The relationship of developmental adaptations with asthma,
allergic rhinitis/conjunctivitis, and atopic dermatitis: multivariable
analysis
In the multivariable analysis, preterm birth was positively associated
with asthma between 7 and 11 years (ORs, 1.29–1.36) (Figure 3A) (Table
2a). Meanwhile, overweight gain was positively associated with asthma at
9 and 10 years (ORs, 1.17–1.21) (Figure S3A). For allergic
rhinitis/conjunctivitis, its positive association with preterm birth and
overweight gain was only seen at 8 and 5.5 years, respectively (Figures
3B and S3B) (Table 2b). No significant associations between preterm
birth and overweight gain were determined with atopic dermatitis
(Figures 3C and S3C) (Table 2c). The results of the confounding factors
are shown in Table 2.
Discussion
To the best of our knowledge, this is the first longitudinal study that
has highlighted the similarities and differences in the age-specific
associations of the three atopy-related diseases with early life factors
using a large and a long-term
cohort. The protective effect of
daycare attendance during infancy in preventing the development of
childhood asthma attenuated after 10 years old, while the protective
effect of exposure to infectious agents in preventing the development of
allergic rhinitis/conjunctivitis remained throughout childhood. This
effect was not observed in atopic dermatitis. In contrast, a history of
severe airway infection showed an increased risk for developing asthma
throughout childhood. In addition, preterm birth was a significant risk
factor for developing asthma between the ages of 7 and 11 years, with a
small effect on allergic rhinitis/conjunctivitis and atopic dermatitis.
Overweight gain in infancy did not significantly affect the development
of atopy-related diseases.
Daycare attendance has prevented the development of asthma in selected
age groups, and its protective effect remained throughout childhood in
allergic rhinitis/conjunctivitis, whereas the opposite was seen in
atopic dermatitis. Contact with other infants in daycare or siblings at
home reflects frequent exposure to infectious agents12. In a study comparing the characteristics between
Amish and Hutterites 13, the mechanism of protection
against asthma has been determined to be related with innate immunity
mediated by microbes in dust. The transient protective effect of daycare
attendance in this study confirmed the result of a previous longitudinal
study 5 that investigated the relationship between
airway symptoms and early daycare attendance. On the contrary, early
life daycare attendance increased the subsequent risk of developing
atopic dermatitis 14. This inverse relationship could
be related to the differences of barrier intensity and indigenous
microbiota between the airway and the skin. A previous study reported
that early life daycare attendance may cause non-atopic eczema with a
different pathogenesis from that of atopic diseases15. This shows that a number of different mechanisms
play a role in the development of allergic airway diseases and skin
disease associated with daycare attendance. On the other hand, this
current study did not indicate an association between older siblings and
the prevention of developing of asthma in children, which is in line
with a report by Nicolaou et al 16.
The effect of an episode of severe airway infection on the subsequent
development of asthma and allergic rhinitis/conjunctivitis was harmful.
Some patients may have early colonization of pathogenic bacteria in the
airways, which may then predispose them to bronchiolitis with symptoms
severe enough to warrant hospitalization resulting in an increased
susceptibility to developing childhood asthma. This was opposite to the
protective effect of exposure to microbes when attending daycare. The
mechanisms of the inverse association of severe airway infection and
daycare with allergic airway diseases remain unknown. However, a highly
variable microbial composition in early life 17 that
is induced by commensal and pathogenic bacteria and environmental
microbes could be the difference on whether the immune system becomes
susceptible or resistant to allergic airway diseases. The airway18 and gut microbiomes 19, 20 were
also suggested to be one of the features which may potentially alter the
phenotype of immune responses. In addition, Illi et al. suggested that
the number and sites of infections early in life may determine the risk
of subsequent asthma 21. A complicated network may be
involved in the association between infection and allergic diseases.
This study confirmed the fact that babies born before 37 weeks of
gestation are prone to suffer from childhood asthma 9.
A meta-analysis of European children pointed out that preterm birth in
infants was associated with asthma and that preterm birth mainly
explains the association between a lower birth weight and asthma in
childhood 9. It has been regarded that patients with
immature lung growth in early life experience altered lung structure
such as bronchial wall thickening, sub-pleural opacities and fibrosis,
increased respiratory symptoms 22, and ongoing
respiratory morbidity 23, eventually resulting in lung
dysfunction and chronic lung diseases 24-27 in
childhood and adulthood that exhibit hyperreactivity with chemokine and
cytokine stimulation 28.
Moreover, our study indicated that overweight gain did not seem to be as
relevant to the development of asthma in children, although the cause of
obesity-related asthma in children was shown to occur in infancy in a
European birth cohort study. This might be explained by the small number
of obese children and adults in Japan 29.
Our study has some limitations. First, we did not measure the bronchial
hyperresponsiveness to diagnose asthma 5. The
prevalence of asthma in this study was similar to that of asthma in
another survey in 2002 that assessed children with asthma across 11
prefectures in Japan 30. Second, we did not have a
replication population. Instead, we assessed 3 atopic diseases with
allergic manifestations using different age groups. Furthermore, we used
a cohort study that covers a large population.
In conclusion, we have demonstrated markedly different patterns in the
relationship of the potent factors in infancy and the development of
atopy-related diseases in childhood. A dynamic interaction is supposed
to be involved between the genetic attributes, organ maturation,
environmental factors, barrier dysfunction, microbiome abnormalities,
and immune system. Further cohort studies are required to determine
whether preventing or delaying early life influences in growing years
could modify atopy-related diseases progression.
Acknowledgments: The authors would like to thank participants
and the Japanese Ministry of Health, Labour, and Welfare for their
contributions.