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The Relationship between Infant Airway Function,
Childhood Airway Responsiveness, and Asthma
Stephen W. Turner, Lyle J. Palmer, Peter J. Rye, Neil A. Gibson, Parveenjeet K. Judge, Moreen Cox,
Sally Young, Jack Goldblatt, Louis I. Landau, and Peter N. Le Soue
¨
f
School of Paediatrics and Child Health, University of Western Australia, and Department of Respiratory Medicine, Princess Margaret Hospital
for Children, Perth, Australia
The relationship between reduced pulmonary function in early life
and persistent wheeze (PW) in school-aged children remains uncer-
tain. In this study, V
˙
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 V
˙
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 V
˙
maxFRC at 1 month and atopy aged
11 years (p ⫽ 0.002) or reduced V
˙
maxFRC and increased AR aged
11 years (p ⫽ 0.015). When all factors were considered, reduced
V
˙
maxFRC at 1 month (p ⫽ 0.03) and increased AR aged 11 years
(p ⬍ 0.001) were independently associated with PW (n ⫽ 17) com-
pared 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.
Keywords: 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 child-
hood wheeze include male sex and a history of maternal asthma
or smoking (4, 5). Atopy (4, 6) and increased airway respon-
siveness (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 incom-
pletely 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 pul-
monary 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 pulmo-
nary function precede the development of respiratory symptoms
or, alternatively, are a consequence of the disease process re-
sponsible for respiratory symptoms. Several studies have con-
firmed that infants with reduced pulmonary function, as evi-
(Received in original form July 3, 2003; accepted in final form January 25, 2004)
Supported by National Health and Medical Research Council of Australia grant
number 9938107 (S.W.T.).
Correspondence and requests for reprints should be addressed to Stephen W.
Turner, M.D., School of Medicine, Department of Child Health, Aberdeen Chil-
dren’s Hospital, Foresterhill, Aberdeen AB25 2ZG, Scotland. E-mail: s.w.turner@
abdn.ac.uk
This article has an online supplement, which is accessible from this issue’s table
of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 169. pp 921–927, 2004
Originally Published in Press as DOI: 10.1164/rccm.200307-891OC on February 5, 2004
Internet address: www.atsjournals.org
denced by reduced V
˙
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
V
˙
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
V
˙
maxFRC, in addition to increased AR and atopy, may also be
an important determinant of respiratory symptoms and pulmo-
nary function in children.
The relationship between reduced V
˙
maxFRC and persistent
childhood wheeze is unclear, and this is in part due to the techni-
cal and practical difficulties in undertaking a study of this nature.
One study has reported that there was no association between
reduced V
˙
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
V
˙
maxFRC soon after birth would be associated with PW at 11
years of age, independent of atopy and increased AR in child-
hood. Some of the results of this study have been previously
reported as abstracts (17, 18).
METHODS
Subjects
The cohort was enrolled before birth and was selected from a white
population attending an antenatal clinic between June 1987 and Novem-
ber 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 paren-
tal consent was obtained for each assessment.
Protocol
At enrollment, parents received instructions that would assist in de-
tecting 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 pres-
ence 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.
922 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004
Infant Pulmonary Function Measurement
The techniques used have been described (19). After sleep was induced
with chloral hydrate, V
˙
maxFRC was determined from the rapid thora-
coabdominal compression technique during tidal breathing. In accor-
dance with published guidelines (20), V
˙
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 V
˙
maxFRC to doubling concentrations of nebulized
histamine solutions (from 0.125 to 8 mg/ml). The airway challenge
ended if a 40% reduction in V
˙
maxFRC was provoked or if the final
concentration had been administered. AR was expressed as the concen-
tration of histamine provoking at least a 40% reduction in V
˙
maxFRC
(PC
40
). As previously (7), those individuals in whom V
˙
maxFRC did not
fall by 40% after inhalation of the maximal concentration of histamine
were assigned the value PC
40
⫽ 16 mg/ml.
Childhood Pulmonary Function and AR
Childhood pulmonary function was measured with a portable spirome-
ter (Pneumocheck Spirometer 6100; Welch-Allyn, Skaneateles Falls,
NY) in accordance with published guidelines (22). Childhood pulmo-
nary 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 FEV
1
occurred or the maximal cumulative dose had been administered
(7.8 mol). The response of pulmonary function to inhaled histamine
was expressed using one of two methods: first, the dose of histamine
(M) that provoked at least a 20% fall in FEV
1
(PD
20
) (increased AR
was defined as PD
20
of less than 7.8-M histamine) (24), and second, the
dose–response slope (DRS), which was calculated as follows:
冢
FEV
1
prechallenge ⫺ FEV
1
postchallenge
FEV
1
prechallenge
cumulative dose of histamine
冣
⫻ 100
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 pteronyssi-
nus, cat dander, dog dander, Alternaria alternans, and Aspergillus fumi-
gatus (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 V
˙
maxFRC and PC
40
at 1 month and dose response
slope at 6 and 11 years were skewed with long right-handed tails and
were log
10
transformed before analysis (a constant of three was added
to DRS to allow values of zero or less to be included). Chi-square test,
TABLE 1. COMPARISON OF CHARACTERISTICS OF THE 156 CHILDREN WHOSE DETAILS ARE
PRESENTED IN THIS STUDY WITH THE ORIGINAL COHORT
Individuals in whom
Individuals Placed into Pulmonary Function Was
a Wheeze Category Assessed on Each Occasion Original Cohort
Male 54% (85/157) 52% (49/95) 56% (136/243)
Mother smoked during pregnancy 17%
*
(25/157) 18% (17/95) 24% (57/242)
Parental asthma
†
30% (46/153) 29% (27/93) 31% (73/232)
V
˙
maxFRC z score at 1 mo of age (SD) ⫺0.01 (1.02), n ⫽ 157 0.00 (1.06), n ⫽ 95 ⫺0.04 (0.99), n ⫽ 243
PC
40
at 1 mo of age,
‡
(95% CI) 1.01 (0.82, 1.36), n ⫽ 131 1.10 (0.83, 1.34), n ⫽ 77 1.04 (0.80, 1.14), n ⫽ 202
Definition of abbreviations:CI⫽ confidence interval; PC
40
⫽ concentration of histamine provoking at least a 40% reduction in
V
˙
maxFRC.
*
p ⬍ 0.05 compared with the original cohort.
†
Data missing for 11 fathers.
‡
Expressed as geometric mean and 95% confidence intervals (1.96 ⫻ SEM).
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 vari-
ables) and PC
40
at 1 month (explanatory variable) adjusting for sex and
V
˙
maxFRC (used in previous analyses) (7). Longitudinal associations
between measurements of V
˙
maxFRC in infancy and FEF
25–75
% in chil-
dren 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 V
˙
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:
PC
40
aged 1 month, sex, length aged 1 month, maternal or paternal
smoking during pregnancy, and parental asthma. Variables were re-
moved 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
Subjects
At 1 month of age, 243 infants underwent an assessment of
pulmonary function; V
˙
maxFRC was measured in all individuals
and PC
40
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.
Prevalence of Asthma and Wheeze
Recent wheeze was reported in 37 (33%) individuals in the first
year, 61 (36%) individuals aged 2 years, 40 (35%) individuals
Turner, Palmer, Rye, et al.: Infant Lung Function and Asthma 923
TABLE 2. DETAILS IN EARLY INFANCY FOR GROUPS DEFINED BY CHILDHOOD WHEEZE
NW W0–3 W4–6 W11 PW Trend Test
(n ⫽ 67)(n ⫽ 28)(n ⫽ 39)(n ⫽ 6 )(n ⫽ 17 )(p )
Male 54% (36/67) 43% (12/28) 59% (23/39) 50% (3/6) 65% (11/178) NS
Mother smoked
during pregnancy 15% (10/67) 29% (8/28) 21% (8/39) 17% (1/6) 18% (2/17) NS
Parental asthma* 23% (15/66) 30% (8/27) 26% (10/38) 50% (3/6) 63% (10/16) 0.03
V
˙
maxFRC z score 0.08 (0.96), 0.36 (1.28), ⫺0.21 (0.94), 0.22 (0.41), ⫺0.59 (0.90),
at 1 mo (SD) n ⫽ 67 n ⫽ 28 n ⫽ 39 n ⫽ 6n⫽ 17 0.02
PC
40
1mo
†
1.05 (0.77, 1.45), 1.34 (0.82, 2.21), 0.81 (0.59, 1.10), 1.04 (0.17, 6.34), 0.73 (0.49, 1.09),
n ⫽ 59 n ⫽ 26 n ⫽ 30 n ⫽ 6n⫽ 11 NS
Definition of abbreviations:NW⫽ no wheeze; 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; PC
40
⫽ concentration of histamine provoking
at least a 40% reduction in V
˙
maxFRC.
* Data missing for 11 fathers.
†
Expressed as geometric mean and 95% confidence interval (1.96 ⫻ SEM).
aged 3 years, 34 (27%) individuals aged 4 years, 33 (31%) aged
5 years, 26 (22%) aged 6 years, and 31 (17%) aged 11 years.
The incidence of wheeze was inversely related to age (
2
5
⫽
24.84, p ⬍ 0.001). At 11 years of age, 55 (28%) children had a
history of wheeze ever. A history of PDA was confirmed by
questionnaires in 55 (45%) children aged 6 years of which 28
(24%) children reported current PDA; at 11 years of age, the
respective figures for PDA ever and PDA currently were 73
(38%) and 28 (15%).
PC
40
Aged 1 Month and Respiratory Symptoms at 11 Years
Where PC
40
at 1 month of age was known, a history of diagnosed
asthma ever by 11 years of age (n ⫽ 59) was associated with
reduced PC
40
at 1 month of age compared with no history of
diagnosed asthma (n ⫽ 106) (geometric means 0.72 [95% confi-
dence interval [CI], 0.56, 0.94] vs. 1.09 [95% CI, 0.86, 1.38] p ⫽
0.04). There was no reduction in PC
40
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 PC
40
at
1 month and current wheeze and current PDA at 11 years of age.
V
˙
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 V
˙
maxFRC z score (⫺0.31 [SD 0.96], n ⫽ 64) com-
Figure 1. Box and whisker plot showing median and quartiles
values for z scores of V
˙
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.
pared 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 V
˙
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
V
˙
maxFRC z score aged 1 month for those individuals with cur-
rent 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 V
˙
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 V
˙
maxFRC and increased AR at 11 years were
considered, PW was more likely to be present for those individu-
als in both the lowest terctile for V
˙
maxFRC z score and with
increased AR,
2
8
for trend across groups with increased AR ⫽
19.0, p ⫽ 0.015 (Figure 2), for trend across groups without in-
creased AR
2
8
⫽ 12.2 (p ⬎ 0.1). PW was also most prevalent
among those individuals in the lowest tercile for V
˙
maxFRC z
924 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004
Figure 2. The relationship between terciles of V
˙
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 V
˙
maxFRC aged 1 month
in the lowest tercile and increased AR aged 11 years also
contained the majority of individuals with persistent wheeze
(black).
2
6
for trend across groups with increased AR ⫽ 19.0,
p ⫽ 0.015.
score aged 1 month and atopy aged 11 years (Figure 3),
2
8
for
trend across groups with atopy ⫽ 25.0, p ⫽ 0.002, and
2
8
for
trend across groups without atopy ⫽ 3.6, p ⬍ 0.8.
Comparisons between Wheezing Groups at 6 and
11 Years of Age
At 6 and 11 years of age, the prevalence of atopy, the dose
response slope, and prevalence of PDA differed significantly
between groups (Tables 3 and 4). There was also a nonsignificant
trend for reduced FEF
25–75%
at 6 and 11 years of age to be associ-
ated with PW when compared with NW. At 11 years of age,
mean z scores for FEV
1
were higher for the W11 and W0–3
groups compared with W4–6 and PW groups (analysis of vari-
ance, p ⫽ 0.005).
Longitudinal Tracking of Pulmonary Function
Pulmonary function data were available at 1 month, 6 years, and
11 years of age in 95 individuals. Table 1 compares the details
Figure 3. The relationship between terciles of V
˙
maxFRC at
1 month of age, atopy aged 11 years, and respiratory symp-
toms in childhood. The group containing individuals with z
scores of V
˙
maxFRC aged 1 month in the lowest tercile and
atopic aged 11 years also contained the majority of individuals
with persistent wheeze (black).
2
6
for trend across groups with
atopy ⫽ 25.0, p ⫽ 0.002.
of these individuals with the entire cohort. Figure 4 illustrates
how the mean z scores for all measurements of pulmonary func-
tion (i.e., V
˙
maxFRC at one month and FEF
25–75
at ages 6 and
11 years) within each wheezing group were consistently lower
during the period of follow-up for the group with PW (⫺0.57,
SD 0.91) compared with the NW (0.19, SD 0.88) and W0–3
groups (0.08, SD 1.04) (analysis of variance, p ⫽ 0.001).
Cox Proportional Hazards Model
When all variables were considered, V
˙
maxFRC aged 1 month
(hazards ratio ⫽ 0.18; 95% CI, 0.00, 0.73; p ⫽ 0.03) and DRS
aged 11 years (hazards ratio ⫽ 8.68; 95% CI, 3.27, 23.1; p ⬍
0.001) were independently associated with PW.
DISCUSSION
This study was designed to determine the relationship between
lung function in early life and respiratory outcome in later child-
hood, and the data suggest that airway function in early infancy
was associated with persistent childhood wheeze. Cross-sectional
Turner, Palmer, Rye, et al.: Infant Lung Function and Asthma 925
TABLE 3. DETAILS AT 6 YEARS OF AGE IN CHILDREN GROUPS DEFINED BY CHILDHOOD WHEEZE
NW W0–3 W4–6 W11 PW Trend Test
Atopic 31% (13/39) 24% (4/20) 32% (8/25) 0% (0/5) 77% (9/12) p ⫽ 0.009
Dose response slope* 2.8 (1.8, 4.3), n ⫽ 38 4.1 (2.0, 7.0), n ⫽ 18 3.3 (2.0, 5.0), n ⫽ 22 3.2 (0.2, 9.0), n ⫽ 4 18.9 (7.1, 44.3), n ⫽ 12 p ⬍ 0.001
Mean FEF
25–75
z score (SD) 0.28 (0.85), n ⫽ 38 0.03 (1.11), n ⫽ 18 ⫺0.01 (0.84), n ⫽ 24 ⫺0.41 (0.51), n ⫽ 4 ⫺0.43 (0.80), n ⫽ 12 NS
Mean FEV
1
z score (SD) 0.09 (0.79), n ⫽ 40 ⫺0.14 (0.91), n ⫽ 19 ⫺0.09 (0.73), n ⫽ 25 ⫺0.32 (0.29), n ⫽ 4 ⫺0.19 (0.72), n ⫽ 12 NS
Diagnosed asthma 5% (2/44) 10% (2/21) 36% (10/28) 20% (1/5) 72% (11/15) p ⬍ 0.001
Definition of abbreviations:NW⫽ no wheeze; 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.
* Expressed as geometric mean ⫾ 95% confidence interval (1.96 ⫻ SEM).
analyses demonstrated a relationship between reduced V
˙
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
V
˙
maxFRC at 1 month of age was shown to be associated with
PW, and this relationship was independent of atopy and in-
creased AR in infancy and childhood and, additionally, factors
that may influence V
˙
maxFRC. Individuals with atopy or in-
creased AR at 11 years of age who also had reduced V
˙
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 V
˙
maxFRC at 1 month of age and increased AR at 11
years of age (Figure 5).
Current understanding of the relationship between infant
pulmonary function and childhood asthma has been mostly in-
fluenced by a study from Tucson, which demonstrated an associa-
tion between reduced V
˙
maxFRC and transient and not PW (4).
The findings of this study are in contrast to the previous study
because we have found individuals with transient wheeze to have
normal pulmonary function at 1 month of age. The techniques
used to determine infant pulmonary function in the two studies
were very similar. The wheeze outcomes at 11 years of age can-
not be compared between the two studies because the Tucson
group has not published the relationship between V
˙
maxFRC in
infancy and wheeze at 11 years of age for their cohort. In keep-
ing with our findings, a study of young children with recurrent
wheeze with a follow-up to 6 years of age has reported that in-
dividuals with persisting wheeze had reduced V
˙
maxFRC at 17
months of age when compared with individuals with transient
wheeze (8). Both our study and the Tucson study agree that re-
duced V
˙
maxFRC in infancy is associated with reduced FEF
25–75%
at 11 years of age (12, 13, 16). We are not able to account for
the different outcomes that we have observed from our cohort
compared with the cohort in Tucson.
TABLE 4. DETAILS AT 11 YEARS OF AGE IN CHILDREN GROUPS DEFINED BY CHILDHOOD WHEEZE
NW W0–3 W4–6 W11 PW Trend test
Atopic 53% (34/64) 46% (13/28) 42% (15/36) 50% (3/6) 88% (15/17) p ⫽ 0.03
Dose–response slope*
(95% CI) 1.6 (1.2, 2.1), n ⫽ 66 2.3 (1.4, 3.4), n ⫽ 29 1.7 (1.2, 2.4), n ⫽ 34 2.4 (1.4, 3.6), n ⫽ 6 8.2 (3.2, 17.4), n ⫽ 17 p ⬍ 0.001
Mean FEF
25–75
z score
(SD) 0.08 (0.74), n ⫽ 64 ⫺0.28 (0.60), n ⫽ 28 0.08 (0.86), n ⫽ 37 0.06 (0.73), n ⫽ 6 ⫺0.46 (1.01), n ⫽ 16 NS
Mean FEV
1
z score
(SD) ⫺0.03 (0.97), n ⫽ 65 0.41 (0.97), n ⫽ 28 ⫺0.21 (0.96), n ⫽ 37 1.10 (0.88), n ⫽ 6 ⫺0.28 (1.0), n ⫽ 17 0.005
Diagnosed asthma 3% (2/67) 4% (1/28) 10% (4/39) 50% (3/6) 82%* (14/17) p ⬍ 0.001
Definition of abbreviations:CI⫽ confidence interval; NW ⫽ no wheeze; 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.
* Expressed as geometric mean ⫾ 95% confidence interval (1.96 ⫻ SEM).
A relationship between reduced V
˙
maxFRC in infants, in-
creased AR in childhood, and PW might explain why early
wheeze is transient in some children but persistent in others.
Reduced V
˙
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 V
˙
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 in-
creased 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 V
˙
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 phe-
notypes. 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 sup-
port 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 V
˙
maxFRC at 1 month of age, as evidenced by flow
926 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004
Figure 4. Chart demonstrating mean z scores for V
˙
maxFRC at 1 month
and FEF
25–75%
at 6 and 11 years of age for groups determined by wheeze
outcome.
limitation during tidal expiration, transient wheeze, and in-
creased AR in childhood (16). In this study, we report that
reduced V
˙
maxFRC and increased AR in childhood were inde-
pendently 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 in-
creased childhood AR associated with atopy.
This study has confirmed previous observations that measure-
ments of V
˙
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
Figure 5. Schematic representation of the relationship between re-
duced V
˙
maxFRC in infancy and AR in childhood, which appears to be
important to persistent childhood wheeze and asthma.
interrelationship might not be expected. The coefficient of varia-
tion for V
˙
maxFRC in infants may vary between 11% and 36%
(27), although measurement of V
˙
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 FEV
1
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 V
˙
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 chil-
dren 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). V
˙
maxFRC does not distin-
guish between reduced airway caliber and altered airway compli-
ance; 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 out-
comes because antenatal exposure to tobacco products has been
associated with reduced V
˙
maxFRC in our cohort (21) and an-
other (33). Despite adjusting V
˙
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 re-
ported 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 question-
naire 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 V
˙
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 evi-
denced by reduced V
˙
maxFRC, determined at an early age and
the later onset of increased AR associated with atopy. Our data
TABLE 5. THE FINAL OUTPUT FROM A COX PROPORTIONAL
HAZARDS REGRESSION MODEL IN WHICH THE OUTCOME
VARIABLE WAS CODED PERSISTENT WHEEZE (⫽ 1) AND
NO WHEEZE (⫽ 0)
RR 95% CI for RR p Value
Dose–response slope aged 11 yr 8.68 3.27, 23.1 ⬍ 0.001
V
˙
maxFRC aged 1 mo 0.18 0.00, 0.73 0.03
Definition of abbreviations:CI⫽ confidence interval; RR ⫽ relative risk.
Predictive variables included log V
˙
maxFRC and log PC
40
aged 1 month, log
dose response slope aged 11 years, atopy aged 11 years, sex, maternal smoking
during pregnancy, age (weeks), length (cm), and weight (kg) at 1-month
assessment.
Turner, Palmer, Rye, et al.: Infant Lung Function and Asthma 927
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
V
˙
maxFRC in early life and increasing atopy in childhood require
further study.
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, accom-
modation and honorarium ($1500) from GSK for speaking at approximately two
conferences/workshops each year; P.N.L. has no declared conflict of interest.
Acknowledgment : The authors acknowledge the contribution of many colleagues
over the last 15 years and are indebted to the families involved in the Osborne
Park family asthma study.
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