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Randomized Trial to Prevent Sensitization to Mite Allergens in Toddlers and Preschoolers by Allergen Reduction and Education
One-Year Results
Stella Tsitoura, MD;
Katerina Nestoridou, MD;
Panayotis Botis, MD;
Wilfried Karmaus, MD;
Calin Botezan, MD;
Jurgis Bojarskas, MD;
Hassan Arshad;
Joachim Kuehr, MD;
Johannes Forster, MD;
for the SPACE Group
Arch Pediatr Adolesc Med. 2002;156:1021-1027.
ABSTRACT
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Objective To evaluate the effectiveness of prevention measures against dust mite
sensitization.
Design European (England, Germany, Greece, Lithuania) multicenter prospective
single-blind randomized control trial with a follow-up of 12 months.
Participants Toddlers and preschoolers, with at least 1 parent with atopic symptoms
and sensitization, who initially were not sensitized to mite allergens.
Interventions A combination of education and a simple preventive measure (mattress
encasement) to reduce mite allergen exposure.
Setting Community-based study.
Main Outcome Measures Sensitization to mite allergens (skin-prick test or specific immunoglobulin
E).
Results Of 636 children (mean age, 3.1 years) included in the study, 566 (89%)
participated in the first-year follow-up. The incidence of sensitization to
mite allergens was 10 (3%) of 330 in the intervention vs 20 (6.5%) of 306
in the control arm, including loss of follow-up (intention-to-treat principle).
Allergic symptoms were more common in sensitized than in nonsensitized children
and so was the prevalence of physician-diagnosed asthma, eczema, and food
allergy.
Conclusions This simple, harmless, and inexpensive measure can be used in toddlers
and preschoolers of parents with atopic disorders to reduce sensitization
to mite allergens. With regard to clinical manifestations of atopy, follow-up
studies are needed to determine the effectiveness of the intervention.
INTRODUCTION
THE PREVALENCE of allergic disorders in childhood is about 20% to 30%
in Europe. In the last several decades, the prevalence of hay fever,1 allergic asthma, and atopic eczema has increased.2-4 Atopic disorders share
common characteristics, such as hereditary transmission, dependence on allergen
exposure, childhood onset, and likelihood of progression to chronic disease.
The incidence and prevalence of sensitization against inhalant allergens increase
during the first decade of life.5-6
The best single predictor for asthma, which has the greatest effect
on childhood morbidity in developed countries, is allergic sensitization to
mite allergens.7-8 Sensitization
to mite allergens commonly starts to be measurable by serum antibodies or
by the skin-prick test (SPT) early in childhood. In a German study of 7-year-old
children, of whom 3.5% had asthma and 7.5% had a diagnosis of recurrent bronchitis,9 a relative risk (RR) of 4.3 was determined for sensitization
against mite allergens.6 Also, the incidence
of asthmalike symptoms is related to mite sensitization.10
Besides being asthmatic, more than half of the children with atopic
eczema are sensitized to mite allergens, which often exacerbates the clinical
disease.11-12 The incidence of
allergic sensitization depends on mite allergen exposure in childhood.6, 13-14 A previous study showed
that a vigorous reduction of the allergen load could have a preventive effect
on sensitization.5 Additionally, children with
a family history of atopy are most prone to sensitization.15
Following this evidence of potential risk factors, we designed an environmental
intervention trial and investigated the effectiveness of simple avoidance
measures, such as allergen-impermeable encasement of mattresses, for which
mite allergen reductions are reported,16-21
along with health education measures to prevent sensitization to house dust
mites. The study as a whole included newborns, toddlers/preschoolers, and
school-aged children of parents who had a history of atopic manifestation
and thus a high atopic risk. This article reports the results in the toddlers
and preschoolers after 12 months of observation.
SUBJECTS AND METHODS
The effects of reduction of mite allergen exposure on the prevention
of sensitization to house dust mites and the development of allergic disease
in toddlers and preschoolers (1.5-5 years of age) at high atopic risk were
studied in 4 European countries (Germany, Greece, Lithuania, and England)
in a randomized controlled environmental trial. The study followed the intention-to-treat
principle. The study children were recruited in each country by using the
National Health System Service for approach (eg, the general routine check-up
of children in England, Germany, and Lithuania) or by using daycare centers
(Greece).
Screening questionnaires were used to identify children at higher atopic
risk by asking their parents if they themselves ever had asthma, hay fever,
and eczema. The questions had been validated in large cohort studies (the
German MAS and the ISAAC studies).22-23
Parents who had a positive questionnaire outcome were invited to undergo screening
for sensitization either by SPT screening or specific IgE determination. An
SPT or IgE determination was also performed in the child.
Before the parent(s) were informed about their child's test results,
they received a self-administered questionnaire on demographic variables,
birth characteristics of the child, the child's history of atopic and respiratory
disorders, and household conditions. The question regarding parental educational
attainment took different European systems into consideration and focused
on years and type of education (school, university, manual training, etc).
We asked about maternal smoking during the pregnancy and smoking in the household.
Questions on household conditions asked about pets, carpets, and signs of
molds, for example.
INCLUSION CRITERIA
We included children who (1) were local residents (migrants were excluded
for ease of follow-up); (2) had a positive parental screening questionnaire
result and positive parental SPT or parental IgE results; (3) were not sensitized
to mite allergens at the beginning of the study (ie, had negative results
on SPT or specific IgE against mite allergens); (4) and had atopic manifestations,
such as bronchial asthma, hay fever, or atopic eczema.
INFORMATION AND RANDOM ALLOCATION
Parents of these children were informed about the study and asked to
give their written informed consent. The study was approved by the local ethics
committees of the participating institutions.
The allocation of children to the intervention and control arms was
based on the day of the visit, according to a block randomization of a 2-week
period. Since all parents received an educational program, the parents of
participants were not made aware of the group to which they belonged, nor
were the examiners in the follow-up. However, parents might have identified
that only 1 group received a mattress cover. Thus, we defined the study as
single-blinded.
ALLERGY ASSESSMENT
Skin-prick testing was carried out by trained staff members under the
supervision of a physician, using the same equipment and technique in all
countries. The allergens Dermatophagoides pteronyssinus, Dermatophagoides farinae, grass pollens,
and cat dander (concentration: 10-histamine equivalent in SPT) (ALK Scherax,
Hamburg, Germany) and the negative (sodium chloride, 9 g/L) and positive (histamine
hydrochloride, 10 mg/mL) controls were applied to the forearm with the aid
of an SPT needle. The wheal reactions were marked with a pen, and the circle
was transferred to paper using a transparent strip. The largest and perpendicular
diameters of each wheal reaction were measured by means of a transparent ruler,
and the arithmetic mean was calculated. A positive test result required a
wheal diameter of at least 3 mm larger than the negative control or, alternatively,
a wheal diameter of at least 2 mm larger than the negative control and an
allergen wheal to histamine ratio equal to or larger than 0.5. Sensitization
to a mite allergen required a positive test for D pteronyssinus or D farinae. Alternatively, specific IgE
concentrations against the same allergens were determined by the MagicLite
(ML) test (Chiron Diagnostics, Fernwald, Germany). The test results were regarded
as positive if values were equal to or greater than 1.43 ML units. Both approaches
were compared and were found to provide identical classifications.24
To assure equality of testing procedures between the different countries,
at least 1 member of the staff participated in a centralized training, as
did the supervising physician. During the course of the study, the conduction
of SPT was controlled by site visits and monitoring in the different centers.
MEASURES OF PREVENTION, HEALTH EDUCATION, AND COUNSELING
All parents were given background information on allergies and the higher
than average risk of their child to develop an allergy. A booklet on environmental
influences on children's health and detailed preventive recommendations was
handed out to the parents of the prevention/intervention group, with additional
oral explanations if necessary. A similar booklet, without information on
mattress covers, was distributed to parents of the control group. Both groups
were told that some "measures" were being employed.
INTERVENTION ARM
Environmental measures primarily focused on reduction of mite allergens.
The child's mattress was covered with a special dust mite–impermeable
encasement (ACb; Dr Beckmann, GmbH, Seefelden, Germany) unless it had a vinyl
mattress (as in England). Other mattresses in the child's room were also covered.
All of this material was provided by the study. Parents were advised to discourage
the child from sleeping in or playing on uncovered beds. Advice was also given
to remove the carpet from the child's room and to select curtains that could
be washed in hot water. Weekly washing of soft toys and bedding (as well as
of pillows and blankets) in hot water was recommended to eliminate mites (alternatively,
soft toys could be deep frozen for 3 days per week). Parents were advised
to ventilate the child's room whenever possible. They were told to use a damp
cloth when dusting and to vacuum once per week in the absence of the child.
Storage of toys, books, and clothes in cupboards was recommended so they would
not collect dust. Smoking was discouraged in the house, as well as pet holding.
If pet holding occurred despite the recommendation, parents were advised not
to allow the pet to visit the child's bedroom. In most centers, a health care
visitor made a home visit at 6 months to ensure that the dust mite–impermeable
encasement was in place and to repeat the instructions. In Germany, however,
the use of the encasement was ascertained by questionnaire. In addition, information
about the child's symptoms was obtained in all centers.
CONTROL ARM
The brief standard recommendations of the relevant health authorities
in each country were reiterated. These were slightly different among the participating
centers. Recommendations common to all countries were avoidance of exposure
to pets in bedrooms, good ventilation of rooms, and avoidance of cigarette
smoking. As in the intervention group, information about the child's atopic
symptoms was obtained at the 6-month follow-up.
FOLLOW-UP INVESTIGATIONS
After 12 months, the parents and their child were invited to participate
in a follow-up examination, including SPT or IgE determination and a questionnaire
on symptoms (for the wording of atopic symptoms, see Table 4). The SPT (England and Greece) or IgE determination (Germany
and Lithuania) was blinded.
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Table 4. Association Between Symptoms and New Sensitization to Mite
Allergen at the 12-Month Follow-up
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STATISTICAL ANALYSIS
The data were entered at each facility and then sent to the data center
to be checked for consistency. EPI-INFO (Centers for Disease Control and Prevention,
Atlanta, Ga) was used for data entry, as this tool was available in all centers,
and SAS (SAS Institute, Cary, NC) was used for data analyses.25
Following the intention-to-treat principle,26-27
we included all randomized children in the arms in which they were randomly
assigned, regardless of their compliance and regardless of subsequent loss
of follow-up. To compensate for the loss of follow-up, we applied 2 approaches:
we assumed that (1) all participants lost to follow-up acquired an allergic
sensitization to mite allergens (SPT or IgE); and (2) all participants lost
to follow-up did not develop an allergic sensitization (SPT or IgE).
The LOGIST procedure of the SAS was used to estimate the crude and adjusted
RRs. We controlled for potential confounding of environmental factors despite
randomization. We included information from the initial questionnaire on individual
characteristics (sex, low birth weight), smoking of the parents (during pregnancy
and in the household), and housing conditions (pets, molds, carpets) as sources
of antigens. The education of the parents was grouped as low level (finished
school before age 18 years), medium level (finished school at age 18 years
or later with and without theoretical education), or high level (college/university
degree). The education of the parents was grouped as medium level (finished
school at age 18 years or later with and without theoretical education) or
high level (university). Confounders were excluded if they were only weakly
associated with sensitization (RR 1.1 or RR 0.9) in the crude analysis
or if they did not change the association between intervention and sensitization
by more than 10%.28 Additionally, we statistically
controlled for the effect of the centers in all models. To verify that the
randomization was effective, we also compared the prevalence of symptoms and
of household conditions in the intervention and control arms.
RESULTS
Between May 1997 and May 1998, we recruited 636 toddlers and preschoolers
(Figure 1). On average, 7.7 families
had to be screened per 1 child included (636/4871). Three hundred thirty children
were randomly allocated to the intervention group and 306 to the control group.
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Figure 1. Profile of the trial of primary
prevention if asthma is in high-risk toddlers and preschoolers. SPT indicates
skin-prick test.
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Regarding parents' characteristics or child's asthma, with the exception
of education, there were no important initial differences between the centers
and the 2 arms (Table 1). Compared
with the other centers, more parents from the Isle of Wight (England) finished
school before age 18 years (P<.001). However,
there was no statistical difference between the intervention and control arms.
After 12 months, for 90.9% of the children in the intervention and 86.9% of
those in the control arm, questionnaires were returned (Table 1). Participation was lower in the Lithuanian sample. Fewer
children participated in the SPT/IgE determination but the proportion did
not show statistically significant differences between the control and intervention
arms.
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Table 1. Characteristics of the Participating Groups and Proportion
of Participation in the Initial Examination*
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When assuming that all participants lost to follow-up had no allergic
sensitization, 20 children (6.5%) in the control and 10 (3.0%) in the intervention
group developed sensitization to mite allergens after 1 year (Table 2, P = .04 for the crude association).
When assuming that all participants lost to follow-up developed a sensitization,
the incidence of allergic sensitization to mite allergens was 24.8% for the
control and 16.4% for the intervention group (P =
.008 for the crude association). The difference showed up in all centers,
with the exception of the Isle of Wight center. The samples from the individual
centers are too small to gain statistical significance.
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Table 2. Crude Incidences in the Different Countries in the 12-Month
Observation Period
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After adjusting for necessary confounding variables, we found that the
control group was at significantly higher risk than the intervention group
for sensitization at 12 months (Table 3). The presence of pets was the only confounder that had to be controlled
for.
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Table 3. Crude Incidence (%) and Crude and Adjusted Relative Risk (RR)
for Sensitization to Mite Allergens in the First Year of Observation*
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A comparison of atopic manifestations in children with and without sensitization
to mites can emphasize the clinical significance of the SPT/specific IgE determination.
The prevalence of clinical manifestations is available for the 566 children
who participated in the 12-month follow-up. Children with sensitization had
a higher prevalence of symptoms of asthma and eczema (Table 4) and a higher prevalence of reported physicians' diagnoses
of food allergy and asthma (Figure 2).
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Figure 2. Association between reported physicians'
diagnoses and new sensitization to mite allergen.
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COMMENT
Our hypothesis was that allergen avoidance measures reduce allergic
sensitization. In this environmental prospective randomized controlled trial,
it was found that after 1 year of introduction of dust mite avoidance measures,
the incidence of sensitization to mite allergens (primary outcome variable)
was 3% in the intervention group vs 6.5% in the control group. The RR of the
preventive measures was 0.36 (95% confidence interval, 0.16-0.83).
To increase the efficacy, participation, and compliance of the study,
we included only toddlers and preschoolers at high risk of atopy. It was required
that 1 parent have a history of asthma, atopic eczema, or hay fever, and that
at least 1 parent was sensitized (positive SPT or specific IgE results) to
one of the common allergens tested. We were interested in new cases of sensitization
to mite allergens and excluded all children whose SPTs were positive for D pteronyssinus or D farinae in
the initial screening. When we planned the study, we purposely chose countries
in which the incidence of house dust mite sensitization would vary. However,
we were surprised that the Greek sample had such a low incidence (total of
2 cases in the control arm, Table 2).
To our knowledge, only 2 other prospective randomized trials on the
prevention of sensitization have been published. A clinical trial on house
dust mites and food allergen avoidance in newborns, conducted in Isle of Wight,
showed a reduction in the incidence of both positive SPTs for house dust mites
and eczema at ages 1, 2, and 4 years in the intervention group.5, 13, 29
We followed the selection criteria of high-risk children in this study and
included parents with a history of atopy (asthma, eczema, hay fever). A recently
published trial on the prevention of asthma in newborns from Canada focused
on asthma as the selection criterion.30 This
study did not report a reduction in sensitization; however, it reported a
reduction in the incidence of asthma in newborns. A third ongoing trial in
newborns, which has not yet published clinical outcomes, showed a reduction
of the mite allergen concentration on encased mattresses of about 95%.31
Overall, regarding mite allergen avoidance, Custovic et al32
listed 28 studies of patients who either had asthma, allergic rhinitis, or
atopic eczema. A variety of measures were applied, including insecticides,
regular vacuum cleaning, air filtration, ionizers, and plastic and semipermeable
mattress covers. With encasement of mattresses, a significant reduction of
the allergen load was reported for different age groups of patients.16-21
We did not assess allergen load, but rather investigated the clinical outcomes
related to allergen-impermeable mattress covers and other mite allergen avoidance
measures.
The benefits of mite allergen avoidance for the prevention of sensitization
have only been assessed in newborns. This is the first report, to our knowledge,
that avoidance seems to be effective in toddlers and preschoolers. We had
to recruit 4871 families to select 636 children at higher risk of atopy (7.7
parents per selected child). In a Canadian randomized trial in newborns, 6.8
women who were registered to give birth were screened to select each newborn
recruited for the intervention program.30 One
thousand one hundred sixteen families were screened to include 120 children
at risk of atopy whose parents agreed to follow the stringent allergen-avoidance
methods applied in the Isle of Wight intervention study (10.7 families per
selected child).5, 13
Some variables showed differences in the distribution between control
and intervention arms within 1 country and others between centers (eg, education, Table 1). However, in total, all confounders
except 1 could be removed from the explanatory model. This reassured us that
random allocation was effective. Additionally, preceding symptoms of the child
and parental variables were not unequally distributed in the intervention
and control arms (Table 1). The
only other predictor, which was confounding and showed a significant association
with the incidence of sensitization, was the presence of a pet in the home,
ascertained in the initial survey (Table
3). There was no important initial difference in holding the pet;
29.4% of the households in the control arm and 31.8% in the intervention arm
had a pet. This proportion was higher in children in England (54.9% vs 65.5%)
but not significantly different, and lower in children in Greece (19.4% vs
21.9%). Additionally, there was a difference in the incidence of sensitization
between these 2 countries. Thus, joint confounding of country and pets in
the household, which could not be removed by randomization, might explain
why pet holding had to remain in the model. It is known that cat allergens
remain suspended in the air for extended periods even after removal of the
cat from the home, taking 12 to 16 weeks to fall below the levels triggering
asthma.33 Data from areas with low sensitization
to mite allergens show that sensitization to domestic animals has the strongest
association with asthma.34
All parents received advice and a booklet about the prevention of asthma.
However, we cannot exclude that parents of a child who did not receive a mattress
cover may have known their child was in the control group. For this reason,
we did not investigate symptoms but focused on SPT or IgE results that could
not be influenced by parental information. Nevertheless, the association between
sensitization and clinical manifestations emphasizes the clinical significance
of sensitization and its prevention. Symptoms of asthma and eczema were 2
to 3 times more common in sensitized than in nonsensitized children, and the
prevalence of asthma and food allergy was higher, according to doctors' diagnoses
(Table 4, Figure 2).
We have demonstrated that a multifaceted intervention program focused
on encasement of mattresses reduced the incidence of sensitization to mite
allergens in high-risk children. The intention of the study was to test effectiveness.
For this purpose, we focused on toddlers/preschoolers who were at higher risk,
which limits generalizability to all children aged 1.5 to 5 years. However,
we assume that our finding offers evidence that reducing exposure to house
dust mite allergen also reduces the risk of developing sensitization in toddlers
and preschoolers. All applied measures offer a simple and effective approach
to the reduction of mite allergen exposure in children at high atopic risk.
It is important to determine if prolonged avoidance of mite allergens can
produce a sustained primary preventive effect on sensitization and a secondary
preventive effect in sensitized children by lowering the occurrence of symptoms.
| What This Study Adds
Very few trials have attempted to establish asthma-prevention methods
in children. Sensitization to dust mite allergens is a major risk factor for
the development of asthma. We conducted a randomized trial to determine whether
the use of allergen-impermeable mattress covers and parental education reduces
the risk of allergic sensitization to mite allergens in children between 1.5
and 5 years of age. The incidence of sensitization was statistically significantly
lower in the intervention arm (3%) than in the control arm (6.5%). This finding
suggests that a simple program of prevention measures in childhood may reduce
the risk for later development of asthma.
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AUTHOR INFORMATION
Accepted for publication May 24, 2002.
Financial grants were obtained for the international cooperation by
the BIOMED 2 program of the European Union, Brussels, Belgium, for the cooperation
of Austria, England, Germany, and Greece (PL95-1211), with an extension for
Lithuania (BMH4-96-1211). Additionally, the German Ministry for Research,
Berlin, Germany funded investigations in Lithuania (BMBF-01 KX 9811/7). In
Isle of Wight, St Mary's Hospital National Health Service Trust Research and
Development funds provided support for the research nurse.
Other members of the SPACE (Study on Prevention of Allergy in Children
in Europe) Group include Tara Dean, PhD, Thomas Frischer, MD, Gerhard Halmerbauer,
MD, Fritz Horak, MD, Jolanta Kudzete, MD, Sharon Matthews, RGN, Christof of
Reihle, MD, Kerstin Richter, MD, Agnes Schwieger, MD, Antje Seidel, MD, and
Laima Vaideliene, MD.
Blood tests of D pteronyssinus and
D farinae were facilitated with the help of Bayer Diagnostics, Fernwald,
Germany (MagicLite system) and blood tests of total and nutritional IgE by
Pharmacia & Upjohn, Uppsala, Sweden (CAP system).
We thank Linda Fortin, BA, at the Department of Epidemiology, Michigan
State University, East Lansing, Mich, for editorial support.
Corresponding author and reprints: Wilfried Karmaus, MD, MPH, Department
of Epidemiology, Michigan State University, 4660 S Hagadorn Rd, Suite 600,
East Lansing, MI 48823 (e-mail: karmaus{at}msu.edu).
From the Department of Social Medicine, P & A Kyriakou Children's
Hospital, Athens, Greece (Drs Tsitoura, Nestoridou, and Botis); Department
of Epidemiology, Michigan State University, East Lansing (Drs Karmaus and
Botezan); Kaunas Children's Hospital, Kaunas, Lithuania (Dr Bojarskas); the
David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of
Wight, England (Mr Arshad); University Children's Hospital, Freiburg, (Dr
Kuehr); and St Josefkrankenhaus, Freiburg, Germany (Dr Forster).
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