By Nadja Hawwa Vissing MD, PhD
Summary
Chairman: Flemming Skovby
Opponent: Erika Von Mutius
Opponent: Freddy Karup Pedersen
Lower respiratory infections (LRI) in childhood are common and account for considerable morbidity and health care utilization. The frequency of LRI varies significantly between otherwise healthy children, but extrinsic and intrinsic triggers of such variation are poorly understood. Traditionally, the variation has been explained by environmental exposures such as day care attendance, breastfeeding, crowding, siblings, tobacco smoke exposure, low socioeconomic status, and male sex, but these risk factors only explain a minor proportion of the variation. Confidence in the results is hampered by lack of reproducibility between studies, and few studies are based on longitudinal data collection. Little is known about the role of microbial exposures before the onset of infectious episodes and if this affects the infant’s developing immune system. The aim of this thesis was to investigate the association between neonatal airway colonization and risk of the LRI in a validated study cohort, and whether a possible association could be reflected in the early immune response to airway pathogens.
In study I, we aimed to ascertain the quality of information on child’s health, including asthma, allergy, eczema, respiratory infections and other health symptoms collected in the COPSAC2000 cohort. Records from General Practitioners from the first 3 study years were collected as an external reference and compared to COPSAC data. The COPSAC study exhibited full sensitivity to the main study objectives of the cohort, atopic diseases, and high sensitivity to respiratory, infectious and skin related illness. In particular, sensitivity on LRI was 96%. There was no evidence of bias from concurrent asthmatic disease or socioeconomic status. In conclusion, the study confirmed that COPSAC data is a valid source for investigating childhood illness related to atopic and infectious diseases, and furthermore supported the strengths of the longitudinal birth cohort design in general.
In Study II, we investigated the relation between neonatal airway colonization and LRI during the first 3 years of life. Hypopharyngeal aspirates were collected at 4 weeks of age, revealing that 21% of the healthy neonates were colonized with Streptococcus pneumoniae, Hemofilus influenzae and/or Moraxella catarrhalis. Colonization with at least one of these microorganisms was significantly associated with two-fold increased incidence of LRI, independently of concurrent or later asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to LRI.
In Study III, we studied a possible association with the immune response to pathogenic bacteria and incidence of LRI during the first 3 years of life. We assessed the in vitro systemic immune response by stimulating peripheral blood mononuclear cells collected at age 6 months with S.pneumoniae, H.influenzae and/or M.catarrhalis and quantified the production of a range of cytokines. Incidence of LRI was associated to an immune response pattern characterized by perturbed production of several cytokines, rather than production of one specific cytokine, and was independent of concurrent asthma. This suggests that children at risk of future LRI present a distinct systemic immune response upon exposure to common airway pathogens in early life, possibly reflecting an aberrant immune system.
In conclusion, our findings from a validated birth cohort study show that asymptomatic neonatal airway colonization with potential pathogens doubles the risk of LRI in early childhood, possibly through interaction with an aberrant immune system.
