By Julie Kyvsgaard
Summary
Chair person: Klaus Müller
Opponent: Varpu Elenius
Opponent: Sune Leisgaard Mørck Rubak
ABSTRACT
Asthma-like symptoms, including cough, wheeze, and breathlessness, are common in preschool children and often result in hospitalisation. These symptoms can be a significant burden for the children, their families, and the society. Although risk factors for childhood asthma have been extensively studied, there is a notable gap in research regarding their impact on the prevalence of asthma-like episodes during early childhood and whether such effects vary with age.
Respiratory tract infections (RTIs) are well-known triggers for episodes with asthma-like symptoms in early childhood, which may suggest that risk factors of asthma-like episodes in this period of life could be explained by an increased infection susceptibility. Further, early-life RTIs, especially more severe lower RTIs requiring hospitalisation or physician-attendance, have been linked to the development of asthma and reduced lung function later in life. However, we still need further studies focusing on how the burden of common infections in early childhood, including specific subtypes of infections, influences the risk of developing asthma. Additionally, it is unknown whether the various risk factors exert their asthma associations through an increased burden of infections in early life.
Finally, some studies have suggested a synergistic effect between early-life RTIs and atopy in relation to risk of asthma, but further investigations are needed to fully understand the complex interactions between infection burden, allergic traits, and asthma risk.
This PhD thesis is based on data collected from the COpenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010), a population-based prospective mother-child cohort, which consist of 700 children. The main objectives of the thesis were:
- To investigate risk factors for the number of asthma-like episodes from birth up to age 3 years and determine if these risk factors exert an age-specific pattern.
- To explore whether the identified risk factors for the burden of asthma-like episodes at ages 0−3 years exert their effect through an increased infection burden.
- To examine if the burden of common infections, including their specific subtypes, in early life associate with the risk of later asthma and reduced lung function. Additionally, to explore the interaction between the burden of infections and respiratory allergy in relation to asthma risk.
In Paper I we assessed the influence of various of pre-, peri, and postnatal variables on risk of asthma-like episodes from birth to 3 years. These episodes were recorded prospectively in daily diary cards by the parents. Furthermore, we explored the age-related impact of these risk factors on the frequency of asthma-like episodes.
We found that several variables—including male sex, low birth weight, maternal asthma, maternal antibiotic use, a high asthma exacerbation polygenic risk score (PRS), and a high airway immune score—were correlated with an elevated number of asthma-like episodes from birth up to age 3 years. Interactions highlighted that the impact of maternal asthma, preterm birth, caesarean section (C-section), and low birth weight grew with increasing age. In contrast, having sibling(s) at birth showed a decreasing impact with increasing age. A combined risk factor score based on the clinical risk factors available at birth, comprising male sex, low birth weight and maternal asthma, demonstrated a stepwise increase in the risk of experiencing more episodes.
In conclusion, using unique diary-recordings, we identified several risk factors for asthma-like episodes and revealed their age-related patterns. This aids knowledge to the aetiology of the burden of asthmatic symptoms in early life and could potentially contribute to a more personalised prognosis and treatment approach.
In Paper II, we investigated if the established risk factors for asthma-like episodes from birth to age 3 years were mediated by an increased infection burden. This infection data was also recorded prospectively by the parents using daily diary cards, which encompassed details on specific subtypes of infections.
Our findings revealed that the heightened burden of common infections partially mediated the impact of certain risk factors on the frequency of asthma-like episodes. Specifically, the associations with maternal asthma, antibiotic use during pregnancy, sibling(s) at birth, the asthma exacerbation PRS, and the airway immune score were all partially mediated through an increased infection burden. The infection subtypes responsible for this pattern included colds, pneumonia, gastroenteritis, and fever episodes. However, acute otitis media (AOM) and acute tonsillitis did not mediate any of the associations. Interestingly, factors like male sex, low birth weight, and maternal antibiotic use after birth did not have a mediating effect by infectious episodes.
In conclusion, our study indicates that many risk factors determining the burden of asthma-like episodes in early childhood partially act through an increased susceptibility to infections. This suggests that implementing preventive strategies against early-life infections could potentially lower the burden of asthma-like symptoms.
In Paper III, we explored the influence of the burden and subtypes of infections during early life on the risk of developing asthma and diminished lung function up to age 10 years. Additionally, we examined the synergistic relationship between early-life infection burden and respiratory allergy concerning subsequent asthma development.
We discovered that a high burden of infections during early years was associated with an increased risk of asthma from ages 3 to 10 years. Notably, the infection subtypes that drove this association were colds, pneumonia, gastroenteritis, and fever episodes, whereas AOM or acute tonsillitis did not exhibit such a linkage. Further, a higher infection burden was not correlated adverse lung function measures. Though, burden with pneumonia predicted lower Forced expiratory volume in the first second (FEV1) and maximal mid expiratory flow (MMEF). Interestingly, we found no direct association between infection burden or subtypes and allergic rhinitis at age 6 years. However, in relation to asthma risk, a significant interaction between cold burden and allergic rhinitis was observed, showing a significantly higher risk of asthma in children with allergic rhinitis compared to those without.
To conclude, children exposed to a high burden of infections—particularly colds, pneumonia, gastroenteritis, and fever—in the first 3 years of life are at increased risk of asthma, especially if they also develop allergic rhinitis. Our insights support the potential of preventing early-life infections prevention as strategy to reduce the risk of asthma.
The first 2 studies provide valuable insights into the origins of asthma-like symptoms in early childhood by identifying risk factors, exploring their age-related patterns, and investigating their effect through early-life infections. The 3rd study contributes to our understanding how burden and subtypes of early-life infections correlate with the later risk of asthma and lung function measures. Furthermore, we illustrate how early-life burden with colds and the onset of allergic rhinitis interact in terms of asthma risk, which supports the so-called “two-hit hypothesis”. Overall, our findings suggest that implementing preventive strategies targeting early-life infections could diminish the burden of asthma-like episodes in early childhood and later asthma risk, particularly in individuals at high risk.
