This Article Abstract Full Text (PDF) Online Data Supplement Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rasmussen, F. Articles by Sears, M. R. Search for Related Content PubMed PubMed Citation Articles by Rasmussen, F. Articles by Sears, M. R.

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

A Longitudinal Population Study from Childhood to Adulthood

Firestone Institute for Respiratory Health, St. Joseph's Hospital and McMaster University, Hamilton, Ontario, Canada; and Departments of Medicine and Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

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: searsm{at}mcmaster.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
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.

Key Words: asthma • longitudinal study • pulmonary function tests • remodeling • children

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
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 ß₂-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

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
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

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
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, 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).

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. 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).

View this table: [in this window] [in a new window]   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

View this table: [in this window] [in a new window]   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

Table 5 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).

View larger version (18K): [in this window] [in a new window]   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).

View larger version (27K): [in this window] [in a new window]   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.

View larger version (30K): [in this window] [in a new window]   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.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

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.

	Acknowledgments

 
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.

	FOOTNOTES

 
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form August 1, 2001; accepted in final form March 6, 2002

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 

1. Elias JA. Airway remodeling in asthma: unanswered questions. Am J Respir Crit Care Med 2000;161:168S–171S.
2. Roche W. Inflammatory and structural changes in the small airways in bronchial asthma. Am J Respir Crit Care Med 1998;157:191S–194S.
3. Pedersen S. Why does airway inflammation persist? Is it failure to treat early? Am J Respir Crit Care Med 2000;161:182S–185S.
4. Strachan DP, Griffiths JM, Johnston ID, Anderson HR. Ventilatory function in British adults after asthma or wheezing illness at ages 0–35. Am J Respir Crit Care Med 1996;154:1629–1635.[Abstract]
5. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194–1200.[Abstract/Free Full Text]
6. Gold DR, Wang X, Wypij D, Speizer FE, Ware JH, Dockery DW. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996;335:931–937.[Abstract/Free Full Text]
7. Sherrill D, Sears MR, Lebowitz MD, Holdaway MD, Hewitt CJ, Flannery EM, Herbison GP, Silva PA. The effects of airway hyperresponsiveness, wheezing, and atopy on longitudinal pulmonary function in children: a 6-year follow-up study. Pediatr Pulmonol 1992;13:78–85.[Medline]
8. Grol MH, Gerritsen J, Vonk JM, Schouten JP, Koeter GH, Rijcken B, Postma DS. Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years: a 30-year follow-up study. Am J Respir Crit Care Med 1998;160:1830–1837.[Abstract/Free Full Text]
9. Quanjer PH, Stocks J, Polgar G, Wise M, Karlberg J, Borsboom G. Compilation of reference values for lung function measurements in children. Eur Respir J 1989;4:184S–261S.
10. Quanjer PH, Borsboom GJ, Brunekreff B, Zach M, Forche G, Cotes JE, Sanchis J, Paoletti P. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 1995; 19:135–142.[Medline]
11. Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG J. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol 1993;15:75–88.[Medline]
12. Sears MR, Burrows B, Herbison GP, Flannery EM, Holdaway MD. Atopy in childhood. III. Relationship with pulmonary function and airway responsiveness. Clin Exp Allergy 1993;23:957–963.[CrossRef][Medline]
13. Sears MR, Burrows B, Flannery EM, Herbison GP, Holdaway MD. Atopy in childhood. I. Gender and allergen related risks for development of hay fever and asthma. Clin Exp Allergy 1993;23:941–948.[CrossRef][Medline]
14. Sears MR, Jones DT, Holdaway MD, Hewitt CJ, Flannery EM, Herbison GP, Silva PA. Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children. Thorax 1986;41:283–289.[Abstract]
15. Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, Rosenthal RR, Sheffer AL, Spector SL, Townley RG. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975; 56:323–327.[CrossRef][Medline]
16. Bibi H, Montgomery M, Pasterkamp H, Chernick V. Relationship between response to inhaled albutarol and methacholine bronchial provocation in children with suspected asthma. Pediatr Pulmonol 1991;10:244–248.[Medline]
17. Sears MR, Herbison GP, Holdaway MD, Hewitt CJ, Flannery EM, Silva PA. The relative risks of sensitivity to grass pollen, house dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 1989;19:419–424.[CrossRef][Medline]
18. European Respiratory Society. Standardized lung function testing: official statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:1–100.[CrossRef][Medline]
19. Toelle BG, Peat JK, Salome CM, Mellis CM, Woolcock AJ. Toward a definition of asthma for epidemiology. Am Rev Respir Dis 1992;146:633–637.[Medline]
20. Merkus PJ, Ten-Have OA, Quanjer PH. Human lung growth: a review. Pediatr Pulmonol 1996;21:383–397.[CrossRef][Medline]
21. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981;123:659–664.[Medline]
22. Solberg HE. International Federation of Clinical Chemistry (IFCC), Standing Committee on Reference Values: the concept of reference values. J Clin Chem Clin Biochem 1987;25:337–342.[Medline]
23. Kelly WJ, Hudson I, Phelan PD, Pain MC, Olinsky A. Childhood asthma in adult life: a further study at 28 years of age. Br Med J Clin Res Ed 1987;294:1059–1062.
24. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med 1988;319:1112–1117.[Abstract]
25. Dezateux C, Stocks J. Lung development and early origins of childhood respiratory illness. Br Med Bull 1997;53:40–57.[Abstract/Free Full Text]
26. Rasmussen F, Siersted HC, Lambrechtsen J, Hansen HS, Hansen NC. Impact of airway lability, atopy, and tobacco smoking on the development of asthma-like symptoms in asymptomatic teenagers. Chest 2000; 117:1330–1335.[Abstract/Free Full Text]
27. Laprise C, Laviolette M, Boutet M, Boulet LP. Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling. Eur Respir J 1999;14:63–73.[Abstract]
28. Chapman ID, Foster A, Morley J. The relationship between inflammation and hyperreactivity of the airways in asthma. Clin Exp Allergy 1993;23:168–171.[CrossRef][Medline]
29. Sluiter HJ, Koeter GH, de Monchy JG, Postma DS, de Vries K, Orie NG. The Dutch hypothesis (chronic non-specific lung disease) revisited. Eur Respir J 1991;4:479–489.[Abstract]

This article has been cited by other articles:

				M. R. Sears Population prevalence of COPD Eur. Respir. J., January 1, 2008; 31(1): 218 - 218. [Full Text] [PDF]

				J. H. Lee, T. Haselkorn, L. Borish, L. Rasouliyan, B. E. Chipps, and S. E. Wenzel Risk Factors Associated With Persistent Airflow Limitation in Severe or Difficult-to-Treat Asthma: Insights From the TENOR Study Chest, December 1, 2007; 132(6): 1882 - 1889. [Abstract] [Full Text] [PDF]

				L-P. Boulet and P. J. Sterk Airway remodelling: the future Eur. Respir. J., November 1, 2007; 30(5): 831 - 834. [Full Text] [PDF]

				M. R. Sears Lung function decline in asthma Eur. Respir. J., September 1, 2007; 30(3): 411 - 413. [Full Text] [PDF]

				M. Nuijsink, W. C. J. Hop, P. J. Sterk, E. J. Duiverman, J. C. de Jongste, and on behalf of the Children Asthma Therapy Optimal ( Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial Eur. Respir. J., September 1, 2007; 30(3): 457 - 466. [Abstract] [Full Text] [PDF]

				A. L. James and S. Wenzel Clinical relevance of airway remodelling in airway diseases Eur. Respir. J., July 1, 2007; 30(1): 134 - 155. [Abstract] [Full Text] [PDF]

				C. L. Odgers, A. Caspi, J. M. Broadbent, N. Dickson, R. J. Hancox, H. Harrington, R. Poulton, M. R. Sears, W. M. Thomson, and T. E. Moffitt Prediction of Differential Adult Health Burden by Conduct Problem Subtypes in Males Arch Gen Psychiatry, April 1, 2007; 64(4): 476 - 484. [Abstract] [Full Text] [PDF]

				C. Bergeron, M. K. Tulic, and Q. Hamid Tools used to measure airway remodelling in research Eur. Respir. J., March 1, 2007; 29(3): 596 - 604. [Abstract] [Full Text] [PDF]

				M. M. Choe, P. H. S. Sporn, and M. A. Swartz Extracellular Matrix Remodeling by Dynamic Strain in a Three-Dimensional Tissue-Engineered Human Airway Wall Model Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 306 - 313. [Abstract] [Full Text] [PDF]

				C. G. Irvin Lessons from structure-function studies in asthma: myths and truths about what we teach J Appl Physiol, July 1, 2006; 101(1): 7 - 9. [Full Text] [PDF]

				R. H. Brown, D. B. Pearse, G. Pyrgos, M. C. Liu, A. Togias, and S. Permutt The structural basis of airways hyperresponsiveness in asthma J Appl Physiol, July 1, 2006; 101(1): 30 - 39. [Abstract] [Full Text] [PDF]

				H. Moshammer, G. Hoek, H. Luttmann-Gibson, M. A. Neuberger, T. Antova, U. Gehring, F. Hruba, S. Pattenden, P. Rudnai, H. Slachtova, et al. Parental Smoking and Lung Function in Children: An International Study Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1255 - 1263. [Abstract] [Full Text] [PDF]

				C. Bergeron and L.-P. Boulet Structural changes in airway diseases: characteristics, mechanisms, consequences, and pharmacologic modulation. Chest, April 1, 2006; 129(4): 1068 - 1087. [Abstract] [Full Text] [PDF]

				J Naranjo Orellana, R A Centeno Prada, M D Carranza Marquez, and J Ribas Use of {beta}2 agonists in sport: are the present criteria right? * Commentary. Br. J. Sports Med., April 1, 2006; 40(4): 363 - 366. [Abstract] [Full Text] [PDF]

				P Ernst Inhaled corticosteroids moderate lung function decline in adults with asthma Thorax, February 1, 2006; 61(2): 93 - 94. [Full Text] [PDF]

				R. Boogaard, S. H. Huijsmans, M. W. H. Pijnenburg, H. A. W. M. Tiddens, J. C. de Jongste, and P. J. F. M. Merkus Tracheomalacia and Bronchomalacia in Children: Incidence and Patient Characteristics Chest, November 1, 2005; 128(5): 3391 - 3397. [Abstract] [Full Text] [PDF]

				M. W. Pijnenburg, E. M. Bakker, W. C. Hop, and J. C. De Jongste Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma: A Randomized Controlled Trial Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 831 - 836. [Abstract] [Full Text] [PDF]

				A. Simpson, N. Maniatis, F. Jury, J. A. Cakebread, L. A. Lowe, S. T. Holgate, A. Woodcock, W. E. R. Ollier, A. Collins, A. Custovic, et al. Polymorphisms in A Disintegrin and Metalloprotease 33 (ADAM33) Predict Impaired Early-Life Lung Function Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 55 - 60. [Abstract] [Full Text] [PDF]

				L. A. Lowe, A. Simpson, A. Woodcock, J. Morris, C. S. Murray, A. Custovic, and for the NAC Manchester Asthma and Allergy Study Gr Wheeze Phenotypes and Lung Function in Preschool Children Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 231 - 237. [Abstract] [Full Text] [PDF]

				E. Baraldi, G. Bonetto, F. Zacchello, and M. Filippone Low Exhaled Nitric Oxide in School-Age Children with Bronchopulmonary Dysplasia and Airflow Limitation Am. J. Respir. Crit. Care Med., January 1, 2005; 171(1): 68 - 72. [Abstract] [Full Text] [PDF]

				L. A. Lowe, A. Woodcock, C. S. Murray, J. Morris, A. Simpson, and A. Custovic Lung Function at Age 3 Years: Effect of Pet Ownership and Exposure to Indoor Allergens Arch Pediatr Adolesc Med, October 1, 2004; 158(10): 996 - 1001. [Abstract] [Full Text] [PDF]

				D N R Payne, Y Qiu, J Zhu, L Peachey, M Scallan, A Bush, and P K Jeffery Airway inflammation in children with difficult asthma: relationships with airflow limitation and persistent symptoms Thorax, October 1, 2004; 59(10): 862 - 869. [Abstract] [Full Text] [PDF]

				A. Woodcock, L. A. Lowe, C. S. Murray, B. M. Simpson, S. D. Pipis, P. Kissen, A. Simpson, and A. Custovic Early Life Environmental Control: Effect on Symptoms, Sensitization, and Lung Function at Age 3 Years Am. J. Respir. Crit. Care Med., August 15, 2004; 170(4): 433 - 439. [Abstract] [Full Text] [PDF]

				S. Pedersen Progression of Asthma: Small Steps and a Long Way to Go Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 206 - 207. [Full Text] [PDF]

				R. A. Covar, J. D. Spahn, J. R. Murphy, and S. J. Szefler Progression of Asthma Measured by Lung Function in the Childhood Asthma Management Program Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 234 - 241. [Abstract] [Full Text] [PDF]

				E. W. Gelfand, A. Joetham, Z.-H. Cui, A. Balhorn, K. Takeda, C. Taube, and A. Dakhama Induction and Maintenance of Airway Responsiveness to Allergen Challenge Are Determined at the Age of Initial Sensitization J. Immunol., July 15, 2004; 173(2): 1298 - 1306. [Abstract] [Full Text] [PDF]