Title: Atopic sensitization in childhood depends on the type of green area around the home in infancy Tiia Voor1,2*, Meelis Pärtel3*, Aleksandr Peet1,2, Liisa Saare1,2, Heikki Hyöty4,5, Mikael Knip6,7, John Davison3, Martin Zobel3#, Vallo Tillmann1,2#1 Children´s Clinic of Tartu University Hospital, Estonia2 Institute of Clinical Medicine, University of Tartu, Estonia3 Institute of Ecology and Earth Sciences, University of Tartu, Estonia4 Faculty of Medicine and Health Technology, Tampere University, Finland5 Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland6 Pediatric Research Center, New Children’s Hospital, Helsinki University Hospital, Helsinki, Finland7 Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FinlandTo the editor,The prevalence of allergy has increased worldwide (1) and a green environment is essential in developing immune responses and may protect against allergy (2, 3). However, previous studies have not distinguished the effects of different green area types.Here we tested how the type and spatial scale of green area around the infancy home are associated with atopic sensitization up to the age of 9 years.The study group comprised 280 children from the Estonian DIABIMMUNE project birth cohort (4) whose sera were measured for different allergen-specific IgE (sIgE) antibodies at the ages 0.5, 1.5, 3, and 9 years. Subjects were divided into 3 groups by sIgE results. 86 children who had at least one sIgE ≥0.7 kU/L were categorized into the group of definite atopic sensitization (Group I); 44 children had some sIgE between 0.35-0.69 kU/L and were classified as uncertain sensitization (Group II); 150 children had all measured sIgE below 0.35 KU/L, and they formed the control group (Group III). The types of surrounding green areas during the first six months of life were obtained from digital maps of Estonia. The land was divided into agricultural fields, forests, grasslands and wetlands (Figure 1A).The combination of various green area types at a radius of 1-10 km around homes in infancy was related to signs of atopy by ordinal regressions, and model weights were compared.This is the first study addressing the correlation between the land-use intensity around child homes and the development of atopic sensitization. A model with the green areas within 8 km had the highest protective weight (Fig. 1B). Among the various types of green areas, the impact of forests was the largest (Fig. 1C), but the best model also included grasslands and wetlands. Agricultural fields had an impact only at 1-2 km scales, and their weight declined strongly at larger scales (Table 1). We used the best model (area of forest, grasslands and wetlands within 8 km) and examined how it predicts atopic sensitization groups (Fig. 1D). The model predicted a decrease in Group I and an increase in control Group III. The uncertain Group II showed a slightly decreasing tendency. The protective effect of forests, grasslands and wetlands against sensitization was evident for both inhaled and food allergens.The world is urbanizing, and the isolation of humans from biodiverse green areas leads to reduced contact with beneficial environmental microbes (5). Ruokalainen et al (2) showed that the greenness around homes was negatively associated with the risk of atopy in children. Contact with natural soil enriched microbiota enhanced immune regulation and may reduce the risk of development of immune-mediated diseases (6). Our results reveal considerable differences in how various green area types might prevent atopic sensitization. The area of biodiverse land (forests, grasslands, wetlands) showed a strong protective effect, while the agricultural land did not. The positive effect of forests, grasslands and wetlands became clearer with increasing spatial scale. The relatively large distance of influence indicates that the biodiversity of beneficial microbes might need a large area.Our study has some limitations. First, we could not study the microbiota of the participants and determine whether the spatial environmental model explained microbiota composition. Secondly, we studied only atopic sensitization and did not diagnose allergic disease. This was because the data were collected using questionnaires completed by parents and were of variable quality.In conclusion, the current results indicate that biodiverse land – such as forests, grasslands, and wetlands – around homes during infancy elicits a strong protective effect against the development of atopy later in childhood. At the same time, intensive croplands have only a very weak effect.