By Sunna Thorsteinsdottir
Chariman: Simon Francis Thomsen
Opponent: Stephan Weidinger
Atopic dermatitis (AD) is a common pruritic, relapsing chronic inflammatory skin disease in children. Therefore, children with AD regularly visit the doctor in the first years of life and use resources from an already burdened healthcare system. Complex interaction between heredity and environment are believed to be the reason for the increased incidence of AD in recent decades.
To date the best known determinant for the development of AD are mutations in the filaggrin gene which is an important component of the intact skin barrier. Clinically the severity of AD measured by the SCORAD scale (Scoring Atopic Dermatitis) is the most commonly used scale; however SCORAD is a cross-sectional instrument and fails to capture fluctuations in AD, duration and chronicity. Studies focusing on environmental predictors for the development of AD have been hampered by differences in the definition of AD. Furthermore, previous studies have focused on determinants for the development of AD while possible determinants of AD persistence are a relatively unexplored area.
The work presented in this PhD thesis is based on data collected in two prospective birth cohorts COPSAC2000 and COPSAC2010 cohort. The COPSAC2000 cohort consists of 411 children who were all born to asthmatic mothers and is therefore a high-risk cohort while COPSAC2010 is a population based cohort of 700 children. The overall objective of this PhD study was to describe in a novel way possible determinants for the severity of AD as well as the impact of the disease in the first 3 years of life, using longitudinal data analysis to replicate our previous findings in a cross-sectional study that exposure to a domestic dog in early life protects children against the development of AD and to elucidate possible determinants of importance for persistent AD.
In paper I we explored whether exposure to domestic dog(s) in early life influenced the development of AD in children using longitudinal data analysis. Our data showed that the children’s risk of developing AD was approximately reduced by half among mothers exposed to domestic dog(s) around birth in both cohorts. The protective effect was strongest among mothers with atopic disease. Moreover we found a dose-response effect of the number of dogs on the development of AD. The mechanism by which a domestic dog exposure has on the mother with atopic disease and its offspring’s development of AD is unknown but we speculate that the microbiology of the dog may influence the immune system of mothers with atopic disease in pregnancy. To date exposure to domestic dog in pregnancy is one of the strongest environmental factors that can reduce the risk of AD in children.
In paper II, we investigated possible predictors influencing the severity of AD by a quantitative symptom assessment during the first 3 years of life. Parents registered daily AD symptoms and the use of topical steroids from birth to 3 years. We found that the load of AD symptoms was highest among 2 year old children. Furthermore, predictors that were positively associated with AD days as well as days with topical steroids were maternal AD, and the children’s allergic sensitization. Furthermore filaggrin gene mutation was found to be positively associated with steroid days. Moreover, we found an additive effect of each of the three following risk factors (maternal AD, filaggrin gene mutation, children’s allergic sensitization). The study is the first of its kind and has an important clinical value as it provides clinical applicable information for prognosis of severity in children with AD.
In paper III, we examined determinants for persistent AD in our COPSAC2000 cohort. Children
with AD were divided at 13 years into two groups, respectively, a group of children with transient AD and a group of children with persistent AD. Here we found that the strongest determinant for belonging to the group of children with persistent AD was the AD genetic risk score. Furthermore, we described in a novel way the fluctuations in the disease by visualizing individual’s children’s AD course at birth, 2, 7 and 13 yrs. In addition, we found that children belonging to the persistent AD group had a higher severity score measured by SCORAD already at AD onset. Additionally we saw a pattern of variations in the minor criteria of Hanifin and Rajka between the groups by using principal component analysis. This study suggests that the children’s genetic make-up is the strongest predictor for the persistence of AD and that clinical factors such as SCORAD and Hanifin and Rajka criteria can be used to predict persistence already at symptom onset.
In conclusion, this thesis shows a strong protective association between dog(s) on the development of AD, specifically in children with mothers with atopic disease and that there is a protective dose- response effect with increased number of dogs. Capturing the fluctuations in AD we used a novel way were we registered daily for three years the load of AD symptoms as well as the daily use of steroid and found that determinants of AD severity were maternal atopic dermatitis, filaggrin mutation in the child and allergic sensitization. However determinants for persistent AD in the child were its genetic disposition. Moreover, we found that the clinical factors, SCORAD and Hanifin and Rajka minor criteria at AD onset could predict whether the child’s AD course would be transient or persistent.