© 2002 American Thoracic Society
Infants with Flow Limitation at 4 WeeksOutcome at 6 and 11 YearsUniversity Department of Paediatrics, Princess Margaret Hospital for Children, Perth, Western Australia, Australia Correspondence and requests for reprints should be addressed to Peter N. Le Souëf, Ph.D., University Department of Paediatrics, Princess Margaret Hospital for Children, GPO Box D184, Perth, WA, 6001 Australia. E-mail: peterles{at}paed.uwa.edu.au
Within a longitudinal study of lung function in 243 infants, we identified a group of 23 individuals with flow limitation in tidal expiration. In infancy, flow-limited children have reduced lung function and increased airway responsiveness (AR), and at 2 years of age they are diagnosed with asthma more frequently. We hypothesized that these observations would persist throughout childhood. Data from ages 3 to 11 years were analyzed. Only at 4 years of age did the flow-limited group have increased wheeze compared with other cohort members (odds ratio, 4.25; 95% confidence interval [CI], 1.11 to 16.2; p = 0.04; n = 114). At 6 years of age, 117 cohort members were seen. The flow-limited group (n = 14) had greater AR (p = 0.009) and reduced mean FEV1 (131 ml; 95% CI, 16 to 246; p = 0.03) and FEF25–75 (0.28 L/second; 95% CI, 0.05 to 0.52; p = 0.02). At 11 years of age, 183 children were seen and the flow-limited group (n = 18) had greater AR (p = 0.02) and a trend toward reduced mean FEF25–75 (0.24 L/second; 95% CI, -0.02 to 0.49; p = 0.08). Atopy and parental asthma were not increased in the flow-limited group. We suggest that the physiologic abnormality that causes flow limitation in early infancy may identify an at-risk group, different from asthma, who have reduced lung function and increased airway responsiveness in later life.
Key Words: bronchial hyperreactivity • child • longitudinal studies • respiratory function tests
Prospective longitudinal studies have the potential to associate pulmonary function in early life with respiratory symptoms and outcome later in life. A study of individuals from the age of 7 years found that frequent wheezing and reduced pulmonary function persisted in two-thirds of individuals 21 years later (1), and one-third of 28-year-olds with recent-onset wheeze had previously reported wheezing illness as young children. This finding and those from other studies (2–4) provide evidence that reduced pulmonary function and respiratory symptoms in childhood persist into adult life, but it is not clear whether reduced pulmonary function is acquired after birth or is a congenital phenomenon. This question can be answered only by longitudinal studies from early infancy. A few studies have demonstrated that parameters of pulmonary function measured shortly after birth are predictive of respiratory outcome in early childhood. One study has described an association between reduced maximal flow at functional residual capacity (V·maxFRC) at 2 months of age and wheezing illness up to 3 years of age (5). A second group has reported increased wheezing lower respiratory tract infection in the first year of life in boys with reduced V·maxFRC and in girls with increased airway responsiveness (AR) at 1 month of age (6). In our cohort of healthy term infants, pulmonary function and AR were measured at 1 month of age in 243 individuals (7). Those who wheezed only in the first year had reduced V·maxFRC at 4 weeks of age, whereas those who wheezed in the second year or in the first 2 years had reduced V·maxFRC at 1, 6, and 12 months of age (7). At 6 years of age, increased AR at 4 weeks of age correlated positively with wheeze, cough, and physician-diagnosed asthma and negatively with FEV1 and FVC (8). A group of infants from our cohort was found to be flow-limited in tidal expiration at 4 weeks of age (9). Flow limitation occurs when expiratory flow in tidal breathing cannot be increased by increasing expiratory effort and is associated with severely reduced pulmonary function in infants with bronchopulmonary dysplasia (10), bronchiolitis (11), and cystic fibrosis (12). The flow-limited group in our cohort had reduced lung function at 4 weeks and 6 months of age and increased AR at 12 months of age (9). These infants made up 10% of this randomly selected cohort and were asymptomatic at 4 weeks of age, but by 2 years of age they had a 7-fold higher incidence of physician-diagnosed asthma. The aim of this study was to test the hypothesis that the flow-limited group would continue to experience reduced pulmonary function, increased AR, and increased respiratory symptoms through childhood.
Subjects Healthy term infants were recruited as previously described (13). The method for infant pulmonary function testing at 4 weeks of age, including airway responsiveness, has been previously described (9). The terms "flow-limited" and "not flow-limited" at 6 and 11 years of age refer to the flow limitation at 4 weeks of age. The Medical Ethics Committee of Princess Margaret Hospital (Perth, Australia) approved this study.
Questionnaire Data
Childhood Pulmonary Function and Airway Responsiveness
Skin Prick Tests and Eosinophil Count
Statistics
Subjects Of the 253 infants recruited, 243 attended at 4 weeks of age for an assessment including pulmonary function and histamine challenge. A description of the 23 flow-limited infants at 4 weeks of age compared with other cohort members is given in Table 1. At 6 years of age, 117 (48%) subjects were seen (14 flow-limited; mean age, 6.2 years [range, 4.2–8.7 years]). At 11 years of age, 183 (75%) of the subjects who were seen at 4 weeks of age were seen again (18 flow-limited individuals; mean age, 11.0 years [range, 8.3–13.1 years]). Six (5%) children seen at 6 years of age were not seen at 11 years of age, including three flow-limited cases. Table 2 compares details of those seen at 6 and 11 years of age with those seen at 4 weeks of age. Tables 3 and 4 compare the flow-limited group with the rest of the cohort at 6 and 11 years, respectively.
Questionnaire Data Of the infants seen at 4 weeks of age, questionnaire data were available for 113 (47%) at 3 years of age, 126 (52%) at 4 years of age, and 106 (44%) at 5 years of age. Questionnaire data were available for all children at 6 years of age and in all but one case at 11 years of age (in this case the parent refused to provide any information). For eight subjects who participated in the 11-year study, questionnaire data were available, but not data concerning pulmonary function, airway responsiveness, or markers of atopy. There was increased wheeze in the absence of upper respiratory tract infection among the flow-limited group only at 4 years of age (4 of 12 compared with 12 of 114; odds ratio, 4.25; 95% confidence interval [CI], 1.11 to 16.2; p = 0.04). Between 3 and 11 years of age, there was no increase in physician-diagnosed asthma in the flow-limited group.
Childhood Pulmonary Function and Airway Responsiveness
Skin Prick Tests and Eosinophil Count Skin prick testing was performed in 107 subjects (91%, 13 flow-limited) at 6 years of age and in 172 subjects (94%, 17 flow-limited) at 11 years of age. Eosinophil counts were performed in 100 subjects (85%, 13 flow-limited) at 6 years of age and in 152 subjects (83%, 12 flow-limited) at 11 years of age. There were no differences between the flow-limited group and the remainder of the cohort at 6 or 11 years of age with respect to atopy or eosinophil count.
We have followed a group of individuals with flow limitation of tidal expiration in infancy and found increased AR and reduced pulmonary function in childhood. This is the first study to follow up infants with flow limitation and the first to associate reduced infant lung function with increased childhood AR. Extrapolating the results from other studies (1, 19) to our cohort, individuals in the flow-limited group may be expected to retain their increased AR and trend in reduced pulmonary function into adult life. Our results are consistent with those of Martinez and coworkers (20), who have described the presence of abnormal but asymptomatic pulmonary function in a group of six-year- old children with reduced V·maxFRC in early infancy and who wheezed transiently, that is, only in the first 3 years. Our study has described the group outcome at a much later age with larger numbers and has included an assessment of airway responsiveness. We are able to report that among subjects with reduced V·maxFRC at 4 weeks of age, reduced FEV1 at 6 years of age resolves fully, and reduced FEF25–75 at 6 years of age has mostly resolved by 11 years of age. The presence of increased AR at 11 years of age suggests an ongoing airway abnormality in the flow-limited group, the clinical significance of which is not apparent. Regression to the mean of reduced infant lung function and increased AR may be occurring and perhaps the subclinical findings of the flow-limited group may disappear in time. Increased AR has persisted in the flow-limited group throughout childhood but significant differences in pulmonary function at 6 years of age have resolved by 11 years of age, although the trend in FEF25–75 persists. Recurrence of wheeze in young adults with trivial wheeze during early childhood but not adolescence has been previously reported (1); we hypothesize that the flow-limited group will regain their symptoms in adult life. The association between increased AR and reduced lung function has been reported in cross-sectional (21, 22) and longitudinal studies (22–25). Longitudinal studies have shown increased AR to be a risk factor for reduced growth in FEV1 in late childhood (23) and accelerated decline in FEV1 in middle age (24, 25). No such associations were found between increased AR and reduced FVC, suggesting that increased AR is associated with reduced airway caliber and not reduced lung size. What is not clear is whether the relationship between increased AR and reduced pulmonary function is the result of one upon the other or whether both are influenced by a third factor. O'Connor and coworkers (25) suggest three hypotheses to account for the association: (1) exogenous stimulants such as tobacco smoke causes airway inflammation, which results in both increased AR and reduced lung function; (2) an intrinsic epithelial abnormality causes both phenomena; and (3) reduced lung function causes obstructed, distended airways and this physical stress induces increased AR. The same group adds in a later article the suggestion that neuroregulatory alterations to the airways and lung parenchyma could account for both increased AR and reduced lung function (26). Reduced airway caliber, reduced airway compliance, or both of these properties at birth could link flow limitation, wheezing illness in early childhood, and subsequent reduction in pulmonary function and increase in AR. At 1 and 6 months of age, the flow-limited group had reduced total respiratory compliance and reduced V·maxFRC (an index of airway caliber) (9). Among infants, other groups have reported increased wheezing illness in association with altered airway compliance (27), reduced V·maxFRC (6, 20, 28), and reduced total respiratory resistance (5). There are at least two mechanisms that could explain the increased AR associated with flow limitation. First, the reduced airway caliber and compliance could be a consequence of increased airway smooth muscle mass or tone, so that when the smooth muscle is stimulated by inhaled histamine, a greater degree of bronchoconstriction is reached more readily. Second, the obstructed airways of the flow-limited group could limit the distribution of inhaled histamine, resulting in a much higher histamine concentration in more proximal airways, causing them to undergo more intense bronchoconstriction. The follow-up of our cohort was less than 50% at 6 years of age and improved to more than 75% at 11 years of age. In pooling the data from the 6- and 11-year studies, 21 members (88%) of the flow-limited group were seen in childhood along with 167 members (76%) of the remainder of the cohort. We have made exhaustive efforts to contact subjects, and in the process we have located five in other states and are aware of at least another six that have moved overseas. Significantly, more children whose parents were nonsmokers at enrollment were available for follow-up compared with those who had smoking parents. This may have affected the analysis, although among those followed up successfully, neither maternal nor paternal smoking was a significant factor in outcome measures. The consistency in increased AR and trend in reduced FEF25–75 seen among subjects at 6 to 11 years of age indicate that the observations are likely to be valid and not influenced by incomplete follow-up. We believe that the flow-limited group forms one end of a continuous spectrum rather than a group discrete from the general population. Their anthropomorphic measurement from birth, current markers of atopy, and respiratory symptoms are not different from the remainder of the cohort, suggesting that the underlying cause for the group differences is not in utero nutrition or growth failure or atopy in childhood. We find that the association between increased AR and reduced lung function is present in infancy and persists into childhood. This strongly suggests that the association is due to an underlying factor present in very early life that may include in utero tobacco exposure or genetic factors. In summary, we have observed increased AR and reduced pulmonary function in the flow-limited group during childhood. We suggest that the mechanism(s) responsible for flow limitation in infancy accounts for the association between reduced pulmonary function and increased AR seen in our population and others. We will monitor this cohort to establish whether over time the flow-limited group experiences an accelerated decline in lung function and again becomes symptomatic.
The authors are grateful to colleagues who have provided helpful assistance over the years of this cohort study. The authors are also grateful for the ongoing cooperation of the families involved in the Osborne Park Family Asthma Study.
Supported by NHMRC grant 9938107 (S. W. T.). 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 October 2, 2001; accepted in final form December 13, 2001
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ABSTRACT
INTRODUCTION
2 analysis was used to compare questionnaire data obtained at 3, 4, and 5 years of age; differences in pulmonary function and DRS were determined by multilinear regression, adjusting for age, sex, height, current smoke exposure, and in utero smoke exposure; in addition atopy was used in analyses of DRS. For graphic demonstration of pulmonary function data, percent predicted (%pred) FEV1 and FEF25–75 values were derived from linear regression coefficients and compared by the Student t test. Analyses were performed with a standard statistical software package (SPSS release 9.0.1; SPSS, Chicago, IL). 
