Early life infections, medications, and atopic sensitization in the development of immune-mediated diseases in Finland, Estonia, and Russian Karelia

Background: The incidence of immune-mediated diseases, such as type 1 diabetes (T1D), celiac disease (CD), and allergic diseases, has been increasing since the 1950s. This trend has been particularly conspicuous in affluent Westernized countries. Etiologies behind these diseases are still poorly understood, but socioeconomic circumstances and environmental factors may play a crucial role in their pathomechanisms. The hygiene hypothesis aims to explain the rising trend in immune-mediated diseases by suggesting that children’s developing immune systems are vulnerable to malfunction in environments that provide inadequate microbial exposure early in life. Aims: This thesis aims to explore how early clinical infections, their medications, and allergic sensitization associate with the development of T1D, CD, and allergies in three geographically close areas in Finland, Estonia, and Russian Karelia. These neighboring countries have shown clear contrasts in the frequencies of immune-mediated diseases, standards of hygiene, and socioeconomic circumstances. Methods: As part of the DIABIMMUNE study, over 4500 children from Finland, Estonia, and Russian Karelia were prospectively followed either from birth to 3 years of age or from 3 to 5 years of age. Children attended regular clinical visits that comprised physical examinations and the collection of biological samples for the assessment of immune-mediated outcomes. Children’s parents prospectively reported all participating children’s illnesses, infections, medications, and allergic symptoms that appeared during the follow-up. Results: Regarding infectious illnesses, respiratory infections were most frequently reported, followed by gastrointestinal infections, unlocalized febrile episodes, and other localized infections. Compared to Russian Karelian and Estonian children, Finnish children experienced more infections and used more medications. Finnish children also had the highest frequency of T1D, CD, and allergic sensitization. In all, progression to T1D was associated with a higher number of infections, and progression to CD with a higher number of febrile infections. Of systemic antibiotics and antipyretic analgesics, penicillin and acetaminophen, respectively, were the most common. Children who progressed to T1D or CD and their unaffected peers used medications similarly. Children with and without allergic sensitization had similar frequencies of infectious diseases and their medications. Children carrying genetic risk for autoimmunity developed immunoglobulin E (IgE) sensitization more often than their general-population peers. Early IgE sensitization associated with an increased risk for the development of clinical allergy symptoms and CD, but not for T1D. The predictive value of the sensitization for clinical allergies was age-dependent, and in all, sensitization predicted allergy-related symptoms quite poorly. Sensitization tests predicted allergic symptoms caused by aeroallergens better than those caused by dietary allergens, and the results for aeroallergen sensitization were more consistent between serum and skin testing methods. Conclusions: Immune-mediated diseases, early-life infections, and the use of various medications were more common in Finland than in the neighboring areas of Estonia and Russian Karelia. The co-occurrence of allergic and autoimmune diseases may suggest that, to a certain extent, these diseases share some common pathomechanisms. Keywords: aeroallergen, allergy, antibiotic, antipyretic analgesic, atopy, autoimmunity, celiac disease, childhood infection, dietary allergen, Estonia, Finland, human leukocyte antigen, hygiene hypothesis, IgE sensitization, islet autoimmunity, Russian Karelia, skin prick test, type 1 diabetes.