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.
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ABSTRACT: The NACManchester Asthma and Allergy Study is a prospective study of the development of asthma and allergies in childhood. The subjects (995 children at age 3 years) were recruited in utero by screening parents in the antenatal clinic using skin prick testing and a questionnaire regarding allergic diseases. Children were assigned to risk groups according to parental atopic status (high risk, both parents atopic; medium risk, one parent atopic; low risk, neither parent atopic). A subgroup of those at high risk (with no pets in the home) was randomized to stringent environmental control (allergen impermeable covers for the parental and infant bed, hot washing of bedding weekly, HEPA vacuum cleaner, hard floor for the nursery), and the remainder followed a normal regime. The children have been followed prospectively. The environmental influences are very clearly defined. Measurements of environmental exposures include levels of house dust mite; cat and dog allergens during pregnancy and early life; pet ownership and exposure; childcare arrangements; number of siblings; vaccination uptake; thorough dietary questionnaire; and endotoxin exposure. Further unique objective outcome in the cohort is the assessment of lung function in preschool children using specific airways resistance, which at age 3 years clearly reflects both genetic and environmental influences.Pediatric Allergy and Immunology 02/2002; 13 Suppl 15:32-7. · 3.38 Impact Factor
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ABSTRACT: Early exposure to dust mite allergens may be critical for primary sensitization. Reducing exposure may offer a realistic chance for primary prevention of sensitization and asthma, but it is essential to implement measures that can achieve and maintain the low-allergen environment. Our purpose was to assess the effectiveness of mite allergen avoidance measures in achieving and maintaining a low-allergen environment during pregnancy and in the first year of life. The Manchester Asthma and Allergy Study is a prospective, prenatally randomized study that follows the development of asthma and atopy in a cohort of infants at high risk (both parents atopic) who are randomly allocated to full mite allergen avoidance or to a normal regimen. Avoidance measures comprise (1) mite-proof covers (mattress, pillow, and quilt) for parental bed, (2) high-filtration vacuum cleaner, (3) vinyl flooring in infant's bedroom, (4) new crib and portable crib mattresses encased in mite-proof material, (5) benzyl benzoate (Acarosan) applied on carpets and soft furniture, (6) bed linens washed in hot water weekly, and (7) washable soft toys. Dust samples from the parental bed, bedroom floor, living room floor, infant's mattress, and nursery floor were collected between the 10th and 14th weeks of pregnancy, immediately after birth, and then at age 6 months and 1 year, and Der p 1 levels were determined by mAb-based ELISA. Recovered Der p 1 from maternal mattress was reduced by 97. 25% (95% confidence interval [CI] 95.25%-98.41%) during the second and third trimesters of pregnancy, with the effect persisting for 6 months (98% reduction, 95% CI 97.25%-99.1%) and 12 months (97.6% reduction, 95% CI 95.7%-98.6%) after the birth (active vs control, P <.000001). Total Der p 1 from bedroom floor in the active group was reduced by 53.7% (95% CI 25.7%-71.2%) in samples collected within 4 weeks of the child's birth, with the percentage reduction being 62. 8% (95% CI 39.3%-77.2%) at 6 months and 26.5% (95% CI -24% to 57.1%) at 1 year (active compared vs control, P <.007). Der p 1 levels in crib mattress and nursery floor in the active group were extremely low (crib mattresses geometric mean [95% CI] 2.3 ng [1.6-3.4] at birth, 6.8 ng [4.5-10] at age 6 months, and 15.6 ng [9.8-24.8] at age 1 year [active vs control, P =.001]; nursery 1 ng [0.9-1.1] at birth, 1.7 ng [1.2-2.5] at age 6 months, and 2 ng [1.3-3.5] at age 1 year [active vs control, P <.00001]). The total amount of allergen recovered at age 1 year was 29-fold (95% CI 15.1- to 56.7-fold) higher in the control group than in the active group. The avoidance measures used in this study achieved and maintained a low mite allergen environment during pregnancy and in the first year of life in homes of infants at risk of atopy.Journal of Allergy and Clinical Immunology 02/2000; 105(2 Pt 1):252-8. · 12.05 Impact Factor
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ABSTRACT: Asthma places huge demands on health-care services, and its prevalence is increasing. Reduction of exposure to environmental allergens could offer a realistic chance for primary prevention. Our aim was to ascertain whether or not living in a low-allergen environment reduces the risk of asthma and atopic diseases in infants. We assigned infants to four risk groups according to parental atopic status. We enrolled 291 high-risk couples (both parents atopic, no pets) into a prospective, prenatally randomised, cohort study, and allocated them to environmental manipulation, in which measures to reduce prenatal and postnatal allergen exposure were undertaken (active HRA) (n=145) or no intervention (control HRC) (n=146). Two further prospective groups were studied: 161 high-risk infants with pets in the home (HRP group) and 168 low-risk infants, whose parents were both non-atopic (LR group). The main outcome measures were signs and symptoms of atopic disease at 1 year of age. 103 families dropped out or were lost to follow up. At age 1 year we followed-up 133 HRA, 118 HRC, 140 HRP, and 126 LR infants. Children in the HRA group were less likely to have respiratory symptoms during the first year of life than those in the HRC group. The most pronounced differences were in the relative risks for severe wheeze with shortness of breath (relative risk 0.44 [95% CI 0.20-1.00]), prescribed medication for the treatment of wheezy attacks (0.58 [0.36-0.95]), and wheezing after vigorous playing, crying, or exertion (0.18 [0.04-0.79]). Probability of respiratory symptoms in HRC and HRP infants was similar, whereas it was much lower in the LR than in the HRC group. Cat ownership was significantly associated with sensitisation to cats (24.6 [3.04-199.05]; p=0.003). Environmental manipulation reduces some respiratory symptoms in the first year of life in high-risk infants. Further follow up is needed, however, to ascertain whether living in a low-allergen environment reduces allergy and asthma in later life.The Lancet 08/2001; 358(9277):188-93. · 39.06 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: firstname.lastname@example.org
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.
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