Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years.
ABSTRACT We investigated whether environmental control during pregnancy and early life affects sensitization and lung function at the age of 3 years. High-risk children (n = 251) were prenatally randomized to stringent environmental control (active) or no intervention (control). Questionnaires, skin testing, IgE, and specific airway resistance (sRaw) measurement were completed at the age of 3 years. Children in the active group were significantly more frequently sensitized compared with control subjects (at least one allergen by skin tests: risk ratio, 1.61; 95% confidence interval [CI], 1.02-2.55; p = 0.04; mite by IgE: risk ratio, 2.85; 95% CI, 1.02-7.97; p = 0.05). However, sRaw was significantly better in the active group (kiloPascal/second, geometric mean [95% CI]: 1.05 [1.01-1.10] vs. 1.19 [1.13-1.25], p < 0.0001, active vs. control). Maximal flow at functional residual capacity was measured using rapid thoracic compression at the age of 4 weeks in a subgroup. Prospective lung function data (at infancy and 3 years) were obtained in 32 children (14 active and 18 control). There was no difference in infant lung function between the groups, but at 3 years, sRaw was significantly lower in the active compared with control children (p = 0.003). Stringent environmental control was associated with increased risk of mite sensitization but better results for some measurements of lung function in high-risk children at the age of 3 years.
- [Show abstract] [Hide abstract]
ABSTRACT: In most children with asthma and atopy, onset of disease occurs early in life, indicating a crucial role of in utero and early childhood environment. However, only a small part of this burden of disease established early in life has been explained. To examine the effects of early environmental exposures on the development of asthma and atopy within the setting of an affluent urban population. The authors followed 526 German children from birth to 5 years of age. Parental interviews in pregnancy and then yearly assessed the health of the child and environmental characteristics. Endotoxin and allergens in house dust were measured at 3 months. Atopic sensitization was assessed at 1 and 5 years. In atopic mothers, acute atopic symptoms during pregnancy were associated with increased risk of early atopic dermatitis (adjusted odds ratio [aOR] 1.74, 95% confidence interval [CI] 1.00-3.02) and allergic rhinitis at 5 years (aOR 2.11, 95% CI 1.01-4.41). Further, maternal illnesses during pregnancy (ie, repeated common colds) increased the risk of asthma at 5 years (aOR 2.31, 95% CI 1.12-4.78). Endotoxin in the child's mattress was inversely associated with atopic sensitization (aOR 0.79, 95% CI 0.64-0.97) and asthma (aOR 0.71, 95% CI 0.55-0.93). A contrasting effect of early endotoxin and mite exposure was observed for mite sensitization: mite exposure increased the risk of mite sensitization at 5 years (aOR 1.30, 95% CI 1.11-1.53), whereas endotoxin exposure was inversely associated with mite sensitization (aOR 0.73, 95% CI 0.57-0.95). Factors affecting the in utero environment, such as maternal atopy and infections, and bacterial exposure in pregnancy or early life may act as immunomodulators enhancing or inhibiting the development of asthma and atopy in childhood.Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 02/2014; 112(2):132-139.e1. · 3.45 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Asthma is the most common chronic disease of childhood and, in the latter part of the 20th century, reached epidemic proportions. Asthma is generally believed to result from gene-environment interactions. There is consensus that a 'window of opportunity' exists during pregnancy and early in life when environmental factors may influence its development. We review multiple environmental, biologic and sociologic factors that may be important in the development of asthma. Meta-analyses of studies have demonstrated that multifaceted interventions are required in order to develop asthma prevention. Multifaceted allergen reduction studies have shown clinical benefits. Asthma represents a dysfunctional interaction with our genes and the environment to which they are exposed, especially in fetal and early infant life. The increasing prevalence of asthma also may be an indication of increased population risk for the development of other chronic non-communicable autoimmune diseases. This review will focus on the factors which may be important in the primary prevention of asthma. Better understanding of the complex gene-environment interactions involved in the development of asthma will provide insight into personalized interventions for asthma prevention.Expert Review of Clinical Immunology 12/2013; 9(12):1267-78. · 2.89 Impact Factor
- Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 12/2013; 111(6):465-507. · 3.45 Impact Factor
Early Life Environmental Control
Effect on Symptoms, Sensitization, and Lung Function at Age 3 Years
Ashley Woodcock, Lesley A. Lowe, Clare S. Murray, Bridget M. Simpson, Spyros D. Pipis, Patricia Kissen,
Angela Simpson, and Adnan Custovic on behalf of the NAC Manchester Asthma and Allergy Study Group
North West Lung Centre, Wythenshawe Hospital, Manchester, United Kingdom
We investigated whether environmental control during pregnancy
and early life affects sensitization and lung function at the age of
3 years. High-risk children (n ? 251) were prenatally randomized
tostringent environmentalcontrol(active) orno intervention(con-
in the active group were significantly more frequently sensitized
compared with control subjects (at least one allergen by skin tests:
risk ratio, 1.61; 95% confidence interval [CI], 1.02–2.55; p ? 0.04;
mite by IgE: risk ratio, 2.85; 95% CI, 1.02–7.97; p ? 0.05). However,
geometric mean [95% CI]: 1.05 [1.01–1.10] vs. 1.19 [1.13–1.25],
p ? 0.0001, active vs. control). Maximal flow at functional residual
capacity was measured using rapid thoracic compression at the age
of 4 weeksin a subgroup. Prospective lung functiondata (at infancy
but at 3 years, sRaw was significantly lower in the active compared
with control children (p ? 0.003). Stringent environmental control
was associated with increased risk of mite sensitization but better
at the age of 3 years.
Keywords:asthma; atopy;environmentalcontrol;lung function;primary
There are strong associations between allergic sensitization and
asthma and early life allergen exposure and sensitization. These
raise the questions of whether reducing exposure to allergens
in early life can reduce sensitization and whether this has any
effect on the development of allergic disease. The National
Asthma Campaign Manchester Asthma and Allergy Study is a
birth cohort study investigating risk factors for the development
of asthma and allergic diseases (1–3). Nested within the cohort
is a randomized trial of the effect of stringent environmental
control in high-risk children with no pets at birth (2, 3). We have
previously reported that compliance with this regime is excellent
(it achieved a low-allergen environment during pregnancy and
in early life  and low mite (Dermatophagoides pteronyssinus),
cat (Felis domesticus), and dog (Canis familiaris) allergen levels
were maintained until age 3 years ). Clinical data at the age
of 1 year suggested that environmental manipulation can reduce
respiratory symptoms (3), but these early symptoms may not
relate to the development of asthma.
(Received in original form January 19, 2004; accepted in final form May 7, 2004)
Supported by the National Asthma Campaign and the Moulton Charitable Trust.
Correspondence and requests for reprints should be made to Adnan Custovic,
M.D., Ph.D., North West Lung Centre, Wythenshawe Hospital, Manchester M23
9LT, UK. E-mail: email@example.com
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200401-083OC on May 13, 2004
Internet address: www.atsjournals.org
Vol 170. pp 433–439, 2004
in subjectively reported symptoms, which is inevitable in an
intensive environmental intervention, emphasizes the need for
objective outcomes (e.g., lung function). Preschool children cannot
always reliably perform lung function requiring forced maneuvers.
Specific airway resistance (sRaw) can be measured during nor-
mal tidal breathing using a single-step procedure without the
measurement of thoracic gas volume, which obviates the need
ment is potentially useful in young children, as a parent can
accompany the child inside the plethysmograph cabinet if neces-
sary (6). sRaw is a measure of airway caliber independent of lung
size, and airway narrowing results in elevated values. We have
previously reported on predictors of lung function at the age of
3 years in the observational arm of the cohort (7). We now report
risk children to investigate the effect of environmental control
during pregnancy and early life on these outcomes.
Subjects were recruited prenatally by screening parents using skin test-
ing and questionnaires regarding allergic diseases (1). High-risk couples
living in homes without pets (both parents atopic, mother sensitized to
indoor allergen) were randomized to stringent environmental control
(active) or normal regime (control) (1, 2). Of 1,499 couples meeting
the inclusion criteria, 511 were identified as high risk, and 251 were
prenatally randomized (Figure 1). The study had the approval of the
local research ethics committee.
Environmental control measures introduced prenatally are described in
detail elsewhere (1). The intervention comprised allergen-impermeable
covers for the maternal and child’s bed, an allergen-impermeable cot/
carrycot mattress, a high-filtration vacuum cleaner, vinyl flooring in the
child’s bedroom, bed linen that was hot washed weekly, and a washable
We visited homes immediately after birth and at the age of 3 years.
Dust samples from the child’s bed, the child’s bedroom floor, the paren-
tal bed, and the lounge floor were collected on each occasion. Mite
(Der p 1), cat (Fel d 1), and dog (Can f 1) allergens were assayed using
monoclonal antibody-based enzyme-linked immunoassays (2, 4). We
estimated cumulative allergen exposure over the first 3 years of life as
a sum of allergen levels in four sites at two time points.
During the first 3 years of life, parents kept diary cards regarding their
child’s health capturing symptoms, physician-diagnosed illnesses, and
medication. Children attended a review at the age of 3 years (? 4 weeks).
A standard respiratory questionnaire (2) was interviewer administered.
Sensitization status was ascertained by skin prick testing (mite, cat,
dog, mixed grasses, milk, egg [Bayer, Elkahrt, IN]; sensitization defined
as a wheal diameter 3 mm greater than negative control) and measure-
ment of specific serum IgE (mite, cat, dog, milk, egg; UniCAP assay
[Pharmacia, Uppsala, Sweden]; sensitization defined as a concentration
of allergen-specific IgE ? 0.35 kU/L).
sRaw was measured using a constant-volume whole-body plethys-
mograph (Jaeger, Wu ¨rzburg, Germany) as previously described (7), by
434AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1702004
Figure 1. Schematic representation of trial profile.
HR ? high risk.
a single-step procedure from the simultaneously measured changes of
respiratory flow and plethysmographic pressure, omitting the measure-
ment of total gas volume. sRaw was calculated from the medians of
five technically acceptable loops (7). Three measurements of effective
sRaw were performed, and the mean of these was used in the analysis
(i.e., each child performed at least 15 loops). Children were asymptom-
atic at the time of lung function assessment.
A subgroup of 69 infants was randomly recruited for lung function
tests at the age of 1 month (8). V˙maxFRC was measured using rapid
thoracic compression technique (8).
We aimed to determine the magnitude of effect of environmental con-
trol on symptoms, sensitization, and lung function. Outcome data are
presented as relative risks and 95% confidence intervals (CIs) (9). We
estimated the outcome probabilities for active in relationship to the
control group. To assess the independent effect of being in the active
group on sensitization, adjustment for potential confounding factors
(parental asthma, maternal smoking, child’s sex, presence of older sib-
lings, pet ownership at the age of 3 years) was modeled using multivari-
ate logistic regression. Analysis of the factors affecting lung function
was performed using general analysis of variance models. Results are
presented as adjusted geometric means, 95% CI, F values, and p values.
Figure 1 shows the trial profile; 239 participants attended the
follow-up at the age of 3 years (128 active and 111 control). The
groups were well matched for sex, breast-feeding, number of
siblings, socioeconomic status, parental history of asthma, and
maternal smoking (3). Five participating families in the active
(3.8%) and seven in the control group (5.9%) withdrew between
follow-ups at 1 and 3 years. By the age of 3 years, 9 families
(three active and six control) acquired a dog, and 11 families
(four active and seven control) acquired a cat.
A full set of eight dust samples at birth and at the age of 3 years
was collected from 219 participants (91.6%; 117 active and 102
control). Allergen levels are expressed both as micrograms of
allergen per gram of dust and total allergen recovered (Table 1).
Der p 1 and Fel d 1 allergen levels were substantially and signifi-
cantly lower in the active group compared with control group
(both concentration and total allergen), whereas for Can f 1,
there was a significant difference between the groups in the total
allergen recovered but not in allergen concentration.
Table 2 shows the frequency of signs and symptoms suggestive
of atopic diseases in the two groups. The estimate of relative
risks for most of the respiratory symptoms and eczema appeared
lower in active compared with the control group, but this did
not reach statistical significance.
Woodcock, Lowe, Murray, et al.: Effect of Environmental Control435
TABLE 1. HOUSE DUST MITE, CAT, AND DOG ALLERGEN LEVELS IN TWO GROUPS
(n ? 117)
(n ? 102)p Value
Der p 1, ?g/g
Total Der p 1, ng
Fel d 1, ?g/g
Total Fel d 1, ng
Can f 1, ?g/g
Total in Can f 1, ng
Total quantity of dust, mg
Definition of abbreviations: Can f ? Canis familiaris; Der p ? Dermatophagoides pteronyssinus; Fel d ? Felis domesticus.
Data expressed as ?g/g dust and total allergen recovered in ng, geometric means, and 95% confidence intervals.
Number represents the sum of allergen levels in lounge floor, parental mattress, child’s mattress, and child’s bedroom floor at
birth and at the age of 3 years.
skin tested (except for egg, which was not performed in a further
of children developed positive skin test to inhalant allergens,
and dust mite was the most common sensitizer. The estimate of
relative risk of being sensitized (skin test positive to at least one
allergen) was significantly higher in the active group compared
with the control group (relative risk, 1.61; 95% CI, 1.02–2.55).
In the multivariate logistic regression analysis, controlling for the
effect of sex, socioeconomic status, maternal smoking, breast-
feeding, and position in sibship, atopic sensitization was signifi-
cantly and independently associated with active group (odds
ratio, 2.00; 95% CI, 1.04–3.86; p ? 0.04), male sex (odds ratio,
2.49; 95% CI, 1.30–4.75; p ? 0.006), and being a first-born child
(odds ratio, 1.90; 95% CI, 1.00–3.62; p ? 0.05). Inclusion of
cumulative exposures to Der p 1, Fel d 1, and Can f 1 (or levels
in any sampling site at any time point) did not affect the results.
Repeat of the analysis using a 2-mm cut-off point for wheal
diameter to define sensitization did not materially change the
IgE levels. A total of 122 children (51%) provided a blood
sample for measurement of total and specific serum IgE. There
was no difference in the level of total serum IgE between the
two groups (kU/L, geometric means and 95% CI: 21, 14–32 versus
26, 18–39, active and control group, respectively, p ? 0.41). How-
ever, the proportion of children sensitized to dust mite was signifi-
cantly higher in the active compared with control group (relative
TABLE 2. SYMPTOMS SUGGESTIVE OF ALLERGIC DISORDERS IN TWO GROUPS OF CHILDREN
(n ? 128)
(n ? 111)
Relative Risk and p Value
(95% Confidence Interval)n%n%
Current wheeze (last 3 mo)
Wheeze age 1 to 3 yr
Wheezy attacks requiring medication
? 3 episodes of severe wheeze
Wheeze after exertion
Cough apart from colds
Cough after exertion
Cough with excitement
Current asthma medication
0.81 (0.58–1.13), p ? 0.23
0.79 (0.46–1.35), p ? 0.4
0.74 (0.52–1.07), p ? 0.13
0.82 (0.54–1.24), p ? 0.38
0.74 (0.26–2.15), p ? 0.78
0.87 (0.31–2.4), p ? 0.79
0.91 (0.63–1.31), p ? 0.68
0.65 (0.32–1.32), p ? 0.31
0.87 (0.39–1.92), p ? 0.82
0.35 (0.11–1.08), p ? 0.09
1.00 (0.50–2.01), p ? 1.0
0.81 (0.40–1.64), p ? 0.68
0.52 (0.13–2.13), p ? 0.48
0.73 (0.47–1.14), p ? 0.18
risk, 2.85; 95% CI, 1.02–7.97; p ? 0.05; Table 3). Among children
sensitized to dust mite (i.e., specific IgE ? 0.35 kUa/L), there was
no difference in the levels of mite-specific IgE antibodies between
vs. 2.8, 0.7–4.7, active vs. control, respectively, p ? 0.86, Mann-
Whitney U test).
In the multivariate logistic regression analysis, controlling
for the effect of sex, maternal smoking, socioeconomic status,
position in sibship, Der p 1 exposure, and total serum IgE,
sensitization to dust mite was significantly and independently
associated with the active group (odds ratio, 4.00; 95% CI, 1.10–
14.52; p ? 0.03) and the total serum IgE level (odds ratio, 2.03;
95% CI, 1.39–2.96;p ?0.001). Therewas nointeraction between
the risk group and allergen exposure (p ? 0.53).
There was no association between cat and/or dog ownership
at the age of 3 years and either specific sensitization to cat and
dog or sensitization to any allergen.
Of 239 reviewed children, an acceptable sRaw measurement was
obtained in 127 subjects (53.1%; Figure 1); 30 (15 active and 15
control) were accompanied by a parent during the measure-
ments. There was no difference between children who success-
fully completed lung function testing compared with those who
did not in the prevalence of sensitization, reported symptoms,
maternal smoking, and maternal asthma. Similar to our finding
current wheeze had significantly poorer lung function compared
436AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1702004
TABLE 3. ATOPIC SENSITIZATION ASSESSED BY SKIN PRICK TESTING AND SPECIFIC SERUM IGE
(n ? 125)
(n ? 100)
Relative Risk and p Value
(95% confidence interval)n%n%
Skin prick tests
Fel d 1
Can f 1
Fel d 1
Can f 1
1.67 (0.88–3.15), p ? 0.15
1.49 (0.62–3.58), p ? 0.48
1.87 (0.74–4.68), p ? 0.24
1.33 (0.69–2.59), p ? 0.45
2.31 (0.77–6.92), p ? 0.19
1.61 (1.02–2.55), p ? 0.04
Active, n ? 73
Control, n ? 49
2.85 (1.02–7.97), p ? 0.05
1.01 (0.38–2.65), p ? 1.0
0.94 (0.32–2.79), p ? 1.0
2.72 (0.60–12.3), p ? 0.19
1.35 (0.43–4.24), p ? 0.76
1.34 (0.77–2.35), p ? 0.33
Definition of abbreviation: NA ? not applicable.
with those without (sRaw, kPa/s, geometric means, and 95%
CI, 1.22,1.10–1.38 vs. 1.10, 1.06–1.14, wheezers vs. nonwheezers,
respectively, p ? 0.03). There was no effect of allergen exposure
on lung function.
sRaw in the two groups of children is presented in Table 4.
A comparison between two groups was performed using t test.
better in the active group compared with the control group
(Table4).Active childrenhadbettersRaw thencontrolsubjects,
even when subdivided according to personal sensitization and
parentally reported symptoms (i.e., skin test positive active chil-
dren had significantly better lung function then skin test positive
control children; skin test negative active children had signifi-
cantly better lung function compared with skin test negative
control children; for children with a history of wheeze there was
a trend for active children to have better sRaw than control
children; Table 4).
Regression analysis was performed including risk group (ac-
tive or control) and variables for which a significant association
with sRaw was found in the observational part of the cohort (7)
(sex, child’s sensitization status, child’s history of wheeze and
eczema, maternal and paternal history of asthma, maternal
smoking during pregnancy). Effects of individual factors and
TABLE 4. SPECIFIC AIRWAY RESISTANCE IN THE ACTIVE
AND CONTROL GROUP AT 3 YEARS OF AGE (WHOLE
GROUP AND SUBDIVIDED ACCORDING TO PERSONAL
SENSITIZATION AND PARENTALLY REPORTED SYMPTOMS)
ActiveControl p Value
68 Active, 59 control
48 Active, 44 control
20 Active, 14 control
51 Active, 40 control
History of wheeze
17 Active, 19 control
Values are geometric means and 95% Confidence intervals in kPa/s.
* One child who successfully completed lung function measurement was not
interactions between factors were investigated. Independent sig-
nificant associations with sRaw were seen for risk group (F ?
There were no significant interactions between the different risk
factors (e.g., risk group and sensitization status, F ? 0.07, p ?
0.79). The estimated marginal means (means adjusted for other
allocation were as follows: active, 1.11, 95% CI, 1.03–1.20, and
control 1.25, 95% CI 1.16–1.35. For sensitization status, they
were as follows: not sensitized 1.12, 95% CI 1.04–1.20, and sensi-
tized 1.25, 95% CI 1.15–1.35.
Lung Function in Infancy and at 3 Years of Age
Prospective data on lung function in infancy and at the age of
3 years were available in a subgroup of 32 children (14 active
and 18 control). At the age of 4 weeks there was no difference
in V˙maxFRC between active and control children (p ? 0.49;
Figure 2). However, in the same subgroup of children at the age
of 3 years, lung function (sRaw) was significantly better in the
active compared with control group (p ? 0.003; Figure 2).
Our results suggest that stringent environmental control during
pregnancy and early life is associated with increased risk of
sensitization to dust mite, but better results for some measure-
ments of lung function in children at high risk of allergic disease
at the age of 3 years. There were no significant differences in
respiratory symptoms between the groups.
Limitations of the Study
The main limitation of the study is the length of the follow-up,
which is not sufficient to disentangle different wheezing pheno-
types (10). We therefore emphasize the objective measures of
secondary phenotypes, which may or may not be associated with
subsequent asthma (i.e., atopic sensitization and lung function).
Another potential limitation is the fact that lung function is
available in only a subset of subjects. However, this is unlikely
children who completed lung function measurement compared
with those who did not in the prevalence of sensitization, re-
ported symptoms, maternal smoking, and maternal asthma.
Woodcock, Lowe, Murray, et al.: Effect of Environmental Control 437
Figure 2. Prospective data on lung function in the high-risk active (HRA; n ? 14) and high-risk control (HRC; n ? 18) children in infancy and at
3 years of age. Geometric means (GM) and 95% confidence interval (CI) are shown. sRaw ? specific airway resistance.
Comparison with Other Intervention Studies
In the Isle of Wight study, dietary intervention combined with
eczema by the age of 1 year (11). Although at the age of 4 years
the difference for asthma was no longer significant (12), a recent
report from the 8-year follow-up suggested that allergen avoid-
ance in infancy may prevent some cases of childhood asthma (13).
A Canadian cohort study combined dietary restrictions and dust
mite avoidance with advice on avoidance of tobacco smoke and
rehoming the pets and reported a significantly reduced risk for
probable asthma but no difference in allergic sensitization at the
age of 18 months (14). In the Dutch Prevention and Incidence of
zation at the age of 2 years (15). Similarly, in the Australian Child-
hood Asthma Prevention Study, house dust mite avoidance inter-
vention did not affect wheeze and sensitization but surprisingly
resulted in a significantly higher prevalence of eczema (16).
Why Did Children Who Have Environmental Control Become
Sensitized to Dust Mites?
In the National Asthma Campaign Manchester Asthma and
control compared with any of the previously mentioned studies,
resulting in significantly lower allergen levels in the active group
both in early life (2) and at the age of 3 years (4). Follow-up at
the age of 1 year suggested a significant reduction of severe
wheeze and prescription of medication for wheeze but no differ-
ence in allergic sensitization (3). By 3 years of age, although the
relative risks for respiratory symptoms tended to be generally
lower in the active group, the differences did not reach statistical
significance. However, we observed the counterintuitive finding
of a higher prevalence of mite sensitization in the intervention
group, despite considerably lower allergen exposure.
How did the children become sensitized to mite allergens if
they had controlled exposure at home? Our intervention was
very successful in reducing mite allergen levels, and it is unlikely
that more stringent environmental control in the home is feasi-
ble. The avoidance measures focused primarily on the sleeping
areas in the house, and this is where the largest reduction in
allergen levels was achieved (2, 4). We used a composite index
of exposure comprising the sum of allergen levels in all living
areas of the house and at two different time points to give us a
better estimate of child’s actual exposure during early life. It is
clear from our data that even with this complex multifaceted
intervention, there remains a residual mite allergen exposure
within the home. This, coupled with a possible exposure in the
homes of relatives or outside the home, may lead to intermittent
exposure to mite allergen. It is possible that transient and inter-
mittent exposure may favor sensitization in comparison to con-
control removes a protective factor (e.g., endotoxin), exposure
to which could decrease the likelihood of sensitization (17), or
that the lack of exposure in early life resulted in a missed chance
for development of tolerance. However, increased sensitization
with lower allergen exposure in the active group does not have
an adverse effect on either the symptoms of allergic disease or
lung function at the age of 3 years.
Effect of Intervention on Lung Function
It is important to emphasize that the absence of allergen expo-
sure in sensitized individuals cannot explain the observed effect
of intervention on lung function because lung function was sig-
sensitized and nonsensitized children. We have observed an im-
portant disconnect between sensitization and lung function con-
sequent to intervention. We have previously reported that
among 3-year-olds, sRaw is worse in sensitized compared with
nonsensitized children and in high-risk children compared with
medium risk or low risk (7). However, in the active group, sRaw
was significantly better compared with control, despite a higher
proportion of children being sensitized.
ties in airway function and the immunologic component of asthma.
The environmental control clearly reduced exposure not just to
438 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 170 2004
allergens. The total quantity of dust collected from homes was
much lower in the active group, likely resulting in lower exposure
to different microbial and fungal products. These may have differ-
ential effects on the developing lung and on sensitization.
Longitudinal data provide evidence for the important rela-
tionship between deficitsin lung function andthe clinical expres-
sion of asthma, suggesting that the majority of asthma originates
in childhood in association with disordered lung function that
tracks to subsequent persistent disease (18, 19). The Melbourne
Asthma Study assessed lung function from the age of 7 to 42
years (18). Subjects with asthma and severe asthma were found
to have persistent airflow obstruction throughout childhood and
into adult life. The magnitude of the difference in lung function
did not increase over time, suggesting that the deficits had oc-
curred in early childhood and did not progress. Further evidence
of the relationship between childhood events and respiratory
health in adult life comes from a New Zealand study that fol-
lowed 1,037 individuals from the ages of 9 to 26 years (19).
Subjects with a low postbronchodilator FEV1/VC ratio at 26
years of age already had a disordered lung function at the age
of9 years,with aslowprogressive lossof reversibility,suggesting
that airway remodeling begins in early childhood. Furthermore,
with abnormal lung function and the development of asthma by
the age of 6 years (20), and flow limitation in infancy predicts
increased airway responsiveness at the age of 11 years (21). Ex-
trapolating these results to our study, we hypothesize that the
improvement in lung function in early life may affect the subse-
discount the possibility that the variation in lung function may be
the basis for the different responses to the intervention.
Effect of Intervention on Lung Function: In Utero or Postnatal?
Are children born with the deficit in lung function, or does a
loss occur in early life (10)? Data from Tucson suggest that a
deficit in lung function in “persistent wheezers” is not present
early after birth but is acquired during the first years of life (22,
23). In contrast, the recent data from Australia suggest that
reduced lung function in infancy is associated with persistent
wheeze at 11 years of age independently of increased airway
responsiveness and atopic sensitization in childhood (24). In our
study, the differences in lung function between groups could be
of environmental control on lung development in utero. Either
of these seems unlikely. In children with longitudinal data, we
observed no difference in lung function between the active and
control groups in infancy, but there was a marked difference at
the age of 3 years. However, we have to be cautious when
interpreting the lung function data in infancy and at 3 years, as
weused twodifferent measurements,which mayreflect different
pathologies, and direct comparisons are difficult. Nevertheless,
we believe that both methods reflect similar mechanical proper-
ties of the lung. Thus, the difference between the groups is likely
to have arisen after 4 weeks but before 3 years of age because
of some factor(s) affected by environmental control.
Childhood lung function is associated with respiratory disease
in later life (18, 19). Environmental control may improve lung
function in early life and reduce subsequent asthma morbidity
and severity. However, further measures of lung function, such
as forced expiratory measures, are needed at ages 5 to 8 years
to explore further these interesting observations. Furthermore,
the increase in sensitization in the intervention group is of con-
cern, and only further follow-up will determine the long-term
effects of the intervention.
Conflict of Interest Statement: A.W. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript; L.A.L.
does not have a financial relationship with a commercial entity that has an interest
in the subject of this manuscript; C.S.M. does not have a financial relationship
with a commercial entity that has an interest in the subject of this manuscript;
B.M.S. does not have a financial relationship with a commercial entity that has
an interest in the subject of this manuscript; S.D.P. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript; P.K. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript; A.S. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript; A.C. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript.
Acknowledgment: The authors thank all of the parents and children who took
part, all members of National Asthma Campaign Manchester Asthma and Allergy
Study group, and Julie Morris, M.Sc., for statistical advice.
1. Custovic A, Simpson BM, Murray CS, Lowe L, Woodcock A. The Na-
atr Allergy Immunol 2002;13:32–37.
2. Custovic A, Simpson BM, Simpson A, Hallam C, Craven M, Brutsche
M, Woodcock A. Manchester Asthma and Allergy Study: low-allergen
environment can be achieved and maintained during pregnancy and
in early life. J Allergy Clin Immunol 2000;105:252–258.
3. Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A. Effect of
environmental manipulation in pregnancy and early life on respiratory
symptoms and atopy during the first year of life: a randomised trial.
4. Simpson A, Simpson B, Custovic A, Craven M, Woodcock A. Stringent
on mite, cat and dog allergen. Clin Exp Allergy 2003;33:1183–1189.
airway resistance. Pediatr Res 1976;10:998–999.
6. Klug B, Bisgaard H. Measurement of specific airway resistance by ple-
thysmography in young children accompanied by an adult. Eur Respir
7. Lowe L, Murray CS, Custovic A, Simpson BM, Kissen PM, Woodcock
A. Specific airway resistance in three year-old children. Lancet 2002;
8. Murray CS, Pipis SD, McArdle EC, Lowe L, Custovic A, Woodcock A.
Lung function at one month as a risk factor for infant wheezing in a
high risk population. Thorax 2002;57:388–392.
9. Gardner MJ, Altman DG. Statistics with confidence: confidence intervals
and statistical guidelines. London, UK: BMJ Books; 1989.
10. Martinez FD. Development of wheezing disorders and asthma in pre-
school children. Pediatrics 2002;109:362–367.
12. Hide DW, Matthews S, Tariq S, Arshad SH. Allergen avoidance in in-
fancy and allergy at 4 years of age. Allergy 1996;51:89–93.
atopyduring childhoodbyallergen avoidanceininfancy: arandomised
controlled study. Thorax 2003;58:489–493.
14. Chan-Yeung M, Manfreda J, Dimich-Ward H, Ferguson A, Watson W,
Becker A. A randomized controlled study on the effectiveness of a
multifaceted intervention program in the primary prevention of asthma
in high-risk infants. Arch Pediatr Adolesc Med 2000;154:657–663.
15. Koopman LP, van Strien R, Kerkhof M, Wijga A, Smit HA, de Jongste
controlledtrial ofhousedustmite-impermeable mattresscovers:effect
on symptoms in early childhood. Am J Respir Crit Care Med 2002;166:
16. Mihrshahi S, Peat JK, Marks GB, Mellis CM, Tovey ER, Webb K,
Britton WJ, Leeder SR. Eighteen-month outcomes of house dust mite
Prevention Study (CAPS). J Allergy Clin Immunol 2003;111:162–168.
17. Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L,
Maisch S, Carr D, Gerlach F, Bufe A, et al. Environmental exposure
to endotoxin and its relation to asthma in school age children. N Engl
J Med 2002;347:869–877.
18. Phelan PD, Robertson CF, Olinski A. The Melbourne Asthma Study:
1964–1999. J Allergy Clin Immunol 2002;109:189–194.
19. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbi-
son GP, Sears MR. Risk factors for airway remodelling in asthma
manifested by a low postbronchodilator FEV1/vital capacity ratio: a
Woodcock, Lowe, Murray, et al.: Effect of Environmental Control439
longitudinal population study from childhood to adulthood. Am J
Respir Crit Care Med 2002;165:1480–1488.
20. Palmer LJ, Rye PJ, Gibson NA, Burton PR, Landau LI, LeSouef PN.
Airway responsiveness in early infancy predicts asthma, lung function,
and respiratory symptoms by school age. Am J Respir Crit Care Med
21. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Young S, Landau
LI, Le Souef PN. Infants with flow limitation at 4 weeks: outcome at
6 and 11 years. Am J Respir Crit Care Med 2002;165:1294–1298.
22. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. Dimin-
ished lung function as a predisposing factor for wheezing respiratory
illness in infants. N Engl J Med 1988;319:1112–1117.
23. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan
WJ. Asthma and wheezing in the first six years of life. N Engl J Med
24. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Cox M, Young
S, Goldblatt J, Landau LI, Le Souef PN. The relationship between
infant airway function, childhood airway responsiveness and asthma.
Am J Respir Crit Care Med 2004;169:921–927.