Background Personalized monoclonal antibody-based therapies for asthma target cytokines involved in type 2 inflammation. However, definitions of type 2 high asthma (T2H) vary and ha

Dr. von Mutius reports holding grants from the European Commission, the European Research Council, and the German Research Foundation, during the conduct of the study. Dr. von Mutius has also received personal fees from the following organizations for her contribution outside the context of the submitted work: the American Academy of Allergy, Asthma & Immunology, the Ökosoziales Forum Oberösterreich, Mundipharma, HAL Allergie GmbH, from DOC Congress SRL, American Thoracic Society, University of Tampere; GBS RE HEFCE, Novartis Pharma, OM Pharma SA, AbbVie Deutschland GmbH & Co. KG, medUpdate GmbH, and System Analytic Ltd. Dr. Latzin reports personal fees from OM Pharma SA, Roche, Vertex and Gilead, all outside of the submitted work. Dr. Frey reports a personal fee from a GSK scientific board meeting 2016, outside of the submitted work. Dr. Pekkanen reports holding grants from the European Commission and Academy of Finland during the conduct of the study. Dr. Lauener reports holding grants from the Kühne Foundation/Christine Kühne-Center for Allergy Research and Education, the European Union and the Swiss National Research Foundation during the conduct of the study. Dr. Lauener has received fees and/or served on advisory boards from Menarini, Meda, Nestlé, AstraZeneca, the Pfizer Research Prize Foundation, Vifor and the Swiss Government, all outside of the submitted work. Dr. Kabesch reports holding grants from the European Union, German Ministry of Education and Research, German Research Foundation during the conduct of the study. Dr. Kabesch reports a personal fees from Bionorica, ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, and Hipp, all outside of the submitted work. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Cross-sectional studies have shown that exposure to indoor moisture damage and mold may be associated with subclinical inflammation. Our aim was to determine whether early age exposure to moisture damage or mold is prospectively associated with subclinical systemic inflammation or with immune responsiveness in later childhood. Home inspections were performed in children's homes in the first year of life. At age 6 years, subclinical systemic inflammation was measured by serum C-reactive protein (CRP) and blood leukocytes and immune responsiveness by ex vivo production of interleukin 1-beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) in whole blood cultures without stimulation or after 24 hours stimulation with phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG) in 251-270 children. Moisture damage in child's main living areas in infancy was not significantly associated with elevated levels of CRP or leukocytes at 6 years. In contrast, there was some suggestion for an effect on immune responsiveness, as moisture damage with visible mold was positively associated with LPS-stimulated production of TNF-α and minor moisture damage was inversely associated with PI-stimulated IL-1β. While early life exposure to mold damage may have some influence on later immune responsiveness, it does not seem to increase subclinical systemic inflammation in later life.

BACKGROUND:Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the 'asthma-protective' farm effect via Tregs during childhood immune maturation.METHODS:Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+ CD25high FOXP3upper20% ). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents.RESULTS:Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001).CONCLUSIONS:Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical 'time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.

Hintergrund: In ihrer ursprünglichen Bedeutung erklärte die ‚Hygiene-Hypothese‘ die Entstehung von Allergien durch zu wenige Infekte im Kleinkindalter. Im Laufe der Zeit hat sich ein Bedeutungswandel vollzogen: „Hygiene“ wird auch als übertriebene Sauberkeit in Wohlstandgesellschaften interpretiert. Es gibt aber bislang keine Belege dafür, dass Hygieneverhalten und Putzgewohnheiten in direktem Zusammenhang mit Asthma und Allergien stehen. Methodik: Bei 399 Schulkindern aus dem Großraum München wurden im Rahmen der Perinatalen Asthma und Umwelt Langzeit Studie (PAULA) umfangreiche Fragebogeninformationen zu individueller Hygiene und Sauberkeit im Wohnumfeld sowie zu allergischen Erkrankungen gesammelt. In Staubproben vom Wohnzimmerfußboden und von der Kindermatratze wurden die bakteriellen Marker Endotoxin und Muraminsäure gemessen. Staubmarker, Hygieneverhalten und Allergien wurden zueinander in Beziehung gesetzt. Ergebnisse: Individuelle Hygiene war invers mit bakteriellen Bestandteilen in Staubproben vom Fußboden und von der kindlichen Matratze assoziiert, während häufiges Putzen zwar die Staubmenge effektiv reduzieren konnte, jedoch nicht die bakteriellen Marker. Exposition gegenüber Muraminsäure war mit einer geringeren Asthmaprävalenz im Schulalter verbunden (adjustierte Odds Ratio (aOR) 0,59 [95%-Konfidenzintervall (KI) 0,39 – 0,90]). Die Endotoxinmenge in den Matratzenstaubproben vom ersten Lebensjahr der Studienkinder war invers mit dem Auftreten von atopischer Sensibilisierung (aOR 0,73 [KI 0,56 – 0,96]) und mit der Asthmaprävalenz im Schulalter (aOR 0,72 [KI 0,55 – 0,95]) assoziiert. Ein direkter Zusammenhang von Hygieneverhalten und Allergien bestand jedoch nicht (z.B. aOR für Asthma und Haushalthygiene: aOR 1,08 [KI 0,87 – 1,35]). Diskussion: Das häusliche bakterielle Umfeld ist eng mit der Entwicklung von Asthma und Allergien im Kindesalter verbunden. Der Staub und Bakterien reduzierende Effekt von Körperhygiene, wie z.B. Hände waschen, oder Sauberkeit im Haushalt spiegelte sich in objektiven Messungen wider. Trotzdem gab es keine Assoziation zwischen individueller oder Haushaltshygiene und dem Risiko für Asthma oder Allergien. Das legt die Vermutung nahe, dass an der Allergieprävention andere als durch Putzen oder Reinigen zu beseitigende Bakterien beteiligt sind.

Die Prüfung der Lungenfunktion ist auch bei Kindern und Jugendlichen ein wichtiger Bestandteil zur Diagnose und Verlaufsbeurteilung von Atemwegserkrankungen [1]. Bei der klinischen Bewertung der Lungenfunktion ist die Qualität der verwendeten spirometrischen Referenzwerte entscheidend [2,3]. Geeignete Referenzwerte fehlen für Kinder und Jugendliche, vor allem für unter Sechsjährige, was die klinische Anwendung der Lungenfunktionsprüfung in dieser Altersgruppe zusätzlich erschwert [1]. Die bisher meist bei Kindern verwendeten spirometrischen Referenz-

BACKGROUND:Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories.MATERIAL AND METHODS:We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context.RESULTS:There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age.CONCLUSIONS:To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer.

BACKGROUND:Evidence exists that a farming environment in childhood may provide protection against atopic respiratory disease. In the GABRIEL project based in Poland and Alpine regions of Germany, Austria and Switzerland, we aimed to assess whether a farming environment in childhood is protective against allergic diseases in Poland and whether specific exposures explain any protective effect.METHODS:In rural Poland, 23 331 families of schoolchildren completed a questionnaire enquiring into farming practices and allergic diseases (Phase I). A subsample (n = 2586) participated in Phase II involving a more detailed questionnaire on specific farm exposures with objective measures of atopy.RESULTS:Farming differed between Poland and the Alpine centres; in the latter, cattle farming was prevalent, whereas in Poland 18% of village farms kept ≥1 cow and 34% kept ≥1 pig. Polish children in villages had lower prevalences of asthma and hay fever than children from towns, and in the Phase II population, farm children had a reduced risk of atopy measured by IgE (aOR = 0.72, 95% CI 0.57, 0.91) and skin prick test (aOR = 0.65, 95% CI 0.50, 0.86). Early-life contact with grain was inversely related to the risk of atopy measured by IgE (aOR = 0.66, 95% CI 0.47, 0.92) and appeared to explain part of the farming effect.CONCLUSION:While farming in Poland differed from that in the Alpine areas as did the exposure-response associations, we found in communities engaged in small-scale, mixed farming, there was a protective farming effect against objective measures of atopy potentially related to contact with grain or associated farm activities.

The transcription factor STAT6 is crucial for activation of the interleukin (IL)‐4/IL‐13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown.

BACKGROUND:Toll-like receptor (TLR) polymorphisms have been associated with atopic diseases in children and adults. Development of atopic diseases may be modified by TLR-mediated signals that modulate T-regulatory cells (Tregs) early in life when maternal influences are still present and relevant. The aim of this study was to assess whether genetic TLR variants influence Tregs in neonates.METHODS:Twelve single nucleotide polymorphisms located in TLR1, TLR2, TLR4, TLR6, and TLR10 were genotyped in 200 cord blood samples (72 samples from atopic, 128 from nonatopic mothers). Cord blood mononuclear cells were cultured without or with stimulation [lipid A (LpA), peptidoglycan (Ppg), phytohemagglutinin, house dust mite]. mRNA expression of Treg marker genes [forkhead box protein P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3)], TLR2, Th1/Th2 cytokines, and tumor necrosis factor alpha (TNF-α) was measured.RESULTS:In children with the AA genotype of the TLR2 promoter variant rs4696480, gene expression of FOXP3 and Treg marker genes GITR and LAG3 as well as Th2 cytokines and TNF-α secretion was significantly increased in the presence of maternal atopy and Tregs decreased without maternal atopy. In carriers of the GG genotype for TLR2 rs1898830, gene expression of Treg marker genes was significantly decreased with and increased without maternal atopy. FOXP3 expression was also modified by TLR1 rs4833095 (P ≤ 0.03) and trendwise by TLR10 rs4129009 after LpA and Ppg stimulation.CONCLUSIONS:Genetic variations of TLR2, TLR1, and TLR10 affect Treg marker gene expression in cord blood. Gene-immunological interactions of the TLR pathway influence Tregs early in life, modulated by maternal atopy. This may be relevant for immune maturation in the development of atopic diseases in childhood.

Indeed, the current classification moves to the right direction by adopting a clinically meaningful way of thinking and avoiding unnecessary pathophysiological implications; PH owing to left heart disease (Group 2) and chronic thromboembolism (Group 4) are good examples.In this context, sarcoidosis, PLCH and LAM (Group 5.2) represent disorders that, according to the current evidence, are associated with PH mainly due to lung involvement and, therefore, we propose their inclusion in the third category (PH owing to lung disease and/or hypoxia) in any future classification scheme.