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\begin{document}

\title{Age-specific associations of early life infections and preterm birth
with subsequent atopic diseases}



\author[1]{Tadao Nagasaki}%
\author[2]{Takahiro  Tabuchi}%
\author[3]{Hisako  Matsumoto}%
\author[4]{Kenta Horimukai}%
\affil[1]{Kyoto University Graduate School of Medicine Faculty of Medicine}%
\affil[2]{Osaka International Cancer Institute}%
\affil[3]{Kindai University Faculty of Medicine Hospital}%
\affil[4]{Jikei University Katsushika Medical Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: The effects of infection and developmental adaptations in
infancy on the prevalence of subsequent atopy-related diseases at
different ages during childhood are not fully determined. This study
aims to examine the similarities and differences in the age-specific
association of asthma, allergic rhinitis/conjunctivitis, and atopic
dermatitis with early life infection (i.e., daycare, older siblings, and
severe airway infection) and developmental adaptations (i.e., preterm
birth and overweight gain) in children. Methods: In this longitudinal
cohort study (n = 47,015), children were followed from 0.5 to 11 years.
The potential risks and protective factors, including daycare attendance
at 0.5 years, existence of older siblings, history of hospitalization
due to cold/bronchitis/bronchiolitis/pneumonia during 0.5--1.5 years,
preterm birth, and overweight gain at 1.5 years, were assessed using
multivariable logistic regression with adjustments for potential
confounders. Results: A negative association was observed between early
life daycare attendance and asthma at 5.5--9 years, which disappeared
after 10 years. A negative association was also noted throughout
childhood between early life daycare attendance and the presence of
older siblings with allergic rhinitis/conjunctivitis. However, the
association between early daycare and atopic dermatitis was found to be
positive during childhood. In contrast, the early life history of
hospitalization owing to cold/bronchitis/bronchiolitis/pneumonia was
identified to be a risk factor for developing both asthma and allergic
rhinitis/conjunctivitis. Preterm birth was a significant risk factor for
childhood asthma. Conclusion: Different age-specific patterns were
demonstrated in the relationship between early life daycare, severe
airway infection, preterm birth, and atopy-related diseases in
childhood.%
\end{abstract}%



\sloppy


\textbf{Age-specific associations of early life infections and preterm
birth with subsequent atopic diseases}

Tadao Nagasaki\textsuperscript{1}, Takahiro Tabuchi\textsuperscript{2},
Hisako Matsumoto\textsuperscript{3}, Kenta Horimukai\textsuperscript{4}

\textsuperscript{1}Department of Respiratory Medicine, Graduate School
of Medicine Kyoto University, Kyoto, Japan

\textsuperscript{2}Department of Cancer Epidemiology, Cancer Control
Center, Osaka International Cancer Institute, Osaka, Japan

\textsuperscript{3}Department of Respiratory Medicine \& Allergology,
Kindai University Faculty of Medicine, Osaka, Japan

\textsuperscript{4}Department of Pediatrics, Jikei University Katsushika
Medical Center, Tokyo, Japan

\textbf{Running title:} Association of infection and preterm birth with
atopic diseases

\textbf{Corresponding author:} Tadao Nagasaki, MD, PhD

Department of Respiratory Medicine

Graduate School of Medicine Kyoto University

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Telephone: +81-75-751-3830; Fax: +81-75-751-4643

E-mail: nagasaki@kuhp.kyoto-u.ac.jp

\textbf{Word Count:} 2490

\textbf{Conflict of interest:} The authors have no relevant conflicts of
interest to declare.

\textbf{Financial Support:} none.

\textbf{Abstract}

\textbf{Background:} The effects of infection and developmental
adaptations in infancy on the prevalence of subsequent atopy-related
diseases at different ages during childhood are not fully determined.
This study aims to examine the similarities and differences in the
age-specific association of asthma, allergic rhinitis/conjunctivitis,
and atopic dermatitis with early life infection (i.e., daycare, older
siblings, and severe airway infection) and developmental adaptations
(i.e., preterm birth and overweight gain) in children.

\textbf{Methods:} In this longitudinal cohort study (n = 47,015),
children were followed from 0.5 to 11 years. The potential risks and
protective factors, including daycare attendance at 0.5 years, existence
of older siblings, history of hospitalization due to
cold/bronchitis/bronchiolitis/pneumonia during 0.5--1.5 years, preterm
birth, and overweight gain at 2.5 years, were assessed using
multivariable logistic regression with adjustments for potential
confounders.

\textbf{Results:} A negative association was observed between early life
daycare attendance and asthma at 5.5--9 years, which disappeared after
10 years. A negative association was also noted throughout childhood
between early life daycare attendance and the presence of older siblings
with allergic rhinitis/conjunctivitis. However, the association between
early daycare and atopic dermatitis was found to be positive during
childhood. In contrast, the early life history of hospitalization owing
to cold/bronchitis/bronchiolitis/pneumonia was identified to be a risk
factor for developing both asthma and allergic rhinitis/conjunctivitis.
Preterm birth was a significant risk factor for childhood asthma.

\textbf{Conclusion:} Different age-specific patterns were demonstrated
in the relationship between early life daycare, severe airway infection,
preterm birth, and atopy-related diseases in childhood.

\textbf{Key Words:} infection, preterm birth, asthma, allergic
rhinitis/conjunctivitis, atopic dermatitis

\textbf{Key Message:} The etiology of atopic diseases such as asthma,
allergic rhinitis/conjunctivitis, and atopic dermatitis are not fully
understood. Research findings reporting the effects of early life risk
and protective factors on subsequent atopic diseases are inconsistent.
This research revealed the similarities and differences of the
age-specific associations of several atopic diseases that share the
characteristics of atopic manifestations with early life factors using
one cohort. This study could potentially help to modify atopic diseases
progression by preventing or delaying early life influences.

\textbf{Abbreviation:} OR, odds ratio

\textbf{Introduction}

Investigating the etiology of atopic diseases such as asthma, allergic
rhinitis/conjunctivitis, and atopic dermatitis has remained to be
challenge. Reports \textsuperscript{1, 2} have indicated that a part of
the development of atopic diseases is dictated by the growing organs and
immune systems; environmental exposures and host predispositions in
early life can modify the development of atopic diseases. However, the
findings that have been reported on the effects of early life risk and
protective factors on subsequent atopic diseases have been noted to be
inconsistent. In this study, we focused on infection and developmental
adaptations in infants as the two major influencing factors in the
development of diseases related with atopic march.

The effects of infection in early life on atopic diseases, including
asthma, are conflicting. The hygiene hypothesis shows that exposure to
microbes, through contact with other children or livestock, during
immunologic maturation may lower the risk for the subsequent development
of atopic diseases. This hypothesis may explain the increase in the
prevalence of atopic diseases over the last few decades: a lower
opportunity for airway infection and/or exposure to microbes in early
life due to the improvement in hygiene and a decrease in family size.
However, the relationship between infection and subsequent atopic
diseases remains inconsistent. Severe infection, such as hospitalization
with bronchiolitis, has been determined as a risk factor for the
development of asthma \textsuperscript{3}.

The relationship between developmental adaptations in infants and
subsequent atopic diseases also show inconsistent findings. Recently, it
has been shown that the effect of potential factors on asthma, such as
overweight gain, may differ at different ages \textsuperscript{4-6}. The
age-dependent pathophysiology involved in the development of atopic
diseases could explain the inconsistent relationships. Furthermore, to
explore the similarities and differences for asthma, allergic
rhinitis/conjunctivitis, and atopic dermatitis could lead to prevent
occurrence of each disease by revealing common exposures to the three
atopy-related diseases and disease distinct factors. However, there
exist no longitudinal studies that have analyzed the age-specific
association of the three atopic diseases with the early life factors.

The main aim of this study was to assess the longitudinal phenotype,
defined by the association of the three atopy-related diseases with
early life factors and their time course, using one large cohort. We
have investigated the relationships of the characteristics in early
life, including early daycare attendance, existence of older siblings,
history of severe airway infection, preterm birth, and overweight gain,
with the longitudinal prevalence of atopic diseases in a cohort of
children that were followed from birth.

\textbf{Methods}

Data

The Longitudinal Surveys of Babies Born in the
21\textsuperscript{st}Century by the Japanese Ministry of Health, Labour
and Welfare is a birth cohort that was described previously
\textsuperscript{7, 8}. Babies born between January 10 and 17, 2001, in
Japan were included in this study. The Ministry asked households to
participate in the survey by explaining the purpose of obtaining basic
data. The first survey was conducted at 6 months. Follow-up surveys were
conducted at the ages of 1.5, 2.5, 3.5, 4.5, 5.5, 7, 8, 9, 10, and 11
years. We obtained permission from the Japanese Ministry of Health,
Labour and Welfare to use the data for this study. The study protocol
was approved by the Ethics Committee of Osaka International Cancer
Institute (No. 1508119060 and 1508119060-2).

Variables

The questionnaires were sent by mail, filled out by a family member, and
sent back by mail. Asthma, allergic rhinitis/conjunctivitis, and atopic
dermatitis were the common outcomes. The incidence of asthma, allergic
rhinitis/conjunctivitis, or atopic dermatitis was based on a positive
response to the question, ``Has the child visited a physician with the
diagnosis of the disease (bronchial asthma, allergic
rhinitis/conjunctivitis, or atopic dermatitis) in the last year?''

Early life infection (due to daycare attendance, the presence of older
siblings, and severe airway infection) and developmental adaptations
(preterm birth and overweight gain) were used as the main factors.
Information on daycare attendance was obtained when the infant was 6
months of age. The daycare attendance records were then analyzed based
on a positive response to the question, ``Does the child attend a
childcare?'' The data on the existence of older siblings were defined as
having one or more older siblings at 6 months. A history of
hospitalization owing to cold/bronchitis/bronchiolitis/pneumonia during
the last 12 months was evaluated at 1.5 years \textsuperscript{3}.
Preterm birth was defined as delivery at \textless{}37
weeks\textsuperscript{9}. Infant overweight gain was defined as weight
gain above the 90\textsuperscript{th} percentile between the weight at
birth and the weight at the age of 2.5 divided by the exact number of
months between those two measurements. The 90\textsuperscript{th}
percentile is used according to a previous report \textsuperscript{6}.
As potential confounding factors, sex, maternal smoking at 6 months,
breastfeeding, and early atopic dermatitis at 2.5 years were
assessed\textsuperscript{10}. Breastfeeding was defined as feeding [?]4
months\textsuperscript{11}. The evaluated time point of factors was
shown in Table S1.

Statistical analysis

Two groups were compared using \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test. The main
outcomes were asthma, allergic rhinitis/conjunctivitis, and atopic
dermatitis in children. Multivariable logistic regression was used to
estimate the adjusted odds ratios with 95\% confidence intervals for the
following potential factors. Based on previous reports, the factors
related to the incidence of asthma, including daycare attendance,
existence of older siblings, a history of hospitalization owing to
cold/bronchitis/bronchiolitis/pneumonia, preterm birth, and overweight
gain were analyzed and adjusted for the potential confounders of asthma,
including sex, maternal smoking, breastfeeding, and presence of early
atopic dermatitis. We used the same factors to analyze allergic
rhinitis/conjunctivitis; in addition, to analyze atopic dermatitis, we
used the same factors mentioned barring ``presence of early atopic
dermatitis.'' The probability values for the statistical tests were
two-tailed, and P \textless{} 0.05 was regarded as statistically
significant. All statistical analyses were performed via JMP system
version 15 (SAS Institute Inc., Cary, NC, USA).

\textbf{Results}

\textbf{Study characteristics and prevalence of atopic diseases}

Of the 47,015 children born in 2001 in the cohort, the data on the
factors were available in 38,540; 36,798; 36,151; 35,275; 34,145; and
32,913 children at the ages of 5.5, 7, 8, 9, 10, and 11 years,
respectively. The clinical characteristics of the study subjects were
determined to be similar between the ages of 5.5 and 11 years and are
presented in Table 1 and Tables S2--6. The prevalence of asthma was
reported to be 8.6\% at 5.5 years and showed a linear decrease to 5.4\%
at 11 years (Figure S1). Atopic dermatitis showed a similar trend: 7.8\%
at 5.5 years and 5.9\% at 11 years. On the contrary, the prevalence of
allergic rhinitis/conjunctivitis showed a linear increase, with 13\% at
5.5 years and 24\% at 11 years.

\textbf{Protective and risk factors for the development of atopic
diseases: univariable analysis}

In the univariable analysis, early daycare attendance between the ages
of 5.5 and 8 years resulted in a significant reduction in the risk of
developing asthma. Meanwhile, significant risks of developing asthma
were noted for those infants who had a history of hospitalization owing
to cold/bronchitis/bronchiolitis/pneumonia, preterm birth, and
overweight gain (Table 1 and Tables S2--6). Children with
rhinitis/conjunctivitis had inverse associations with early daycare
attendance and older siblings while having a positive association with
overweight gain. Children with atopic dermatitis had a higher frequency
of early daycare, older siblings, and history of hospitalization owing
to cold/bronchitis/bronchiolitis/pneumonia than those without atopic
dermatitis. The results for the confounding factors are shown in Table 1
and Tables S2--6.

\textbf{Relationship of infection with asthma, allergic
rhinitis/conjunctivitis, and atopic dermatitis: multivariable analysis}

Multivariable analyses were performed to investigate the effects of
early daycare attendance, older siblings, and severe airway infection on
asthma development (Table 2a). The strength of the negative association
between daycare attendance and asthma has been noted to decrease with
increasing age; the adjusted odds ratio (OR) of daycare attendance
showed a significant inverse association with asthma between 5.5 and 9
years (0.74 and 0.83, respectively), and this significant reduction in
the risk of asthma disappeared after 10 years (Figure 1A). The
association between older siblings and asthma was negative at 10 and 11
years (ORs, 0.90 and 0.90) (Figure S2A). On the contrary, the
association between the history of hospitalization due to
cold/bronchitis/bronchiolitis/pneumonia and asthma was positive
throughout childhood (ORs between 5.5 and 11 years, 1.66--1.82) (Figure
2A).

For allergic rhinitis/conjunctivitis, early daycare attendance (ORs
between 5.5 and 11 years, 0.74--0.85) (Figure 1B) and older siblings
(ORs between 5.5 and 11 years, 0.66--0.69) (Figure S2B) showed inverse
associations with its incidence throughout childhood (Table 2b). The
association of a history of hospitalization due to
cold/bronchitis/bronchiolitis/pneumonia with allergic
rhinitis/conjunctivitis was found to be positive at the age of 8, 9, 11
years (ORs, 1.17--1.22) (Figure 2B). On the other hand, daycare
attendance and older siblings were identified to be risks for the
development of atopic dermatitis at the age of 5.5 and 7 years. (Figures
1C and S2C) (Table 2c).

\textbf{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.

\textbf{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
agents\textsuperscript{12}. In a study comparing the characteristics
between Amish and Hutterites \textsuperscript{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 \textsuperscript{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 \textsuperscript{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
diseases\textsuperscript{15}. 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 \textsuperscript{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 \textsuperscript{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
airway\textsuperscript{18} and gut microbiomes \textsuperscript{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 \textsuperscript{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 \textsuperscript{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 \textsuperscript{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 \textsuperscript{22}, and ongoing
respiratory morbidity \textsuperscript{23}, eventually resulting in lung
dysfunction and chronic lung diseases \textsuperscript{24-27} in
childhood and adulthood that exhibit hyperreactivity with chemokine and
cytokine stimulation \textsuperscript{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 \textsuperscript{29}.

Our study has some limitations. First, we did not measure the bronchial
hyperresponsiveness to diagnose asthma \textsuperscript{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 \textsuperscript{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.

\textbf{Acknowledgments:} The authors would like to thank participants
and the Japanese Ministry of Health, Labour, and Welfare for their
contributions.

\textbf{Author contributions}

TN and TT designed the study. TN, HM and KH interpreted the data. TN
wrote the manuscript. All authors were involved in the preparation and
review of the manuscript and approved the final submitted version.

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\textbf{Legends to figures}

\textbf{Figure 1.} The adjusted odds ratios and 95\% confidence
intervals of daycare in patients with (A) asthma, (B) allergic
rhinitis/conjunctivitis, and (C) atopic dermatitis at different ages.

\textbf{Figure 2.} The adjusted odds ratios and 95\% confidence
intervals of history of hospitalization due to
cold/bronchitis/bronchiolitis/pneumonia in patients with (A) asthma, (B)
allergic rhinitis/conjunctivitis, and (C) atopic dermatitis at different
ages.

\textbf{Figure 3.} The adjusted odds ratios and 95\% confidence
intervals of preterm birth in patients with (A) asthma, (B) allergic
rhinitis/conjunctivitis, and (C) atopic dermatitis at different ages.

\textbf{Hosted file}

\verb`Tables.doc`  available at \url{https://authorea.com/users/435823/articles/538585-age-specific-associations-of-early-life-infections-and-preterm-birth-with-subsequent-atopic-diseases}

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