Clinical Parameters vs Cytokine Profiles as Predictive Markers of IgE-Mediated Allergy in Young Children.
PLoS One. 2015 Jul 27;10(7):e0132753.
- 1Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
- 2Machine Learning Group, ICTEAM institute, INGI Department, Louvain School of Engineering, Louvain-la-Neuve, Belgium.
- 3Paediatric Gastroenterology and Hepatology unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- 4IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
- 5Cliniques Universitaires Saint-Luc, Obstetric unit, Brussels, Belgium.
- 6Pole Pneumology, ENT and Dermatology, IREC, Université Catholique de Louvain, Cliniques Universitaires St-Luc, Pneumology Department and Center for Allergy, Brussels, Belgium.
- 7Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium; Paediatric Gastroenterology and Hepatology unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
BACKGROUND: Allergy afflicts one third of children, negatively impacting their quality of life and generating a significant socio-economic burden. To this day, this disorder remains difficult to diagnose early in young patients, with no predictive test available.
OBJECTIVE: This study was designed to correlate cytokine profiles with clinical phenotypes of allergy development.
METHODS: Three hundred patients were recruited and followed from birth to 18 months of age. They were given a clinical exam at birth and at 2, 6, 12, and 18 months of age, with skin prick tests at 6, and 18 months, in order to have a record of their medical history and determine their allergic status. In addition, mononuclear cells from 131 patients were isolated from cord blood and from peripheral blood samples at 2, 6 and 18 months of age, to analyse their cytokine and chemokine production.
RESULTS: Cord blood mononuclear cells (CBMCs) from future Immunoglobulin (Ig) E-mediated allergic children produced significantly less Interleukin (IL)-12p70 and IL-15 than cells from the rest of the cohort. Multivariate analyses revealed that the best predictive model of allergy was built on cytokine data, whereas the best predictive model of IgE-mediated allergy was built on clinical parameters.
CONCLUSIONS AND CLINICAL RELEVANCE: Although univariate analyses can yield interesting information regarding the immune responses of allergic children, finding predictive markers of the disorder will likely rely on monitoring multiple parameters. Nonetheless these analyses suggest a potential key role for IL-15 in the development of atopic disease. In addition, the study highlights the importance of clinical parameters in predicting the development of IgE-mediated allergy.
Allergic disorders currently affect one third of children, hampering their quality of life and generating a significant cost to their families and society. Although tremendous efforts have been dedicated to understanding the mechanisms of the disease, current treatments are still more therapeutic than preventive. Immunoglobulin-E (IgE) plays an important role in allergic disease, particularly in adults. Indeed, the binding of IgE to allergens leads to mast cell degranulation and subsequent inflammation. Unlike adults, allergic symptoms in infants are often IgE-independent, making it difficult to diagnose the disorder early. However, early IgE-mediated allergy can lead more commonly to persisting allergy later in life. Therefore, we felt it was important to unravel the early signs of allergy and to determine whether these could be used to identify children at risk of developing the disease.
Clinical parameters, and primarily a family history of allergy, have been traditionally used to predict children at risk of developing allergies and establish preventive measures. However, we wanted to see whether we could find a laboratory-based test that would allow us to predict a future development of allergy more accurately.
Figure 1: Incidence of allergy diagnosed at 18 months in the population studied. The development of allergies at 18 months was best predicted based on the cytokine data obtained from cord blood mononuclear cells.
Figure 2: Incidence of IgE-mediated allergy in the allergic population diagnosed at 18 months.
Children were recruited for this study before birth and full-term babies (37 weeks and above) were enrolled with the parents’ authorization. Clinical parameters including familial, personal and environmental factors were monitored at birth and during follow up visits. At 18 months of age, children were classified as allergic or non-allergic by two expert paediatricians (Figures 1). As expected, we found a higher percentage of children with a family history of allergy among the allergic children. Skin prick tests, a technic wherein a small amount of allergen is introduced into the skin, were performed at 6 and 18 months to detect IgE-mediated allergic reactions. In addition, blood samples were collected at 0, 2, 6 and 18 months. Plasma samples were used to quantify total and allergen-specific IgE levels. Allergic children with positive skin prick tests or detectable plasma levels of allergen-specific IgE were further labelled as IgE-mediated allergics (Figure 2). Mononuclear cells were isolated and stimulated in vitro for subsequent cytokine analysis. Univariate statistical analyses were performed to determine significant differences between allergic and non-allergic children, or between IgE-mediated allergic children and the rest of the group (non-IgE mediated allergic and non-allergic children). These analyses revealed that cord blood mononuclear cells (CBMCs) from future IgE-mediated allergic children produced significantly less IL-12p70 and IL-15 following stimulation than CBMCs from the rest of the cohort (Figure 3). In addition, multivariate analyses taking into consideration the cytokine data and the most relevant clinical data were performed to try and find a predictive model of allergy or IgE-mediated allergy. Interestingly, the best predictive model of allergy was based on cytokine data from CBMCs (Figure 1). In contrast, the best predictive model of IgE-mediated allergy was based on clinical parameters only (Figure 3).
Together these results suggest that clinical parameters remain the most relevant in predicting IgE-mediated allergy development at 18 months. Further analyses are currently underway to determine whether cytokine profile can better predict the allergic status of children at age 3 and 5.