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.
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.
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.
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.
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.
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).
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)
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|
|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†|
|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†|
|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†|
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
Prevalence of Airway Remodeling (low ratio) at Age 18 in Study Members Who Reported Current Asthma at Ages
|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|
|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)|
|Prevalence of Airway Remodeling (low ratio) at Age 26 in Study Members
Reporting Current Asthma At Ages|
|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|
|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|
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)
Prevalence of Airway Remodeling (low ratio) at Age 18 in Study Members Who Showed Airway Hyperresponsiveness at Ages
|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|
|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|
|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|
|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|
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)
Prevalence of Airway Remodeling (low ratio) at Age 18 in Study Members with Symptomatic Airway Hyperresponsiveness at Ages
|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|
|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|
|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|
|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|
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).
FEV1/VC Ratio at Age 18 and Age 26
|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|
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. 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
FEV1/VC Ratio at Age 18 and Age 26
|n (% of Total)||353 (87%)||29 (6.9%)||25 (6.1%)||359 (94.2%)||11 (2.9%)||11 (2.9%)|
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|
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|
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). 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).
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)
Low Ratio at Age 18
Low Ratio at Age 26
Consistently Low Ratio
|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|
|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|
|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|
|FEV1% 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|
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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