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The Relationship between Infant Airway Function, Childhood Airway Responsiveness, and Asthma

School of Paediatrics and Child Health, University of Western Australia, and Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia

Correspondence and requests for reprints should be addressed to Stephen W. Turner, M.D., School of Medicine, Department of Child Health, Aberdeen Children's Hospital, Foresterhill, Aberdeen AB25 2ZG, Scotland. E-mail: s.w.turner{at}abdn.ac.uk

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The relationship between reduced pulmonary function in early life and persistent wheeze (PW) in school-aged children remains uncertain. In this study, maxFRC was assessed at 1 month of age, and the presence of wheeze up to 11 years of age was prospectively identified. At 11 years of age, airway responsiveness (AR) to inhaled histamine and atopy were assessed. Recent wheeze at 11 years of age was associated with a reduced mean z score for maxFRC at 1 month of age (–0.41 [SD 0.91], n = 31) compared with no recent wheeze (0.04 [SD 1.00], n = 153, p = 0.03). Wheeze between 4 and 6 years that persisted at 11 years (PW) was most prevalent among those with reduced maxFRC at 1 month and atopy aged 11 years (p = 0.002) or reduced maxFRC and increased AR aged 11 years (p = 0.015). When all factors were considered, reduced maxFRC at 1 month (p = 0.03) and increased AR aged 11 years (p < 0.001) were independently associated with PW (n = 17) compared with other outcomes (n = 129). Reduced airway function present in early infancy is associated with PW at 11 years of age, and this relationship is independent of the effect of increased AR and atopy in childhood.

Key Words: respiratory sounds • respiratory function tests • longitudinal study • infant

Recurrent childhood wheeze is common (1), begins in early life (2), and may then persist into later life (3). In some individuals, factors present in early life might be lifelong determinants of respiratory outcome. Factors associated with persistent childhood wheeze include male sex and a history of maternal asthma or smoking (4, 5). Atopy (4, 6) and increased airway responsiveness (AR) in young children (7–9) have also been associated with persistent wheeze (PW) in later life. The mechanism for the development of persistent childhood wheeze remains incompletely understood but appears to be complex, and in children, increased AR and atopy may be particularly important.

In addition to increased AR and atopy, abnormalities of pulmonary function are also associated with increased wheeze in children (4, 10), and these abnormalities persist into adulthood (11). What remains uncertain is whether abnormalities of pulmonary function precede the development of respiratory symptoms or, alternatively, are a consequence of the disease process responsible for respiratory symptoms. Several studies have confirmed that infants with reduced pulmonary function, as evidenced by reduced maxFRC, before the onset of respiratory symptoms appear to be at increased risk for the development of bronchiolitis (12), pneumonia (13), and increased wheeze (4, 14–16). Two groups have followed individuals with reduced maxFRC in early infancy and have demonstrated persisting abnormalities of pulmonary function, as evidenced by reduced FEF_25–75% at 11 years of age (12, 13, 16). These data suggest that maxFRC, in addition to increased AR and atopy, may also be an important determinant of respiratory symptoms and pulmonary function in children.

The relationship between reduced maxFRC and persistent childhood wheeze is unclear, and this is in part due to the technical and practical difficulties in undertaking a study of this nature. One study has reported that there was no association between reduced maxFRC in infancy and PW at 6 years of age (4). No study has reported outcomes at 11 years. Investigators in our department have recruited a birth cohort that underwent an assessment of pulmonary function at 1 month of age, before the onset of any respiratory symptoms. The 11-year follow-up of study subjects is now complete. We hypothesized that reduced maxFRC soon after birth would be associated with PW at 11 years of age, independent of atopy and increased AR in childhood. Some of the results of this study have been previously reported as abstracts (17, 18).

	METHODS

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Subjects
The cohort was enrolled before birth and was selected from a white population attending an antenatal clinic between June 1987 and November 1990 as described previously (19). There was no selection for parental asthma. Enrolled individuals who were subsequently born prematurely or who developed respiratory symptoms in the first month of life were excluded from the study. The study was approved by the Medical Ethics Committee of Princess Margaret Hospital for Children. Informed parental consent was obtained for each assessment.

Protocol
At enrollment, parents received instructions that would assist in detecting wheeze, and a parental history of smoking and/or physician-diagnosed asthma (PDA) was noted. Infant pulmonary function was assessed at 1 month of age. A history of recent wheeze or PDA was identified from monthly questionnaires completed by parents in the first year and annually on the child's second, third, fourth and fifth birthdays. Aged 6 and 11 years, individuals underwent an assessment that included questionnaire, spirometry, AR to inhaled histamine, and skin prick testing. At 11 years of age, the presence of reported previous wheeze and PDA was verified using previous questionnaire data.

Definitions
"Recent wheeze" included wheeze caused by all causes present in the past year. "Parental asthma" indicated that at least one parent had a history of PDA at enrollment. "Atopy" was defined as at least one positive skin prick test. Children were grouped according to the presence or absence of wheeze as follows: NW for no wheeze reported at any age; W0–3 for wheeze before but not after the third birthday; W4–6 for wheeze between ages 4 and 6 years but not after; W11 for wheeze at 11 years but not previously; and finally, PW for those who wheezed between 4 and 6 years and at 11 years of age.

Infant Pulmonary Function Measurement
The techniques used have been described (19). After sleep was induced with chloral hydrate, maxFRC was determined from the rapid thoracoabdominal compression technique during tidal breathing. In accordance with published guidelines (20), maxFRC was expressed when appropriate as a z score, after adjustment for sex, age, length, weight, and maternal smoking during pregnancy (21). AR was determined from the response of maxFRC to doubling concentrations of nebulized histamine solutions (from 0.125 to 8 mg/ml). The airway challenge ended if a 40% reduction in maxFRC was provoked or if the final concentration had been administered. AR was expressed as the concentration of histamine provoking at least a 40% reduction in maxFRC (PC₄₀). As previously (7), those individuals in whom maxFRC did not fall by 40% after inhalation of the maximal concentration of histamine were assigned the value PC₄₀ = 16 mg/ml.

Childhood Pulmonary Function and AR
Childhood pulmonary function was measured with a portable spirometer (Pneumocheck Spirometer 6100; Welch-Allyn, Skaneateles Falls, NY) in accordance with published guidelines (22). Childhood pulmonary function was expressed as a z score after adjustment for height, sex, current AR, and current parental smoking status (see Table E1 on the online supplement). The rapid technique was used to determine childhood AR (23). Briefly, increasing doses of inhaled histamine were administered from a handheld dosimeter until either a 20% reduction in FEV₁ occurred or the maximal cumulative dose had been administered (7.8 µmol). The response of pulmonary function to inhaled histamine was expressed using one of two methods: first, the dose of histamine (µM) that provoked at least a 20% fall in FEV₁ (PD₂₀) (increased AR was defined as PD₂₀ of less than 7.8-µM histamine) (24), and second, the dose–response slope (DRS), which was calculated as follows:

The DRS was adjusted for the influence of reduced FEF_25–75%.

Skin Prick Tests
The skin prick test described by Pepys (25) was used to determine sensitivity to these allergens: cows milk, egg white, rye grass, mixed grass (No. 7), Dermatophagoides farinae, Dermatophagoides pteronyssinus, cat dander, dog dander, Alternaria alternans, and Aspergillus fumigatus (Hollister-Stier, Elkhart, IN). The positive control was histamine sulfate (10 mg/ml), and the negative control was 0.9% saline. A positive skin test was defined as a weal of at least 3 mm in any dimension.

Statistical Analysis
The distributions of maxFRC and PC₄₀ at 1 month and dose response slope at 6 and 11 years were skewed with long right-handed tails and were log₁₀ transformed before analysis (a constant of three was added to DRS to allow values of zero or less to be included). Chi-square test, Student's t test (equivariance not assumed), Mann-Whitney U test, Kruskal-Wallis test, or analysis of variance (with Bonferroni correction) were used where appropriate to compare differences between groups.

Logistic regression models were created to study the relationship between current and previous PDA at 11 years of age (outcome variables) and PC₄₀ at 1 month (explanatory variable) adjusting for sex and maxFRC (used in previous analyses) (7). Longitudinal associations between measurements of maxFRC in infancy and FEF_25–75% in children were studied among those individuals in whom data were complete by comparing mean z scores for all measurements of pulmonary function (i.e., three measurements for each individual) between the different wheezing groups.

A Cox proportional hazards model was created to determine the relationship between maxFRC aged 1 month, atopy and DRS aged 11 years (explanatory variables), and PW (outcome variable). In this model, individuals with PW were compared with all other individuals. The following confounding variables were also considered in this model: PC₄₀ aged 1 month, sex, length aged 1 month, maternal or paternal smoking during pregnancy, and parental asthma. Variables were removed in a backward stepwise manner assuming significance at the 5% level.

All reported p values were two sided. Analyses were performed using a standard statistical software package (SPSS release 10.0.7; SPSS, Chicago, IL).

	RESULTS

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Subjects
At 1 month of age, 243 infants underwent an assessment of pulmonary function; maxFRC was measured in all individuals and PC₄₀ in 202 infants. Questionnaire data were available from 112 study subjects aged 1 year, 169 aged 2 years, 113 aged 3 years, 126 aged 4 years, and 106 aged 5 years. At 6 years of age, 117 children were assessed, and at 11 years of age, 185 cohort members were assessed, including 111 children seen at 6 years of age (see Figures E1, E2, and E3 in the online supplement for figures showing the numbers of individuals where details of wheeze, pulmonary function and AR were available during the period of follow-up). Ten individuals were recruited and not assessed aged 1 month but did participate in later assessments. One hundred fifty-seven children could be placed into one of the following groups: NW, n = 67; W0–3, n = 28; W4–6, n = 39; W11, n = 6; or PW, n = 17. Table 1 compares details of these 157 individuals with the original cohort. Wheeze was reported on at least one occasion during the first 3 years in 25 of the 37 (68%) individuals with W4–6 and for 13 of 16 (81%) of individuals with PW where questionnaire data were available.

PC₄₀ Aged 1 Month and Respiratory Symptoms at 11 Years
Where PC₄₀ at 1 month of age was known, a history of diagnosed asthma ever by 11 years of age (n = 59) was associated with reduced PC₄₀ at 1 month of age compared with no history of diagnosed asthma (n = 106) (geometric means 0.72 [95% confidence interval [CI], 0.56, 0.94] vs. 1.09 [95% CI, 0.86, 1.38] p = 0.04). There was no reduction in PC₄₀ at 1 month and a history of wheeze ever (geometric mean, 0.86 [95% CI, 0.67, 1.11]; n = 97) compared with NW ever (geometric mean, 0.97 [95% CI, 0.74, 1.29]; n = 97). There was no relationship between PC₄₀ at 1 month and current wheeze and current PDA at 11 years of age.

maxFRC at 1 Month and Respiratory Symptoms between Ages 4 and 11 Years: Cross-sectional Analyses
Wheeze between 4 and 6 years of age was associated with a reduced mean maxFRC z score (–0.31 [SD 0.96], n = 64) compared with NW during this period (0.16 [SD 1.06], n = 95, p = 0.005). Recent wheeze at 11 years of age was associated with a reduced mean maxFRC z score aged 1 month (–0.41 [SD 0.91], n = 31) when compared with no recent wheeze (0.04 [SD 1.06], n = 153, p = 0.03). There was no significant reduction in mean maxFRC z score aged 1 month for those individuals with current PDA when compared with other children at 6 years of age (–0.21 [SD 0.99], n = 28, vs. 0.02 [SD 1.03], n = 89) and 11 years of age (–0.21 [SD 1.00], n = 28, vs. 0.00 [SD 1.03], n = 157).

Factors Associated with Different Wheezing Outcomes
The mean maxFRC z score aged 1 month for individuals in the NW group was 0.08 (SD 0.96, n = 67), for those in the W0–3 group was 0.36 (SD 1.28, n = 28), for those in the W4–6 group was –0.21 (SD 0.94, n = 39), for those in the W11 group was 0.22 (SD 0.41, n = 6) and –0.59 (SD 0.90, n = 17) for those in the PW group (analysis of variance, p = 0.02; Table 2 and Figure 1) . When both maxFRC and increased AR at 11 years were considered, PW was more likely to be present for those individuals in both the lowest terctile for maxFRC z score and with increased AR, ²₈ for trend across groups with increased AR = 19.0, p = 0.015 (Figure 2) , for trend across groups without increased AR ²₈ = 12.2 (p > 0.1). PW was also most prevalent among those individuals in the lowest tercile for maxFRC z score aged 1 month and atopy aged 11 years (Figure 3) , ²₈ for trend across groups with atopy = 25.0, p = 0.002, and ²₈ for trend across groups without atopy = 3.6, p < 0.8.

View larger version (15K): [in this window] [in a new window]   Figure 1. Box and whisker plot showing median and quartiles values for z scores of maxFRC at 1 month in groups defined by wheeze at different ages. Data from four individuals with z scores of 2.5, 3.8, 3.8, and 4.0 are not included but were included in the analysis. NW = no wheeze reported at any age; W0–3 = wheeze before but not after the third birthday; W4–6 = wheeze between ages 4 and 6 years but not after; W11 = wheeze at 11 years but not previously; PW = those who wheezed between 4 and 6 years and at 11 years of age.

View larger version (38K): [in this window] [in a new window]   Figure 2. The relationship between terciles of maxFRC at 1 month of age, increased airway responsiveness (AR) aged 11 years, and respiratory symptoms in childhood. The group containing individuals with z scores of maxFRC aged 1 month in the lowest tercile and increased AR aged 11 years also contained the majority of individuals with persistent wheeze (black). 26 for trend across groups with increased AR = 19.0, p = 0.015.

View larger version (34K): [in this window] [in a new window]   Figure 3. The relationship between terciles of maxFRC at 1 month of age, atopy aged 11 years, and respiratory symptoms in childhood. The group containing individuals with z scores of maxFRC aged 1 month in the lowest tercile and atopic aged 11 years also contained the majority of individuals with persistent wheeze (black). 26 for trend across groups with atopy = 25.0, p = 0.002.

View larger version (28K): [in this window] [in a new window]   Figure 4. Chart demonstrating mean z scores for maxFRC at 1 month and FEF25–75% at 6 and 11 years of age for groups determined by wheeze outcome.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
This study was designed to determine the relationship between lung function in early life and respiratory outcome in later childhood, and the data suggest that airway function in early infancy was associated with persistent childhood wheeze. Cross-sectional analyses demonstrated a relationship between reduced maxFRC aged 1 month and wheeze between ages 4 to 6 and also at 11 years of age. Longitudinal analysis revealed that reduced neonatal lung function was associated with wheezing at age 4 to 6 years that persisted to 11 years of age. In the final analysis, reduced maxFRC at 1 month of age was shown to be associated with PW, and this relationship was independent of atopy and increased AR in infancy and childhood and, additionally, factors that may influence maxFRC. Individuals with atopy or increased AR at 11 years of age who also had reduced maxFRC aged 1 month were most likely to have PW, but the influence of increased AR subsumed that of atopy. Because the group with PW has the usual phenotype for childhood asthma, the data suggested that for many children asthma is associated with both reduced maxFRC at 1 month of age and increased AR at 11 years of age (Figure 5) .

View larger version (15K): [in this window] [in a new window]   Figure 5. Schematic representation of the relationship between reduced maxFRC in infancy and AR in childhood, which appears to be important to persistent childhood wheeze and asthma.

A relationship between reduced maxFRC in infants, increased AR in childhood, and PW might explain why early wheeze is transient in some children but persistent in others. Reduced maxFRC in infancy in the absence of increased AR in later childhood has, in our cohort, been associated with transient wheeze (12). This study reports that persistent childhood wheeze was, for the majority of cases, present for those individuals with both reduced maxFRC at 1 month and greater levels of AR at 11 years of age. Our data are consistent with other studies that have reported associations between abnormalities of lung function and wheeze in early childhood (4, 14) and between increased AR and PW or asthma in later childhood (24). Childhood asthma is commonly considered to be a complex, multifactorial condition, and the increased likelihood of persistent symptoms for individuals with both reduced maxFRC in infancy and increased AR in childhood is plausible.

The findings of this study suggested that increased AR in infancy and childhood is associated with different wheezing phenotypes. Increased AR present at 1 month of age was associated with future asthma that often resolved, whereas increased AR present at 11 years of age was associated with persisting asthma. There was a trend for individuals in groups W4–6 and PW to have increased AR at 1 month of age compared with other groups, and there is a possibility that with larger numbers of study subjects this trend may have become significant. In this cohort, at 4 weeks of age, increased AR was not influenced by atopy (7), and therefore, increased AR present in infancy may be a nonatopic mechanism for wheeze in younger children. At 11 years of age, increased AR was associated with persistent respiratory symptoms and atopy. Stein and colleagues (26) have proposed that childhood wheeze could be considered as early nonatopic wheeze and later atopic wheeze. Our data would support this concept of wheeze and suggest that the presence of increased AR in either or both infancy or childhood may be an important determinant of wheezing phenotype.

In a previous report, we have reported an association between reduced maxFRC at 1 month of age, as evidenced by flow limitation during tidal expiration, transient wheeze, and increased AR in childhood (16). In this study, we report that reduced maxFRC and increased AR in childhood were independently related to PW. These outcomes, taken from the same cohort, appear to be contradictory. However, at 11 years of age, the formerly flow-limited individuals were no more likely to be atopic than other cohort members (16), whereas in this study, those individuals with PW were mostly atopic. The data from our study therefore suggest that persistent respiratory symptoms are not associated with increased childhood AR per se but increased childhood AR associated with atopy.

This study has confirmed previous observations that measurements of maxFRC in infancy correlate with measurements of FEF_25–75% in childhood (12, 13, 16). Maximal flow at functional residual capacity and FEF_25–75% are flow-related measurements with relatively large intrasubject variability and as such a strong interrelationship might not be expected. The coefficient of variation for maxFRC in infants may vary between 11% and 36% (27), although measurement of maxFRC becomes less variable in older infants (28), and the coefficient of variation for FEF_25–75% in 7 year olds is 15% (29). Children with wheeze have reduced FEF_25–75% but not reduced FEV₁ or FVC, suggesting that FEF_25–75% is a sensitive measurement of pulmonary dysfunction despite increased variability (10).

There are at least two separate mechanisms that may explain the relationship between reduced maxFRC at 1 month and reduced FEF_25–75% and increased wheeze throughout childhood. First, wheeze may be the result of narrow, small airways. This hypothesis is supported by studies of infant pulmonary function that have reported reduced total respiratory conductance in children that subsequently developed wheeze (30, 31). Alternatively, altered airway compliance may result in increased wheezing; abnormal airway wall properties have been demonstrated in infants with a history of wheeze (32). maxFRC does not distinguish between reduced airway caliber and altered airway compliance; therefore, this study is not able to determine the specific underlying abnormality of pathophysiology.

The main findings of this study are based on a proportion of the original cohort with a relatively lower level of in utero smoke exposure, and this loss to follow-up may have affected the outcomes because antenatal exposure to tobacco products has been associated with reduced maxFRC in our cohort (21) and another (33). Despite adjusting maxFRC for exposure to in utero smoke exposure, this study may not be able to exclude definitively a relationship between exposure to in utero tobacco products and increased childhood wheeze. Two recent studies involving large numbers of 6- and 11-year old Perth children (34, 35) have reported prevalences of wheeze very similar to that reported in this study, and this suggests that the symptom frequency reported by cohort members was representative of the general population.

Compared with our findings, two other studies have reported a larger proportion of individuals with wheeze in the first 3 years of life compared with the second 3 years (4, 5). One possible explanation for this apparent difference between our study and other is that wheeze in the first 3 years was underreported in our study because questionnaire data were not available for all study subjects. A second consequence of incomplete questionnaire data is that we cannot exclude the possibility that wheeze was present in the first 3 years but not reported for some children with W4–6 and PW.

In summary, this study demonstrated that reduced maxFRC at 1 month was associated with PW at 11 years of age. The data suggested that the mechanism for PW in many children involves both an intrinsic abnormality in pulmonary function, as evidenced by reduced maxFRC, determined at an early age and the later onset of increased AR associated with atopy. Our data may therefore help to explain why asthma does not develop in all atopic children and why early childhood wheeze does not persist in some individuals. The incidence of childhood wheeze is increasing (36), and mechanisms responsible for reduced maxFRC in early life and increasing atopy in childhood require further study.

	Acknowledgments

	FOOTNOTES

 
Supported by National Health and Medical Research Council of Australia grant number 9938107 (S.W.T.).

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

Conflict of Interest Statement: S.W.T. has no declared conflict of interest; L.J.P. has no declared conflict of interest; P.J.R. has no declared conflict of interest; N.A.G. has no declared conflict of interest; P.K.J. has no declared conflict of interest; M.C. has no declared conflict of interest; S.Y. has no declared conflict of interest; J.G. has no declared conflict of interest; L.I.L. received airfares, accommodation and honorarium ($1500) from GSK for speaking at approximately two conferences/workshops each year; P.N.L. has no declared conflict of interest.

Received in original form July 3, 2003; accepted in final form January 25, 2004

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