Risk Factors for Airway Remodeling in Asthma Manifested by a Low Postbronchodilator FEV1/Vital Capacity Ratio

Abstract

Section:

Airway remodeling may lead to irreversible loss of lung function in asthma. The impact of childhood asthma, airway responsiveness, atopy, and smoking on airway remodeling was investigated in a birth cohort studied longitudinally to age 26. A low postbronchodilator ratio of forced exhaled volume in 1 second (FEV₁) to vital capacity (VC) at age 18 or 26 was used as a marker of airway remodeling. “Normal” study members with no history of asthma ever, no wheezing in the last year, and no smoking ever were used to determine sex- and age-specific reference values for this ratio. The lower limit of normal was defined as the mean ratio minus 1.96 standard deviation, delimiting the 2.5% of the normal population with the lowest FEV₁/VC ratio. A low postbronchodilator FEV₁/VC ratio was found in 7.4% and 6.4% of study members at ages 18 and age 26 and 4.6% at both assessments. Lung function was low throughout childhood in those with a consistently low postbronchodilator FEV₁/VC ratio at both ages. Those with consistently low postbronchodilator ratios also showed a greater decline in the prebronchodilator FEV₁/VC ratio from ages 9 to 26 compared with those with normal postbronchodilator ratios at both ages (males, −12% versus −6%, p < 0.0001; females, −10.5% versus −5.5%, p < 0.01). Asthma, male sex, airway hyperresponsiveness, and low lung function in childhood were each independently associated with a low postbronchodilator FEV₁/VC ratio, which in turn was associated with an accelerated decline in lung function and decreased reversibility. These data suggest that airway remodeling in asthma, as manifested by impaired lung function, begins in childhood and continues into adult life.

Keywords:

asthma; longitudinal study; pulmonary function tests; remodeling; children

Airway remodeling is defined as structural change in the airways and may be responsible for adverse outcomes in lung diseases (1). Until recently, asthma was considered an essentially reversible disorder, but chronic inflammation in asthma can also lead to structural alterations (2), including increase in smooth muscle, vascular proliferation, increase in bronchial glands, and collagen deposition (1). The most obvious way to detect airway remodeling is from pathologic and morphometric studies. However, bronchial biopsies are, at least on a large scale, impossible to obtain for ethical and technical reasons. Indirect methods to detect aspects of airway remodeling include measurement of airway wall thickness by computed tomography or positron emission tomography scans, assessment of cytokine and cell profiles collected from the lumen of the airways, or measurement of changes in lung function as airway remodeling is thought to be the primary reason for loss of reversibility of airway obstruction (1, 3).

Longitudinal studies assessing the natural history of lung diseases have shown that asthma (4, 5), smoking (6), atopy (7, 8), and airway hyperresponsiveness (AHR) (7, 8) are associated with an accelerated loss of lung function (8) and with reduced air flow rates compared with normal subjects. Several studies suggest that the changes may begin in childhood (4, 6–8). Few of these previous reports provide information regarding atopy (two of five) or airway responsiveness to bronchoconstrictor (two of five). Only one of these population-based studies included response to a β₂-agonist to characterize whether airflow limitation was reversible or persistent (4); in that study, asthma in early childhood was a risk factor for irreversible airflow limitation at age 35. However, results were not adjusted for childhood lung function, the bronchodilator challenge was only performed once, and no other objective tests such as a methacholine challenge test or a skin prick test were used to characterize asthma in these subjects.

There are several potential problems associated with the functional assessment of changes in airway caliber over time, especially from childhood into adulthood. Limited data are available regarding the relationship between lung function indices and independent variables from childhood to adulthood in a normal population (9). In children and young adults, the time taken to get air out during a forced expiration is independent of size and age (10). The ratio of forced exhaled volume in 1 second (FEV₁) to vital capacity (VC) is therefore a useful index of the state of the airway unrelated to anthropometric data (11). At least across puberty, this index of airflow is more appropriate than comparisons with predicted values of FEV₁ and VC, which are less precise because of asymmetric growth of height and lung function and different maturation stages between individuals (11, 12).

We have used a longitudinal population-based epidemiologic study to determine the prevalence of a low postbronchodilator FEV₁/VC ratio as a functional marker of remodeling. We have analyzed the impact of childhood asthma, AHR, atopy, sex, pulmonary function, and smoking as predictive factors for the development of airway remodeling so defined.

METHODS

Section:

A birth cohort of 1,037 New Zealand children born between April 1, 1972, and March 31, 1973, have been followed serially for over two decades. Respiratory questionnaires were completed at ages 9, 11, 13, 15, 18, 21, and 26 years (13).

At ages 9, 11, 13, 15, and 21 years, when methacholine challenge was also undertaken, spirometry was undertaken with a Godart water spirometer (14), whereas at age 18 and 26, spirometry was performed using an Ohio computerized spirometer (Ohio Instruments) and a Sensormedics body plethysmograph (Sensormedics Corporation, Yorba Linda, CA), respectively. A bronchodilator (albuterol 5 mg/ml nebulizer solution) was administered to all study members at ages 18 and 26.

The methacholine challenge was modified from Chai and colleagues (14, 15). Methacholine 0.025 to 25.0 mg/ml was given sequentially in 10-fold increasing concentrations, each for five breaths. Termination before the final concentration occurred if FEV₁ declined by more than 20% of baseline value. A concentration of methacholine of 8 mg/ml or less causing a 20% fall in FEV₁ (PC₂₀) was used to identify AHR. In those in whom a methacholine challenge was not safe or practical to perform, an increase in FEV₁ of 10% or more after albuterol was regarded as approximately equivalent to a PC₂₀ of 8 mg/ml or less (16). This occurred in 14 subjects at age 9, and in 7, 4, and 3 subjects at ages 11, 13, and 15, respectively.

Skin Prick Test

Atopic status was assessed at ages 13 and 21 by skin prick tests to 11 common allergens (17). The response of a wheal diameter at least 2 mm greater than that resulting from the negative control was regarded as indicating atopy.

The research ethics committee of the Otago Hospital Board granted ethical approval. Study members gave informed, signed consent before participating in each assessment from age 18, as did their parents in earlier assessments until the study member was aged 18.

Definition and Determination of Airway Remodeling

Study members with no previous history of asthma ever, no history of smoking ever, and no reported wheeze within the previous year were used to determine normal values (18). Age- and sex-specific lower limits of “normal” postbronchodilator FEV₁/VC ratio at age 18 and 26 were used to assess the presence of airway remodeling, calculated as the mean ratio minus 1.96 SD, delimiting 2.5% of the normal population with the lowest FEV₁/VC ratios.

Statistical Analysis

Associations between variables were assessed using the chi-square test, t test, paired t test, and Pearson correlation coefficient. The impact of asthma at age 9, FEV₁ (% predicted) at age 9, AHR at age 9, atopy at age 13, and smoking from age 15 on the development of a low postbronchodilator FEV₁/VC ratio was assessed by multiple logistic regression. Three different outcome variables were tested: a low postbronchodilator FEV₁/VC ratio at age 18, or at age 26, and a consistently low postbronchodilator FEV₁/VC ratio at both ages 18 and 26. Statistical analyses were performed with the Statistical Package for Social Sciences (SPSS-PC 10.0.5) (SPSS Inc., Chicago, IL).

RESULTS

Section:

Study members participating at ages 18 and 26 were comparable with respect to data collected at age 9 for sex, height, weight, the presence of asthma, hayfever, lung function, and hyperresponsiveness to methacholine to those who did not participate at ages 18 and 26.

The mean postbronchodilator FEV₁/VC ratios of the reference study members differed between sexes at both age 18 and age 26 (all comparisons p < 0.0001). Therefore, separate age- and sex-specific lower limits of a normal postbronchodilator FEV₁/VC ratio were determined (Table 1)

TABLE 1. Postbronchodilator fev₁/vc ratio (%, mean ± sd) by sex at ages 18 and 26 in reference study members and in groups defined by diagnosis, symptoms, and airway hyperresponsiveness at different ages
	Males			Females
	FEV₁/VC Ratio  at age 18  (%, mean ± SD)	FEV₁/VC Ratio  at age 26  (%, mean ± SD)	FEV₁/VC Ratio  at age 18  (%, mean ± SD)	FEV₁/VC Ratio  at Age 26  (%, mean ± SD)
Reference study members	87.6 ± 5.2	84.4 ± 5.2	92.4 ± 5.3	89.5 ± 5.2
Lower limit of normal  (mean − 1.96 SD)	77.5	74.5	82.2	79.4
Age 9
No significant wheeze	88.8 ± 6.0	83.7 ± 5.9	91.6 ± 5.5	87.0 ± 5.4
Significant wheeze	86.3 ± 7.4	80.8 ± 7.4	89.2 ± 7.2	83.7 ± 7.3
AHR*	85.9 ± 7.7	79.8 ± 6.9	87.6 ± 8.1	82.3 ± 8.2
AHR + wheeze	84.8 ± 8.5	80.0 ± 7.3	86.8 ± 8.5	80.9 ± 8.3
Asthma	84.7 ± 8.5^†	78.4 ± 7.7^†	87. 5± 9.3^†	82.3 ± 6.6^†
Age 15
No significant wheeze	89.2 ± 5.9	83.6 ± 5.8	91.8 ± 5.4	87.2 ± 5.2
Significant wheeze	86.3 ± 7.3	81.7 ± 7.1	89.2 ± 6.7	84.1 ± 6.7
AHR	83.8 ± 9.7	77.4 ± 8.4	86.2 ± 9.2	80.3 ± 8.8
AHR + wheeze	82.1 ± 9.4	75.8 ± 8.1	86.1 ± 9.4	79.8 ± 9.4
Asthma	78.4 ± 7.7^†	79.9 ± 7.0^†	88.7 ± 7.4^†	82.4 ± 7.7^†
Age 21
No significant wheeze	89.1 ± 5.9	83.9 ± 5.9	91.9 ± 5.3	87.4 ± 5.1
Significant wheeze	87.3 ± 7.2	82.1 ± 6.5	90.0 ± 6.4	85.1 ± 6.4
AHR	84.0 ± 8.0	78.6 ± 8.1	87.4 ± 5.8	82.2 ± 6.7
AHR + wheeze	83.9 ± 8.7	78.8 ± 8.0	86.6 ± 5.8	81.7 ± 6.9
Asthma	75.3 ± 7.7^†	79.4 ± 6.9^†	89.3 ± 6.8^†	83.1 ± 7.1^†

^* PC₂₀ ⩽ 8 mg/ml or bronchodilator response ⩾ 10%.

^† p < 0.001 comparing study members with asthma with those with no significant wheeze at the same age (multivariate analysis of variance).

Definition of abbreviations : AHR = airway hyperresponsiveness; VC = vital capacity.

Measurements given as mean ± SD.

. At age 18, normal data were determined using 189 males and 139 females, and at age 26, 144 males and 123 females. The impact of significant wheeze, AHR, significant wheeze with AHR, and asthma at ages 9, 15, and 21 years on the mean sex-specific postbronchodilator FEV₁/VC ratios at age 18 and 26 is also shown in Table 1. Mean ratios at 18 and 26 are consistently lower in study members with asthma compared with those with no significant wheeze, within each sex, at ages 9, 15, and 21 (p < 0.001 for all comparisons by multivariate analysis of variance).

A postbronchodilator FEV₁/VC ratio below the lower limits of normal was found in 62 of 839 (7.4%) and 58 of 913 (6.4%) study members assessed at ages 18 and 26, respectively. Males were more likely to have a lower ratio than females both at age 18 (45 males [10.3%], 17 females [4.2%], p = 0.0006) and at age 26 (41 males [8.8%], 17 females [3.8%], p = 0.002). Of 788 study members who performed the test at both ages, 36 (4.6%) had a low ratio at both surveys (25 males [6.1%], 11 females [2.9%], p < 0.03).

The sex-specific associations between reported current diagnosed asthma at different ages in childhood, adolescence, and young adulthood and low postbronchodilator FEV₁/VC ratio at age 18 and age 26 are shown in Table 2

TABLE 2. Prevalence of airway remodeling (defined as low postbronchodilator fev₁/vc ratio) at age 18 or age 26 among study members reporting diagnosed asthma at each assessment compared with all others at that assessment, by sex
	Prevalence of Airway Remodeling (low ratio) at Age 18 in  Study Members Who Reported Current Asthma at Ages
	9	11	13	15	18
Males
Current asthma, %	27.8  (10/36)	22.8  (13/57)	28.6  (16/56)	22.2  (16/72)	24.1  (15/62)
All others, %	8.2  (28/338)	8.8  (28/318)	6.9  (20/288)	6.6  (25/376)	8.0  (30/373)
p	< 0.0001	0.002	< 0.0001	< 0.0001	< 0.0001
Females
Current asthma, %	9.1  (2/22)	11.5  (3/26)	9.1  (3/33)	9.3  (5/54)	9.8  (6/61)
All others, %	3.6  (11/306)	3.7  (11/297)	3.9  (11/279)	3.5  (12/343)	3.2  (11/343)
p	0.20	0.09	0.20	0.05	0.02
	Prevalence of Airway Remodeling (low ratio) at Age 26 in Study Members  Reporting Current Asthma At Ages
	9	11	13	15	18	21	26
Males
Current asthma, %	33.3  (12/36)	21.7  (13/60)	27.6  (16/58)	18.1  (23/127)	23.0  (14/61)	21.4  (15/70)	22.0  (20/91)
All others, %	7.1  (26/350)	7.5  (24/321)	5.6  (16/285)	4.6  (35/750)	7.1  (25/352)	6.2  (24/386)	5.6  (21/375)
p	< 0.0001	0.001	< 0.0001	< 0.0001	< 0.0001	< 0.0001	< 0.0001
Females
Current asthma, %	13.0  (3/23)	13.3  (4/30)	9.1  (3/33)	12.7  (7/55)	10.3  (6/58)	9.5  (7/74)	10.5  (9/86)
All others, %	2.7  (9/329)	2.5  (8/318)	2.4  (7/294)	2.7  (10/374)	3.0  (10/333)	2.7  (10/364)	2.2  (8/361)
p	0.008	0.002	0.03	< 0.0001	0.009	0.006	< 0.0001

The absolute numbers in parentheses are the number with a low ratio at 18 or 26 per number at risk.

. The prevalence of current asthma at ages 9, 11, 13, 15, 18, 21, and 26 was, for males, 8.9%, 14.8%, 15.8%, 15.5%, 14.0%, 14.5%, and 18.4%, and for females, was 6.2%, 8.1%, 9.9%, 12.9%, 15.5%, 17.7%, and 19.8%, and for both sexes combined was 7.6%, 11.6%, 12.9%, 14.3%, 14.6%, 16.0%, and 19.0%, respectively. Among males, 18–33% of current diagnosed subjects with asthma at all ages had a low postbronchodilator FEV₁/VC ratio at ages 18 and 26. Fewer females with asthma (9–13%) had a low ratio compared with males with asthma (p = 0.05 at age 13). The cumulative proportion of study members with a low postbronchodilator FEV₁/VC ratio at age 26 who reported current asthma at some time during the study increased from 36% at age 9 to 66% at age 26 (p < 0.0003).

A low postbronchodilator FEV₁/VC ratio at age 18 or age 26 in both sexes was more common among those with AHR at different ages with or without symptoms (Table 3)

TABLE 3. Prevalence of airway remodeling (defined as low postbronchodilator fev₁/vc ratio) at age 18 or age 26 among study members who showed airway hyperresponsiveness (pc₂₀ ⩽ 8 mg/ml or bronchodilator response ⩾ 10%) with or without symptoms at each assessment compared with all others at that assessment, by sex
	Prevalence of Airway Remodeling (low ratio) at Age 18 in  Study Members Who Showed Airway Hyperresponsiveness at Ages
	9	11	13	15
Males
Airway hyperresponsiveness, %	43.2	38.9	42.0	27.9
All others, %	16.9	11.0	8.3	7.3
p	< 0.0001	< 0.0001	< 0.0001	< 0.0001
Females
Airway hyperresponsiveness, %	46.2	30.8	36.4	40.0
All others, %	14.2	8.3	5.6	6.4
p	0.002	0.006	< 0.0001	< 0.0001
	Prevalence of Airway Remodeling (low ratio) at Age 26 in Study Members  Reporting Airway Hyperresponsiveness at Ages
	9	11	13	15	21
Males
Airway hyperresponsiveness, %	41.7	38.7	40.7	36.8	28.6
All others, %	17.2	11.2	9.4	7.0	6.5
p	< 0.0001	< 0.0001	< 0.0001	< 0.0001	< 0.0001
Females
Airway hyperresponsiveness, %	54.5	27.3	50.0	30.8	26.7
All others, %	13.2	8.2	5.6	6.6	7.5
p	< 0.0001	0.03	< 0.0001	0.001	0.008

. Even among subjects who had never reported asthma, AHR was still associated with a low ratio. At age 18, 3 of 22 subjects (14%) with AHR but no asthma had a low ratio compared with 9 of 419 (2%) without AHR or asthma (p < 0.0001). At age 26, findings were similar (2 of 11 [18%] versus 7 of 397 [2%], p < 0.0001) (not tabulated).

Symptomatic AHR, proposed by Toelle and coworkers (19) as an appropriate definition of asthma for epidemiologic studies, was more prevalent in study members with a low ratio, in both sexes and at both ages 18 and 26 (Table 4)

TABLE 4. Prevalence of airway remodeling (defined as low postbronchodilator fev₁/vc ratio) at age 18 or age 26 among study members with symptomatic airway hyperresponsiveness (pc₂₀ ⩽ 8 mg/ml or bronchodilator response ⩾ 10% in association with current significant wheeze) at each assessment compared with all others at that assessment, by sex
	Prevalence of Airway Remodeling (low ratio) at Age 18 in Study Members with Symptomatic Airway Hyperresponsiveness at Ages
	9	11	13	15
Males
Symptomatic airway  hyperresponsiveness, %	28.2	34.4	34.6	38.7
All others, %	7.9	8.0	8.2	8.9
p	< 0.0001	< 0.0001	< 0.0001	< 0.0001
Females
Symptomatic airway  hyperresponsiveness, %	12.5	14.3	20.0	20.8
All others, %	3.1	3.4	3.0	3.0
p	0.01	0.02	0.001	< 0.0001
	Prevalence of Airway Remodeling (low ratio) at Age 26 in Study Members with Symptomatic Airway Hyperresponsiveness at Ages
	9	11	13	15	21
Males
Symptomatic airway  hyperresponsiveness, %	30.7	30.3	25.9	45.2	29.6
All others, %	7.0	6.6	7.5	6.6	6.9
p	< 0.0001	< 0.0001	0.002	< 0.0001	< 0.0001
Females
Symptomatic airway  hyperresponsiveness, %	14.3	9.1	18.8	16.7	15.4
All others, %	1.9	2.8	1.8	2.6	3.1
p	< 0.0001	0.11	< 0.0001	< 0.0001	0.002

. The proportion of symptomatic AHR in childhood with a low postbronchodilator FEV₁/VC ratio was greater in males when compared with females, although the difference between the sexes reached formal statistical significance only at age 15 (p = 0.049).

We examined tracking of FEV₁/VC ratios from age 9 to age 26. Both the prebronchodilator FEV₁/VC ratio from 9 to 26 (Pearson correlation coefficient, r = 0.662) and the postbronchodilator FEV₁/VC ratio from age 18 to age 26 (r = 0.787) showed clear evidence of tracking. In general, study members with a low ratio maintained a low ratio. However, because of the age-specific definition of the normal range of postbronchodilator FEV₁/VC ratio, some shifted from “low” to “normal” and vice versa between ages 18 and 26. Study members were therefore grouped as followed: those with a normal postbronchodilator FEV₁/VC ratio at both ages 18 and 26 (consistently normal), those with a change in postbronchodilator FEV₁/VC ratio status between age 18 and age 26 from normal to low or low to normal (variable), and those with a low postbronchodilator FEV₁/VC ratio at both ages 18 and 26 (consistently low).

Table 5

TABLE 5. Clinical characteristics of subjects according to postbronchodilator fev₁/vc ratio status at age 18 and age 26
	FEV₁/VC Ratio at Age 18 and Age 26
	Males							Females
	Consistently  Normal Ratio	Variable	Consistently  Low Ratio	p	Consistently  Normal Ratio	Variable	Consistently  Low Ratio	p
n  (% of Total)	353  (87%)	29  (6.9%)	25  (6.1%)		359  (94.2%)	11  (2.9%)	11  (2.9%)
Asthma reported ever  during the study	30%	41%	68%	< 0.0001	30%	45%	82%	< 0.0001
Onset of asthma, year	10.7 ± 6.8	10.6 ± 6.8	5.5 ± 5.9	< 0.0001	12.9 ± 9.2	13.1 ± 6.7	8.4 ± 6.6	0.18
Family history of  asthma or hayfever	41%	52%	54%	0.26	46%	67%	54%	0.40
Asthma at age 9	8%	9%	43%	< 0.0001	7%	10%	29%	< 0.0001
AHR at age 9*	17%	23%	55%	< 0.0001	14%	33%	57%	< 0.0001
Wheeze and AHR  at age 9*	9%	14%	41%	< 0.0001	9%	22%	43%	0.008
IgE at age 11^†	4.8 ± 1.6	5.0 ± 1.9	5.4 ± 1.4	0.37	4.6 ± 1.5	5.8 ± 1.6	5.6 ± 0.5	0.05
IgE at age 21^†	3.9 ± 1.8	4.1 ± 1.7	4.7 ± 1.6	0.13	3.7 ± 1.7	4.4 ± 1.9	5.0 ± 2.1	0.03
Atopy at age 13 (at least  one SPT ⩾ 2 mm)	54%	47%	68%	0.30	37%	38%	50%	0.49
House dust mite at  age 13 (⩾ 2 mm)	35%	47%	59%	0.02	25%	13%	38%	0.72
Cat at age 13 (⩾ 2 mm)	16%	18%	23%	0.42	12%	13%	25%	0.30
Atopy at age 21 (at least  one SPT ⩾ 2 mm)	67%	81%	78%	0.10	62%	60%	90%	0.11
House dust mite at  age 21 (⩾ 2 mm)	57%	73%	78%	0.01	51%	50%	90%	0.03
Cat at age 21 (⩾ 2 mm)	28%	38%	48%	0.02	25%	40%	50%	0.05
Smoker at age 26^‡	31%	59%	36%	0.08	43%	82%	64%	0.02
Ever used asthma  medication at age 26	29%	41%	56%	< 0.0001	31%	45%	72%	< 0.0001
Used inhaled steroids	9%	17%	36%	< 0.0001	11%	27%	55%	< 0.0001

^* AHR (PC₂₀ ⩽ 8 mg/ml or bronchodilator response ⩾ 10%).

^† Natural logarithmic values provided.

^‡ More than 10 cigarettes daily for at least 1 year at age 15 or older.

Definition of abbreviations: AHR = airway hyperresponsiveness; IgE = immunoglobulin E; SPT = skin prick tests; VC = vital capacity.

Measurements given as mean ± SD.

shows clinical characteristics of these three groups by sex. Those with consistently low ratios more often had asthma, AHR, and symptomatic AHR. The age of onset of asthma was earlier in males with consistently low ratios when compared with the two other groups. This trend was also seen in females but was not statistically significant. Allergy to house dust mite and cat at age 21 was significantly associated with a low postbronchodilator FEV₁/VC ratio in both sexes, whereas IgE values were significantly higher in only females. Smoking was significantly more prevalent only among females with a low ratio at age 26 when compared with females with a normal ratio at age 26 (p = 0.04). A positive history of asthma or hayfever was not associated with a low ratio nor were most skin tests at age 13. The distribution of asthma and the use of asthma medication and of inhaled steroid differed among the three groups (Table 5). Fewer patients with asthma among those with normal ratios received inhaled steroid during the study period when compared with those with low ratios (73 of 216 [34%] versus 15 of 25 [56%], p = 0.02).

We examined lung function data at all ages at which it was measured from age 9 to age 26. The sex-specific prebronchodilator FEV₁/VC ratios from age 9 to age 26 in the three groups are shown in Figure 1

Figure 1. Mean (95% confidence interval) FEV₁/VC ratio (%) before bronchodilator from age 9 to age 26 by sex. Study members with a consistently normal postbronchodilator FEV₁/VC ratio at both ages 18 and 26 (dashed line). Study members with a change in FEV₁/VC ratio from age 18 to age 26 (dotted line). Study members with a consistently low postbronchodilator FEV₁/VC ratio at both age 18 and 26 (solid line).

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. The prebronchodilator FEV₁/VC ratio was lower at age 9 in the consistently low postbronchodilator group when compared with the consistently normal group both in males (76% versus 88%, p < 0.0001) and in females (74% versus 90%, p < 0.0001). In both males and females, a more pronounced decline in the prebronchodilator FEV₁/VC ratio from age 9 to 26 was found between these groups, in males (−12% versus −6%, p < 0.0001) and in females (−10.5% versus −5.5%, p < 0.01), respectively.

Spirometry values for each of the three groups are shown in Table 6

TABLE 6. Lung function of subjects according to postbronchodilator fev₁/vc ratio at age 18 and age 26
		FEV₁/VC Ratio at Age 18 and Age 26
		Males							Females
		Consistently  Normal Ratio	Variable	Consistently  Low Ratio	p	Consistently  Normal Ratio	Variable	Consistently  Low Ratio	p
n (% of Total)		353 (87%)	29 (6.9%)	25 (6.1%)		359 (94.2%)	11 (2.9%)	11 (2.9%)
FEV₁% predicted  at age 9	(l)	99 ± 11	91 ± 12	91 ± 12	< 0.001	99 ± 10	98 ± 10	86 ± 14	0.03
VC percentage predicted  at age 9	(l)	99 ± 10	99 ± 12	105 ± 14	0.02	100 ± 10	104 ± 10	104 ± 11	0.10
FEV₁% predicted  at age 26	(l)	99 ± 11	88 ± 13	82 ± 16	< 0.0001	100 ± 12	90 ± 11	83 ± 19	< 0.0001
VC percentage predicted  at age 26	(l)	100 ± 11	101 ± 13	104 ± 17	0.05	101 ± 12	99 ± 14	109 ± 17	0.08
ΔFEV₁* at age 18	(l)	0.16 ± 0.16	0.25 ± 0.21	0.57 ± 0.41	< 0.0001	0.11 ± 0.15	0.11 ± 0.15	0.20 ± 0.18	0.09
ΔFEV₁ at age 18	(%)	3.6 ± 4	6.3 ± 5	18 ± 16	< 0.0001	3.3 ± 5	4.1 ± 5	8 ± 11	< 0.0001
ΔFEV₁ at age 26	(l)	0.19 ± 0.22	0.30 ± 0.25	0.46 ± 0.51	< 0.0001	0.14 ± 0.13	0.0 ± 0.38	0.22 ± 0.22	0.70
ΔFEV₁ at age 26	(%)	4.1 ± 5	7.3 ± 7	14 ± 19	< 0.0001	4.1 ± 5	1.5 ± 13	8 ± 11	< 0.0001

^* ΔFEV₁ expressed in both absolute values (L) and as a percentage of the prebronchodilator FEV₁.

Definition of abbreviations: ΔFEV₁ = difference between pre- and postbronchodilator FEV₁; VC = vital capacity.

Measurements given as mean ± SD. Prevalences given as numbers and percentage in parenthesis.

by sex. Those in the consistently low group had lower FEV₁ (% predicted) and males had higher VC as percent predicted at age 9 and age 26. A significantly greater absolute and percentage increase in FEV₁ postbronchodilator at ages 18 and 26 occurred in males with low ratios but not in females.

Males in the consistently low ratio group had a larger change in the FEV₁/VC ratio after bronchodilator at age 18 when compared with those with a consistently normal ratio (8.0% versus 2.3%, p < 0.0001) and at age 26 (4.2% versus 2.5%, p = 0.002) (Figure 2)

Figure 2. Change (95% confidence interval) in the FEV₁/VC ratio (%) after bronchodilator among study members with a consistently low postbronchodilator FEV₁/VC ratio at ages 18 and 26 (solid bars) and study members with consistently normal FEV₁/VC ratio at both assessments (open bars) by sex.

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. A statistically significant difference was not seen in females. In males, the FEV₁/VC response to albuterol decreased significantly from age 18 to age 26 in those with consistently low ratios (p = 0.02), whereas the baseline lung function expressed as the FEV₁ (% predicted) was similar (80% versus 82% predicted, respectively).

Figure 3

Figure 3. Change (95% confidence interval) in FEV₁/VC ratio (%) after bronchodilator among ever asthmatics with consistently low postbronchodilator FEV₁/VC ratios at ages 18 and 26 (solid bars) and ever asthmatics with consistently normal FEV₁/VC ratios at both surveys (open bars), by treatment with inhaled steroids.

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shows change in the FEV₁/VC ratio after bronchodilator in study members with asthma by use of inhaled steroid treatment ever. Among study members with asthma with consistently low ratios, the baseline FEV₁ (% predicted) was lower in those who had received inhaled steroids compared with those who were not given inhaled steroids, at age 18 (73 ± 20% [mean ± SD] versus 88 ± 10%, p = 0.04) and at age 26 (75 ± 18% versus 89 ± 14%, p = 0.04). The change in FEV₁/VC ratio following albuterol decreased between ages 18 and 26 in those receiving inhaled steroid, in both sexes combined (10.2 ± 5% at age 18, 5.5 ± 5% at age 26, p = 0.02), and in males (13.8 ± 5% at age 18, 7.7 ± 5% at age 26, p = 0.04). Females with asthma were not analyzed separately because of the small numbers. There were no statistically significant differences between smokers and nonsmokers in the changes of the FEV₁/VC ratio in response to albuterol from age 18 and age 26 in study members with asthma using inhaled steroids (p = 0.67).

A multiple logistic regression (forced entry) was performed, including sex, diagnosed asthma at age 9, lung function at age 9, AHR at age 9, atopy at age 13 (included as any allergen positive, cat allergy, or house dust mite allergy), and heavy smoking (over 10 cigarettes per day for at least a year) from age 15 or later as independent variables. Three outcome variables were used: a low postbronchodilator FEV₁/VC ratio at age 18, a low postbronchodilator FEV₁/VC ratio at age 26, and a consistently low postbronchodilator FEV₁/VC ratio at both ages 18 and 26 (Table 7)

TABLE 7. Adjusted odds ratios for risk factors and 95% confidence interval associated with low postbronchodilator fev₁/vc ratio at age 18, low postbronchodilator fev₁/vc ratio at age 26, and low postbronchodilator fev₁/vc ratio at both ages 18 and 26
	Low Ratio at Age 18					Low Ratio at Age 26
	OR	95% CI	p	OR	95% CI	p	OR	95% CI	p
Asthma at age 9	1.8	(0.7–4.7)	0.18	3.0	(1.1–8.3)	0.03	3.4	(1.2–9.8)	0.03
AHR* at age 9	2.2	(1.0–5.1)	0.05	2.4	(1.0–6.1)	0.06	3.0	(1.1–8.7)	0.04
Sex, male	2.3	(1.1–4.7)	0.02	3.7	(1.6–8.6)	0.001	2.8	(1.1–7.2)	0.03
Atopy at age 13, ⩾ 2 mm
At least one positive	1.1	(0.5–2.1)	0.87	0.6	(0.3–1.4)	0.25	0.9	(0.3–2.3)	0.78
Cat	0.5	(0.2–1.4)	0.20	0.4	(0.1–1.3)	0.13	0.4	(0.1–1.4)	0.15
House dust mite	1.2	(0.6–2.4)	0.68	0.9	(0.4–2.0)	0.75	1.0	(0.4–2.6)	0.95
Heavy smoking^†	1.5	(0.8–3.0)	0.22	1.2	(0.6–2.7)	0.58	1.5	(0.6–3.7)	0.23
FEV_1% predicted at age 9  (per 10% decrease)	1.40	(1.1–2.0)	0.02	1.75	(1.3–1.9)	0.001	1.49	(1.0–2.2)	0.04

^* PC₂₀ ⩽ 8 mg/ml or bronchodilator response ⩾ 10%.

^† More than 10 cigarettes daily for at least 1 year at age 15 or later.

Definition of abbreviations: AHR = airway hyperresponsiveness; CI = confidence interval; OR = odds ratio; VC = vital capacity.

. There were no significant interactions and no substantial differences in the odds ratios of the other variables when different measures of allergy were included in the equation. Male sex, AHR at age 9, and low lung function at age 9 were each independently associated with low postbronchodilator FEV₁/VC ratios at ages 18 and 26. Asthma at age 9 was significantly associated with a low ratio at age 26 or at both ages 18 and 26, but did not achieve significance related to a low ratio at age 18 alone. Skin test responses (to any allergen or to mite or cat) and heavy smoking were not significant risk factors for low ratios at either age.

DISCUSSION

Section:

We have determined the prevalence of an impaired postbronchodilator FEV₁/VC ratio in study members with asthma compared with normal values from healthy control study members in a longitudinal epidemiologic study. Failure to achieve a ratio within the normal range despite bronchodilator suggests the presence of structural abnormalities in the airway wall preventing full reversibility. Airway remodeling defined in this way occurred in 7.4% and 6.4% of the cohort at ages 18 and 26 years and in up to one-third of patients with asthma. Remodeling was associated with male sex, low lung function, asthma, and AHR in childhood but not with smoking and atopy. A low postbronchodilator ratio at age 18 and age 26 was also associated with an early onset of asthma and a greater decline in FEV₁ (% predicted) and in the FEV₁/VC ratio from age 9 to age 26. Furthermore, subjects with asthma and males with asthma in particular with low ratios showed a decreased response to a β₂-agonist at age 26 compared with age 18 despite treatment with inhaled steroids.

There is limited information on how best to describe lung function and its relationship to independent variables from childhood into adulthood. Several issues have to be considered. Body and lung growths differ between boys and girls and differ with age. At puberty, lung function development is delayed compared with height (11) and differs because of different maturation onsets and stages (20). The FEV₁/VC ratio, which was unrelated to anthropometric data and age in this study (data not shown) and other studies (10), for reasons mentioned in the introduction, allows much tighter comparisons between groups than does FEV₁ (% predicted) (12). We therefore considered the FEV₁/VC ratio as the best available tool to measure changes in lung function across childhood into adulthood. We defined normal study members to determine normal values of lung function (18, 21) and selected the mean minus 1.96 SD as a cutoff, delimiting 2.5% of the normal population with the lowest FEV₁/VC ratios as defining an abnormal result (22). This definition uses “super normal” study members rather than the whole cohort to define normal values, and the cutoff is somewhat arbitrary but widely accepted in biologic studies. Hence, some “healthy” study members will fall below this cut point.

In agreement with others studies (11, 20), the mean FEV₁/VC ratio was consistently higher among females than males and decreased significantly from late adolescence into adult life. This necessitates the use of age- and sex-specific FEV₁/VC ratio data in analysis.

A consistently low postbronchodilator FEV₁/VC ratio was present in 4.6% of the total population. As postbronchodilator airflow limitation was persistent over an eight-year period, it is reasonable to assume that it was permanent. Males were more likely to have a low ratio than females. The great majority of study members with a low ratio had, at some point, reported diagnosed asthma. Therefore, the difference in prevalence of remodeling between the sexes is likely to be explained by the higher prevalence of asthma in boys during childhood compared with girls. A real sex difference in the propensity for developing a low postbronchodilator FEV₁/VC ratio may also exist as about one of four males with asthma developed a consistently low ratio, compared with 1 in 10 females with asthma. These findings suggest that male sex is associated with a worse outcome of asthma in terms of lung function even though most longitudinal studies, including our study, have found a greater likelihood of persistence of childhood asthma in females. The mean age of onset of wheezing in females with asthma was later than in males, and therefore, the mean duration of disease is correspondingly shorter. This may also partly account for the sex differences in the prevalence of remodeling.

We found strong evidence for tracking of lung function with age, confirming previous reports (8, 23). Study members with a consistently low postbronchodilator FEV₁/VC ratio already had a lower FEV₁ (% predicted) and a lower FEV₁/VC ratio when first assessed at age 9. We cannot address the timing of divergence in lung function between the groups, as lung function measurements were not made before age 9 in this cohort, but divergence in lung function indices was evident then and continued throughout childhood and adolescence. Other studies suggest that genetic predisposition or early disease modifies and modulates lung function in early infancy or at birth (24, 25).

Males with consistently low postbronchodilator FEV₁/VC ratios were significantly different in several aspects from males with consistently normal ratios. These differences were less evident in females, either because of increased susceptibility of males or simply because of statistical power. Males had an accelerated decline in FEV₁ predicted and in the FEV₁/VC ratio from age 9 to age 26. They were more reversible to albuterol in terms of both absolute FEV₁ and the FEV₁/VC ratio, but reversibility decreased between age 18 and age 26. These results are in agreement with the hypothesis that airway remodeling is a dynamic process that is active and progresses over time. In another longitudinal population-based study, Strachan and colleagues (4) followed subjects from birth to age 35. They recorded lung function after albuterol inhalation once at age 35 and found that subjects with wheezing or asthma persisting into adulthood had significantly lower FEV₁/VC ratios both before and after bronchodilator compared with normal subjects. Our data suggest early and progressive lung damage, already present at age nine, with a slow progression from a reversible to a less reversible state (1).

The response to albuterol decreased between age 18 and age 26 in study members with asthma, particularly those treated with inhaled steroids. Use of inhaled steroids was clearly a marker of disease severity, as the FEV₁ (% predicted) was lower in these subjects. On the other hand, smoking seemed not to alter reversibility, although the limited sample size for this analysis calls for some reservation in interpretation. Whether the study members in our cohort could be prevented from developing airflow obstruction and maintaining reversibility by more intensive antiinflammatory therapy cannot be determined, as we did not control the amount of inhaled steroid given. At present, there is no direct evidence to demonstrate that early use of antiinflammatory therapy will reduce the persistence of airway inflammation or prevent airway remodeling (3). With these reservations in mind, our findings probably reflect “real-world” treatment of asthma over the last two decades.

AHR was associated with a low postbronchodilator FEV₁/VC ratio. In a previous article from this cohort, Sherrill and colleagues showed that AHR was associated with a worsening FEV₁/VC ratio over time (7). AHR is a central feature of asthma but can be present before the diagnosis of asthma (26). Laprise and coworkers found increased subepithelial fibrosis and numbers of cytokines in subjects with asymptomatic AHR before asthma had developed (27). Rather than considering AHR as a marker of asthma, it might be regarded as a parallel pathologic process (28).

The presence of atopy was not a significant risk factor for airway remodeling, despite a trend for more atopy among study members with a persistent low ratio. As atopy was common in all groups, a large number of subjects would be required to show a significant difference between groups.

We acknowledge that lung function measurement is an indirect measurement of airway remodeling. However, the low postbronchodilator FEV₁/VC ratio has qualities and correlations that suggest that it is useful as a marker of airway remodeling. Although bronchial biopsy to verify airway remodeling and an oral corticosteroid trial to assess reversibility would have been preferable, for obvious reasons these measurements were not possible in an epidemiologic study. Our observations support the concept of a progressive loss of lung function through childhood with less reversible airway narrowing that progresses toward irreversible airway narrowing. This lends some support to the “Dutch hypothesis” (29) that a history of asthma or AHR makes subjects especially susceptible to a more rapid decline of ventilatory function.

In conclusion, airway “remodeling” in adolescents and young adults, as defined by a low postbronchodilator FEV₁/VC ratio, was associated with male sex, asthma, low lung function in earlier childhood, and AHR. A consistently low ratio at two ages 8 years apart identified subjects at risk for an accelerated decline in lung function. We suggest that a low postbronchodilator FEV₁/VC ratio can be used as a marker of airway remodeling in epidemiologic studies and that airway remodeling begins in early childhood.

The authors thank Air New Zealand; Dr. Phil Silva, founder of the study; and the study members and their families for their ongoing commitment and support.

The Dunedin Multidisciplinary Health and Development Research Unit is supported by the Health Research Council of New Zealand. The respiratory program of research has been funded by the Health Research Council, the Otago Medical Research Foundation, and the Asthma Foundation of New Zealand.

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Correspondence and requests for reprints should be addressed to Dr. Malcolm R. Sears, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. E-mail: [email protected]

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Risk Factors for Airway Remodeling in Asthma Manifested by a Low Postbronchodilator FEV₁/Vital Capacity Ratio

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Risk Factors for Airway Remodeling in Asthma Manifested by a Low Postbronchodilator FEV₁/Vital Capacity Ratio