In this study, the risks of the cumulative incidence rates of asthma and
wheezing increased during 0-36 months old in children with a high level
of dust mite allergen exposure in bed dust. Regarding the endotoxin
exposure level, a significant positive OR was occasionally noted in the
onset of asthma and wheezing in the high exposure group. In the
simultaneous exposure to allergen, microorganisms, fungi, and air
pollutants, these were found to interact with each other and promote or
prevent allergic disease.27 As dust mite allergen and
endotoxin were simultaneously investigated in only limited
epidemiological studies, these are individually discussed below.
In an integrated analysis of five geographically different European
birth cohort studies, an association was noted between dust mite
allergen exposure (2-6 months old) and sensitisation to house dust mite
(≤6 years old), but no association was observed with an increase in the
risk of asthma (≤6 years old), suggesting that house dust mite exposure
alone is insufficient to increase the asthma risk and sensitisation with
allergen bridges allergen exposure and the development of
asthma.6,27 Similarly, in this study, the association
of an increase in the risk of high levels of total serum IgE with dust
mite allergen exposure was observed in the Q4 group and the OR was 1.58
(95% CI: 1.08-2.31). In addition, a trend was observed, suggesting an
association between dust mite allergen exposure and sensitisation with
allergen. This finding is consistent with the results of the five
European birth cohort studies. On the contrary, no increase in the
asthma risk was noted in the European cohorts, but a trend was observed
between dust mite allergen exposure and the cumulative incidence rates
of asthma and wheezing in the present study. This may have been due to
differences in the dust mite allergen sampling point and the difference
in the unit of Der 1 (μg/m2, μg/g). Regarding the
sampling point, dust on the floor of the children’s bedroom was
collected in the European cohort studies, whereas dust mite allergen in
bed dust was evaluated in our study. The dust mite allergen
concentration is higher in bed dust than that in dust on the bedroom
floor and the dust mite allergen exposure level in children was also
higher.26 Although it is necessary to pay attention to
a simple comparison of the Der 1 concentration, the geometric mean was
within a range of 0.06-0.97 μg/g in the European cohort studies, but the
Der 1 concentration was higher at 3.88 μg/g in our study performed in
Japan. Regarding the second point, the difference in the unit of Der 1
level, μg/g was used in the European cohort studies, whereas it was
measured as μg/m2 in our study. The risk of mite
sensitisation markedly increased when the Der 1 level exceeded 2
μg/g.28 In the present study, based on analysis of the
amount per gram dust (unit: μg/g), no significant increase in total IgE
levels was noted in the Q3 (3.17-8.37 μg/g) or Q4 (8.37 μg/g or higher)
groups (Supp Info Figure 5), but in the evaluation of the amount per
dust sampling area, a marked increase in total IgE levels was noted in
the Q4 group (158.27 μg/m2 or larger) (Fig. 2),
suggesting that the evaluation of the amount per dust sampling area is
more important. In this study, a significant association with dust mite
allergen was observed for the development of wheezing during 0-12 months
old and the development of asthma during 0-24 months old in analysis by
the onset age. The most important steps towards the development of
mature systematic immune responses are taken in the first 1-2 years of
life.5,29 Therefore, avoidance of early-life exposure
to high concentrations of dust mite allergen may be important to prevent
allergic diseases, such as asthma.
Previous studies have lacked consistency in the association between
endotoxin and asthma. For example, a cohort study was performed in an
urban area of Boston involving children with parents having a medical
history of atopy, in which simultaneous exposure to dust mite allergen
(in the children’s bed) and endotoxin (in family room dust) was
investigated until 2-3 months after birth, and the associations with
asthma, wheezing, and atopy were surveyed until 7 years old. Endotoxin
exposure was associated with an increase in the risk of asthma at 7
years old and wheezing at 1-7 years old (no change in the risk due to
children’s age with wheezing).26 In a meta-analysis of
19 studies involving infants, the OR of wheezing in the high endotoxin
exposure group (endotoxin concentration per gram of dust) compared to
that in the low exposure group was 1.48 (95% CI: 1.10-1.98),
demonstrating a positive correlation, whereas the OR of asthma after the
participants reached school age was 0.82 (95% CI: 0.67-0.97),
demonstrating an inverse correlation.12 Shamosollahi
et al. systematically reviewed endotoxin exposure and health influence
and discussed that “early life exposure to endotoxin at the
environmental level induces respiratory symptoms, including wheezing,
because of airway inflammation”. They reported that early-life
environmental exposure to endotoxin may induce inflammatory reaction,
but continuous exposure to endotoxin may activate immunity in healthy
individuals and prevent the later onset of asthma.30In our study, significantly positive ORs of asthma and wheezing onsets
were occasionally noted in the Q2-Q4 groups of the endotoxin exposure
level in comparison with the Q1 group, supporting the possibility that
environmental exposure to endotoxin in early life induces an
inflammatory reaction. This finding is consistent with the results of
the study in the urban area of Boston, the meta-analysis, and the
systematic review. As the evaluation was performed for up to 3 years in
our study, the risk of (or preventive effect on) endotoxin
exposure-induced asthma at school age will be investigated through a
follow-up survey in the future. The geometric mean endotoxin
concentration was 15.5 EU/mg in a survey conducted in the US (n=6,953),
and it was 2.5-76 EU/mg in other surveys performed in US inner
cities,31 whereas that in dust in the present study
was 16.0 EU/mg, which is within a range similar to that seen in US.
The main strength of this study was that this is the first large-scale
birth cohort study wherein an environmental measurement for both dust
mite allergen and endotoxin and health influence were evaluated using
standardised methods involving approximately 3,000 infants. The
cumulative incidence rate of wheezing and asthma in early life could be
evaluated by conducting annual questionnaire surveys. However, this
study has the following limitations. First, dust mite allergen and
endotoxin exposure were evaluated only at 18 months old. Exposure to
high concentrations of allergens immediately after birth strongly
influences the advancement of paediatric allergic
disease.5,6 Samples were not collected immediately
after birth in our study, but dust was collected at the age of 18 months
old. The association with allergic disease over school age after growth
will be investigated in a follow-up survey. Second, asthma symptoms were
investigated using self-administered questionnaires filled out by
mothers. However, a validation study of questionnaires that followed the
diagnostic criteria of asthma used by allergists reported that the
sensitivity and specificity of asthma symptoms were 0.91 and 0.64,
respectively, in 0-24-month-old children.21 Third,
total IgE levels at 24 months old alone were used as the cut-off for
outcome evaluation of high serum IgE levels, and the specific IgE level
could not be used. The associations with specific IgE and with changes
accompanying growth remain to be investigated.