma, as defined by their need for either of the following: (1) long-term administration of oral glucocorticoids (GCs) for at least the 6 months prior to evaluation; or (2) the need for ⱖ 1,000 ␮g/d inhaled GCs in an attempt to control their disease.1 Patients with vocal cord dysfunction, those with COPD associated with cigarette smoking in the past, and patients with lung diseases other than asthma were excluded from the study. Information collected included patient demographics such as age, sex, race, and history of asthma or atopy. Historical information included the following: age at the time of asthma diagnosis; history of intubation; age at first exposure to oral GCs; duration of long-term administration of oral GCs; and the dosage and type of inhaled and oral GCs. At the time of the evaluation, the patients were in their usual state of health, stable and not acutely ill with asthma. The data collected on hospital admission and during the hospitalization included assessments of lung function, GC pharmacokinetic and lymphocyte proliferation assays, a morning cortisol level, serum IgE levels, total eosinophil count, and the number of positive results of allergen prick skin tests. Pharmacokinetic studies (ie, with methylprednisolone or prednisone) were performed to rule out either poor absorption or rapid clearance as explanations for poor response to GC therapy. Lymphocyte stimulation assays were performed in the presence and absence of GCs. It is a functional assay, and provides information on in vitro response to GCs. As a rule, patients with GC-insensitive asthma require greater concentrations of GCs to suppress lymphocyte activation in vitro than do subjects with GC-responsive asthma.3 Lung Function Studies Airway resistance (Raw), thoracic gas volume, vital capacity, total lung capacity (TLC), and residual volume (RV) were determined (MasterScreen Body Box; Erich Jaeger; Friedburg, Germany). In addition, flow-volume relationships were determined with the following parameters evaluated: FEV1; FVC; and FEV1/FVC ratio. Predicted values for spirometry were obtained from the National www.chestjournal.org

Health and Nutrition Examination Study III of ⬎ 7,000 children and adults.4 The lung function measures were obtained prior to the administration of ␤-agonist therapy, with at least 4 h after the administration of a short-acting ␤-agonist agent and, when applicable, at least 12 h after the administration of a long-acting ␤-agonist agent having elapsed prior to the test being performed. Lymphocyte Stimulation Assay Heparinized blood (21 mL) was obtained before 9:00 am and prior to oral or inhaled GC administration. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation and were suspended in a solution of RPMI medium/10% fetal calf serum at a density of 1 ⫻ 106 cells/mL. The PBMCs then were incubated with phytohemagglutinin at a final concentration of 5 ␮g/mL and with increasing concentrations of hydrocortisone and dexamethasone (range, 10⫺10 to 10⫺6 mol/L) for 72 h at 37°C in 5% CO2. Six hours before harvesting, the PBMCs were transferred to 96-well plates and were pulse-labeled with [3H]-thymidine at a final concentration of 1 ␮Ci per well. The cells then were harvested, counted in a ␤-scintillation counter, and the results were expressed as counts per minute of [3H]-thymidine incorporation. To quantitate GC responsiveness, values for the inhibitory concentration that results in 50% suppression of lymphocyte activation (IC50) were calculated. The IC50 is the concentration of GCs that is required to suppress phytohemagglutinin-induced lymphocyte proliferation by 50%. Prednisone Pharmacokinetic Studies Prednisone pharmacokinetic studies were performed based on previously published methods using a high-performance liquid chromatography method.5 After obtaining a predose blood sample, a dose of prednisone (40 mg/1.73 m2) was administered with blood drawn 2 h and 6 h postdose. Prednisolone clearance was calculated as previously described using the following equation: log prednisolone clearance ⫽ [2.66 ⫹ (6-h postdose prednisolone concentration)(⫺ 0.00167)]. Statistical Analysis The data were analyzed using a statistical software package (JMP; SAS Institute; Cary, NC) and are presented as the mean ⫾ SEM, unless otherwise specified. Comparative analysis of variance between individual groups was performed utilizing the Student t test. A test of proportions between groups was performed using the Pearson ␹2 test. Statistical significance was observed at p ⱕ 0.05.

Results Study Population The mean age of the study cohort (n ⫽ 275) was 27.7 years (age range, 2.3 to 74.0 years) with a relatively equal sex distribution (women, 56%). All patients ⱕ 18 years old were considered to be children and represented 45% of the cohort. Of all the subjects studied, 78% had experienced the onset of their asthma in childhood. Seventy-nine percent were white, 19% were African-American, and 2% were other. The cohort had chronic, severe, persistent asthma, as defined by the need for therapy with CHEST / 124 / 4 / OCTOBER, 2003

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long-term administration of oral GCs in 76% of the subjects, with a mean daily prednisone equivalent dose of 27.2 ⫾ 3.0 mg for a mean duration of 4.0 ⫾ 0.4 years. Therapy with high-dose inhaled GCs also was required, with a mean daily dose of 1,173 ⫾ 47 ␮g. Twenty-six percent of the cohort had required at least one intubation for an acute severe asthma exacerbation. Children With Severe Asthma Compared to Adults With Severe Asthma Children (n ⫽ 125) differed from the adults (n ⫽ 150) in a number of parameters (Table 1). First, although women accounted for the majority of adult asthma patients (68%), only 38% of the children with severe asthma were female. Second, a greater percentage of children were AfricanAmerican compared to adults. Third, children had received a lower dose of oral GCs at hospital admission and required long-term therapy with oral GCs for a significantly shorter length of time. In

addition, children displayed more rapid prednisolone clearance and were significantly more responsive to GCs in vitro compared to the adults. With regard to lung function, children with severe asthma had significantly less airflow limitation than the adults, as measured by FEV1 (percent predicted) and FEV1/FVC ratio. FEV1 values of ⱖ 80% of predicted were noted in 41% of the children and in only 3% of the adults. In contrast, the FEV1 was ⱕ 60% of predicted in the majority of adults, compared to only 28% of the children studied. Last, children had evidence for greater hyperinflation, as measured by TLC, and had evidence for a greater degree of airway closure, as measured by an elevated RV, while displaying less Raw. Comparison of Adults With Onset of Asthma in Adulthood vs Childhood Table 2 compares the characteristics of adults with onset of asthma in adulthood to those with

Table 1—Characteristics of Children vs Adults With Severe Asthma* Parameter

Children (n ⫽ 125)

Adults (n ⫽ 150)

p Value

Age, yr Female sex, % Race White African American Other Duration of asthma, yr History of intubation, % Medication use Requiring long-term oral GC use, % Admission oral GC dose, mg Duration of oral GC use, yr Inhaled GCs, ␮g/d Long-acting ␤-agonist use, % Leukotriene-modifying agent use, % Laboratory parameters Atopic,† % IgE, IU/mL Admission am cortisol level, ␮g/dL Total eosinophil count, cells/␮L Log IC50, nmol/L Hydrocortisone Dexamethasone Prednisolone clearance, mL/min/1.73 m2 Lung function parameters TLC, % predicted RV, % predicted FVC, % predicted FEV1, % predicted FEV1/FVC ratio, % Raw, % predicted sGaw, % predicted

12.5 ⫾ 0.4 38

34.4 ⫾ 1.0 68

⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001

67 30 2 9.8 ⫾ 3.4 23

89 8 3 22.3 ⫾ 1.3 28

⬍ 0.001 0.53

75 19.2 ⫾ 2.1 2.3 ⫾ 0.3 1,065 ⫾ 68 69 60

80 32.9 ⫾ 5.1 5.3 ⫾ 0.6 1,178 ⫾ 61 80 70

0.30 0.03 ⬍ 0.001 0.30 0.03 0.06

82 505.0 ⫾ 85 4.3 ⫾ 0.6 259 ⫾ 20

88 204.7 ⫾ 49 5.0 ⫾ 0.6 266 ⫾ 31

0.85 0.002

2.00 ⫾ 0.08 1.03 ⫾ 0.07 220 ⫾ 6.3

2.43 ⫾ 0.07 1.25 ⫾ 0.1 189.4 ⫾ 6.6

⬍ 0.0001 0.001 0.001

116 ⫾ 1.6 253.0 ⫾ 10.0 87.8 ⫾ 1.9 74.0 ⫾ 2.1 72.5 ⫾ 1.5 140.3 ⫾ 8.5 64.4 ⫾ 3.7

105.3 ⫾ 1.8 197.6 ⫾ 7.6 70.3 ⫾ 1.5 57.1 ⫾ 1.8 66.9 ⫾ 1.3 311.7 ⫾ 17.9 44.2 ⫾ 4.6

⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 0.0002 ⬍ 0.0001 ⬍ 0.0001

0.71

*Values given as mean ⫾ SEM, unless otherwise indicated. †Indicating one or more positive results of skin-prick tests. 1320

Clinical Investigations

Table 2—Comparison of Adults With Childhood-Onset vs Adult-Onset Asthma* Parameter

Adults With ChildhoodOnset Asthma (n ⫽ 87)

Adults With AdultOnset Asthma (n ⫽ 63)

p Value

Age, yr Female gender, % Age at diagnosis, yr Asthma duration, yr Atopic, % Admission GC dose, mg/d GC dependence, yr Inhaled GC dose, ␮g/d Intubated, % Log IC50 hydrocortisone, nmol/L Prednisolone clearance, mL/min/1.73 m2 TLC, % predicted RV, % predicted FEV1, % predicted FVC, % predicted FEV1/FVC ratio, % Raw, % predicted sGaw, % predicted

36.3 ⫾ 1.3 69 5.20 ⫾ 0.6 31.01 ⫾ 1.45 92 37.3 ⫾ 8.2 5.9 ⫾ 0.8 1319 ⫾ 82 25 2.37 ⫾ 0.10 191.2 ⫾ 9.5 104.8 ⫾ 2.4 193.1 ⫾ 9.7 56.3 ⫾ 2.2 70.2 ⫾ 2.1 67.4 ⫾ 1.6 295.3 ⫾ 23.0 46.2 ⫾ 4.6

46.1 ⫾ 1.5 64 35.4 ⫾ 1.5 11.0 ⫾ 1.2 82 25.1 ⫾ 3.3 4.5 ⫾ 0.8 918 ⫾ 84 31 2.54 ⫾ 0.13 187.3 ⫾ 9.0 106.1 ⫾ 2.8 204.3 ⫾ 12.3 58.2 ⫾ 2.8 70.3 ⫾ 2.6 66.2 ⫾ 2.1 333.5 ⫾ 28 41.4 ⫾ 4.5

⬍ 0.0001 0.58 ⬍ 0.0001 ⬍ 0.0001 0.17 0.24 0.24 0.008 0.47 0.28 0.77 0.72 0.47 0.59 0.95 0.63 0.29 0.46

*Values given as mean ⫾ SEM, unless otherwise indicated.

onset in childhood. Forty-two percent of the adults (63 of 150 adults) had experienced the onset of their disease in adulthood. These subjects were significantly older, had experienced the onset of their disease at a significantly later age, and consequently had a shorter duration of asthma compared to adults with onset in childhood. Despite the significant differences in disease duration, the two groups had similar impairment in lung function, requirements for oral GC therapy, duration of GC therapy, responses to GCs in vitro, and prednisone pharmacokinetics. Relationship Between Asthma Duration and Measures of Disease Severity In the children with severe asthma, the duration of asthma was associated with multiple measures of disease severity. Specifically, asthma duration was associated with the need for oral GCs and the dose of oral GCs (r ⫽ 0.21; p ⫽ 0.03), and the duration of long-term oral GC use (r ⫽ 0.23; p ⫽ 0.02). For example, the longer a child had asthma, the greater was the oral dose of GCs on hospital admission and the longer the child was likely to have required long-term therapy with oral GCs. In addition, the duration of asthma was associated with airflow limitation, as measured by FEV1 percent predicted, FEV1/FVC ratio, and specific airway conductance (sGaw) percent predicted, while it was directly associated with Raw percent predicted (Fig 1, left, A). In the adults with childhood-onset asthma, the duration of diswww.chestjournal.org

ease also was associated with multiple parameters of disease severity. Specifically, asthma duration was associated with increased TLC, RV, and Raw, while it was inversely related to sGaw, FEV1, and FEV1/FVC ratio (Fig 1, right, B). The decline in FEV1 percent predicted per year of asthma was greatest among the children with severe asthma, with a 1.8% predicted per year decline noted, while the decline among adults with childhood-onset asthma, for whom the duration of asthma for the majority of subjects was ⬎ 20 years, was only 0.4% predicted per year. Multivariate analyses were performed to determine whether age, gender, or age at onset of asthma were significant confounders of the association between duration and lung function. For both children and adults, the duration of asthma remained significantly associated with changes in lung function. In contrast to the associations noted between asthma duration and disease severity among asthma patients with onset of asthma in childhood, no associations between duration and severity, as measured by the need for intubation, oral GCs requirement, or impairment in lung function (FEV1: r ⫽ 0.03, p ⫽ 0.77; FEV1/FVC ratio: r ⫽ 0.17, p ⫽ 0.67; Raw: r ⫽ 0.14, p ⫽ 0.34) were found among the adults with onset of asthma in adulthood. Adults with onset of asthma in adulthood had compromised lung function whether they had asthma of short duration or long duration, suggesting that significant compromise in lung function occurred at or very soon after the initial diagnosis of asthma had been made. CHEST / 124 / 4 / OCTOBER, 2003

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Figure 1. Effect of asthma duration on measures of lung function among children with severe asthma (left, A) and adults with onset of asthma in childhood (right, B). Top left, Ai, and top right, Bi: the x-axis is FEV1 (% predicted), while the y-axis represents duration of asthma in years. Middle left, Aii, and middle right, Bii: the x-axis represents the FEV1/FVC ratio (%), while the y-axis represents duration of asthma in years. Bottom left, Aiii, and bottom right, Biii: the x-axis represents Raw (% predicted), while the y-axis represents duration of asthma in years. Squares ⫽ male subjects; circles ⫽ female subjects.

Discussion Little is known regarding the clinical characteristics of severe asthma, nor is it known whether differences exist within different age groups, spanning early infancy to old age. This retrospective cross-sectional study of severe asthma allowed an analysis of the clinical characteristics of both children and adults with severe asthma. Children with severe asthma were more likely to be male, whereas adults were more likely to be female. This age-dependent difference in asthma prevalence between the sexes has been noted by other investigators in subjects 1322

with mild and moderate asthma.6 – 8 Based on in vitro testing, children were significantly more sensitive to the suppressive effects of GCs compared to adults. The etiology for this finding is at present unknown, but it may relate to increased airway inflammation over time among the adults who had a longer duration of asthma and significantly lower lung function. Alternatively, the in vitro response to GCs may vary over time. Studies are currently underway evaluating the effect of age on GC responsiveness in vitro among nonasthmatic control subjects. Of importance, children had less impaired lung Clinical Investigations

function compared to the adults studied. As expected, the mean FEV1 of 57% predicted for the adults is within the NHLBI lung function guidelines for severe persistent asthma. In contrast, children had FEV1 values within the moderate persistent asthma range at 74.0% of predicted. Only 28% of the children studied would have been classified as having severe persistent asthma, while ⬎ 40% would have been classified as having mild persistent asthma based on the NHLBI lung function criteria. Bacharier et al9 performed spirometry in 195 children and compared FEV1 values to asthma severity based on symptoms. Children with mild persistent asthma based on symptoms had a mean FEV1 of 95.1% of predicted. Those with moderate persistent asthma had a mean FEV1 of 90.2% of predicted; while those with severe persistent asthma had a mean FEV1 of 83.8% of predicted. Fuhlbrigge et al,10 performed an analysis of lung function in ⬎ 3,000 children with asthma who were observed for up to 15 years and found ⬎ 90% of all FEV1 values to be ⬎ 80% of predicted. The observation that children from our cohort had significantly less impaired lung function than their adult peers should not come as a surprise. Multiple cross-sectional and longitudinal studies11–13 have demonstrated a small annual decline in lung function among patients with asthma, with a decline of approximately 1% of predicted per year. We too observed a relationship between asthma duration and decline in lung function, but only in subjects whose disease onset had occurred in childhood. Despite higher mean FEV1 values among the children studied, they displayed a greater annual decline in FEV1 than their adult peers, with a loss of 1.8% of predicted per year, compared to the 0.4% predicted decline per year in the adults with asthma onset in childhood. Together, the accumulated data in children with asthma indicate that lung function is likely to be less compromised compared to adults with asthma. As such, lung function criteria for assessing asthma severity may need to be adjusted upward for children. In addition, normal or near-normal lung function in a child with severe asthma is not, in and of itself, reassuring. Many children with life-threatening asthma episodes had FEV1 values on hospital admission of ⬎ 80% of predicted. Therefore, we suggest that in order to appropriately manage the conditions of children with severe asthma, the assessment of disease severity should first take into account the frequency and nature of the symptoms affecting quality of life, the need for aggressive anti-inflammatory therapy, and a history of lifethreatening events. Ideally, lung function should be measured serially over time, with the understanding www.chestjournal.org

that the change in lung function over time may provide valuable information, especially since some children with severe asthma can achieve normal airflow levels.14 The second aim of this study was to identify the distinguishing clinical features among adults who experienced the onset of asthma either in childhood or adulthood. If disease duration is an important contributor to disease severity in all adults with asthma, then adults with childhood-onset asthma, who have the longest duration of asthma, should display the greatest impairment in lung function. This was not the case. No differences in any of the lung function measures were noted among the two groups of adults studied, regardless of disease duration. This suggests that these two subsets of asthma may indeed represent distinct forms of severe asthma, one that is slowly progressive over time, while the other appears to be associated with significant loss of lung function at, or very shortly after, the initial diagnosis is made. Burrows et al15 noted that patients with adult-onset asthma display a steep loss in lung function soon after the diagnosis is made, followed by relatively stable lung function thereafter. Thus, it appears that the duration of disease, albeit after an initial steep decline in lung function, in adult-onset asthma has less of an influence on disease severity, as measured by the impairment of lung function. The mechanisms involved in the apparent rapid decline in lung function among the adult-onset asthma patients are presently unknown. It is possible that some of these asthma patients may have had unrecognized asthma for years, with the diagnosis made only after a significant degree of lung function loss had occurred. Alternatively, adult-onset asthma may be associated with a greater degree of airway inflammation and/or more exuberant repair processes, resulting in rapid airway remodeling. Significant loss of elastic recoil, as recently described by Gelb et al,16 may also explain, at least in part, the significant reduction in airflow. Several factors must be taken into consideration before one extrapolates these findings to asthma patients at large. First, this was a retrospective, cross-sectional study. As such, it is impossible to track disease progression within each patient over time. Second, one must take into account potential selection bias. The reasons for referral to a tertiary center are numerous and complex.17,18 These patients perhaps represented a more highly selected population of patients with severe asthma than the population of persons with severe asthma in general. Third, it could also be argued that some of the subjects in the cohort studied might not have had asthma. Although this study might be limited by its study design, and all of the findings may not be easily CHEST / 124 / 4 / OCTOBER, 2003

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generalized, the data generated provide unique insights for the design of, and evaluation of longitudinal studies. Future studies should be designed to identify and characterize patients who are at greatest risk of severe asthma at disease onset as they may benefit from more aggressive therapy in an attempt to ameliorate the significant decline in lung function.

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comparison of adult-onset asthma with childhood-onset asthma relapsing in adulthood. Allergy 2000; 55:634 – 640 Bacharier LB, Mauger DT, Lemanske RF, et al. Classifying asthma severity in children: is measuring lung function helpful [abstract]? J Allergy Clin Immunol 2002; 109:S266 Fuhlbrigge AL, Kitch BT, Paltiel AD, et al. FEV1 is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 2001; 107:61– 67 Brown PJ, Greville HW, Finucane KE. Asthma and irreversible airflow obstruction. Thorax 1984; 39:131–136 Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70:171–179 Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma N Engl J Med 1998; 339:1194 –1200 Eid N, Yandell B, Howell L, et al. Can peak flow predict airflow obstruction in children with asthma? Pediatrics 2000; 105:354 –358 Burrows B, Lebowitz MD, Barbee RA, et al. Findings before diagnosis of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1991; 88:870 – 877 Gelb AF, Licuanan J, Shinar CM, et al. Unsuspected loss of elastic recoil in chronic persistent asthma. Chest 2002; 121: 715–721 Chan MTS, Leung DYM, Szefler SJ, et al. Difficult-to-control asthma: Clinical characteristics of steroid-insensitive asthma. J Allergy Clin Immunol 1998; 101:594 – 601 Bratton DL, Price M, Gavin L, et al. Impact of a multidisciplinary day program on disease and healthcare costs in children and adolescents with severe asthma: a two year follow-up study. Pediatr Pulmonol 2001; 31:177–189

Clinical Investigations