Background: Chronic rhinosinusitis with and without nasal polyps (CRSwNP/ CRSsNP) is an inflammatory disease affecting the nasal and sinus mucosal lining. Here, to further characterize this heterogeneous disease, we performed an extended endotyping of CRS using the nasal tissue from CRS-patients and a new approach of expression profiling of chemokines related to Th2-type cytokine IL-5. Methods: In this case-control study, we included 66 patients with CRS (CRSwNP n=26; CRSsNP n=40) diagnosed according to the EPOS 2020 criteria. The control group (n=25) consisted of CRS-free patients scheduled for inferior turbinate surgery. The concentration of following chemokines and cytokines was determined in tissue samples obtained during routine surgery from all subjects: TARC/ CCL17, PARC/ CCL18, eotaxin/ CCL11, MCP-3/ CCL7, MIP-1α/ CCL3, IP-10/ CXCL10, ENA-78/ CCL5, and IL-5. The analysis was performed by partition-based clustering. Results: In CRS tissues, the concentration of eotaxin, TARC, total IgE, IL-5, and ECP was significantly higher than in control (p<0.005). The analysis identified seven clusters. Cluster-1 was IL-5- and inflammatory chemokines-negative (11% CRSwNP). Cluster-2 had low IL-5 concentration and elevated MCP-3/CCL7 (100% CRSsNP). Clusters -3 and -4 expressed IP-10/CXCL10 (type-1-dominated), TARC/CCL17 and eotaxin/CCL11 (both type-2-dominated) (CRSwNP 13-31%). Clusters 5-7 had high concentration of IL-5, TARC/ CCL17, PARC/ CCL18, and eotaxin/CCL11 (type-2-dominated), NP 71-100%, asthma 19-50%, N-ERD 29%. Conclusions: Our chemokine expression-based extended analysis identified distinct CRS endotype clusters, possibly impacting future diagnosis, monitoring, and biologics-based treatment of CRS.

Background: From early life, respiratory viruses are implicated in the development, exacerbation and persistence of respiratory conditions such as asthma. Complex dynamics between microbial communities and host immune responses, shape immune maturation and homeostasis, influencing health outcomes. We evaluated the hypothesis that the respiratory virome is linked to systemic immune responses, using peripheral blood and nasopharyngeal swab samples from preschool-age children in the PreDicta cohort. Methods: Peripheral blood mononuclear cells from 51 children (32 asthmatics, 19 healthy controls), participating in the 2-year multinational PreDicta cohort were cultured with bacterial (Bacterial-DNA, LPS) or viral (R848, Poly:IC, RV) stimuli. Supernatants were analyzed by Luminex for the presence of 22 relevant cytokines. Virome composition was obtained using untargeted high troughput sequencing of nasopharyngeal samples. The metagenomic data were used for the characterization of virome profiles and the presence of key viral families (Picornaviridae, Anelloviridae, Siphoviridae). These were correlated to cytokine secretion patterns, identified through hierarchical clustering and principal component analysis. Results: High spontaneous cytokine release was associated with increased presence of Prokaryotic virome profiles and reduced presence of Eukaryotic and Anellovirus profiles. Antibacterial responses did not correlate with specific viral families or virome profile, however, low antiviral responders had more Prokaryotic and less Eukaryotic virome profiles. Anelloviruses and Anellovirus-dominated profiles were equally distributed amongst immune response clusters. The presence of Picornaviridae and Siphoviridae was associated with low interferon-λ responses. Asthma or allergy did not modify these correlations. Conclusions: Antiviral cytokines responses at a systemic level reflect the upper airway virome composition. Individuals with low innate interferon responses have higher abundance of Picornaviruses (mostly Rhinoviruses) and bacteriophages. Bacteriophages, particularly Siphoviridae appear to be sensitive sensors of host antimicrobial capacity, while Anelloviruses are not affected by TLR-induced immune responses.

Background: The impact of physical activity (PA) on immune response is a hot topic in exercise immunology, but studies involving asthmatic children are scarce. We examine the level of PA and TV attendance (TVA) in asthmatic children to assess the role on asthma control and immune response to various stimulants. Methods: Weekly PA and daily TVA were obtained from questionnaires at inclusion of the PreDicta study. PBMC cultures were stimulated with phytohemagglutinin (PHA), R848, poly I:C and zymosan. Cytokines were measured and quantified in cell culture supernatants using luminometric multiplex immunofluorescence beads-based assay. Results: Asthmatic preschoolers showed significantly more TVA than their healthy peers (58.6% vs. 41.5% 1-3h daily and only 25.7% vs. 47.2% ≤ 1h daily). Poor asthma control was associated with less frequent PA (75% no or occasional activity in uncontrolled vs. 20% in controlled asthma; 25% ≥ 3x weekly vs. 62%). Asthmatics with increased PA exhibited elevated cytokine levels in response to stimulants, suggesting a readiness of circulating immune cells for type-1, -2 and -17 cytokine release compared to low-PA and high-TVA subjects. Low PA and high TVA were associated with increased proinflammatory cytokines. Proinflammatory cytokines were correlating with each other in in-vitro immune responses of asthmatic children, but not healthy controls. Conclusion: Asthmatic children show more sedentary behavior than healthy subjects, while poor asthma control leads to a decrease in PA. Asthmatic children profit from exercise, as elevated cytokine levels in stimulated conditions indicate an immune system prepared for a strong response in case of infection.

Staphylococcal Enterotoxins sensitization and response of Omalizumab in severe atopic and non atopic asthma Nicolas Migueres1,2, Anh Poirot1, Nan Zhang ,3,4, Claus Bachert 3,4, Frédéric de Blay1 ,51: Chest Diseases Department, Strasbourg University Hospital, Strasbourg France.2: UMR 7357 Laboratoire des sciences de l’ingénieur, de l’informatique et de l’imagerie ICUBE3: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium4: Division of ENT diseases, CLINTEC, Karolinska Institute, University of Stockholm, Sweden5: EA 3072, Fédération de médecine translationnelle, université de Strasbourg, 67000 Strasbourg, FranceCorresponding author: Nicolas Migueres, [email protected] Diseases DepartmentNouvel Hôpital CivilHopitaux Universitaires de Strasbourg67093 STRASBOURG CEDEXtel: 00 33 6 07 60 51 86,Total word count ( 570 words)Author Contributions: All investigators contributed to the conception and design of the study. All authors contributed to the acquisition, analysis and interpretation of the data. They provided input into the drafting of the manuscript, critical feedback, and final approval for submission of the manuscript for publication. NM is the guarantor of the final content of the manuscript.The authors have no conflicts of interest to declare.

In the airway, IgE is traditionally regarded as a key mediator in allergic diseases, such as AR and allergic asthma. However, growing evidence demonstrates the importance of local IgE in airway inflammatory diseases, irrespective of the presence of allergy. In this review, we discuss the most recent evidence for IgE in chronic rhinosinusitis with nasal polyps(CRSwNP), including the local IgE’s characteristics, the modulation of its synthesis, and function. The levels of local IgE are significantly elevated in polyps independently of IgE serum levels and atopic status. Local IgE is polyclonal and functional, which is correlated with type 2 inflammation. IgE is produced by active B cells and is dependent on the classing switch recombination(CSR). In NPs, this process is triggered by not only allergens but also microbial colonization, especially the superantigen- Staphylococcus aureus. The production of local IgE is modulated by lymphocytes(such as Tfh, ILC2s, iTreg), cytokines(such as IL-4, IL-13, IFN-γ, TGF-β, IL-2, IL-21), transcription factors, and B cell intrinsic factor. Due to the central role of IgE in NPs, it is regarded as an ideal target for therapy and has been proved to be clinically successful. Based on this knowledge, we believe that exploring the trigger and regulatory factors for the activation of local B cells and CSR to IgE will provide more valuable information for us to recognize the pathological mechanisms of local IgE and offer the possible option for new [therapeutic](#/javascript:;) targets of NPs.

Background: The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems. To understand these differences and their implications, the rhinitis market was studied in some of the EU countries. Methods: We conducted a pharmaco-epidemiological database analysis to assess the medications that were prescribed for allergic rhinitis in the years 2016, 2017 and 2018. We used the IQVIA platforms for prescribed medicines (MIDAS® - Meaningful Integration of Data, Analytics and Services) and for OTC medicines (OTC International Market Tracking - OTCims). We selected the five most important markets in the EU (France, Germany, Italy, Poland and Spain). The UK was excluded due to a lack of data. Results: Intra-nasal decongestants were excluded from the analyses because they are not prescribed for allergic rhinitis. For both Standard Units (SU) and costs, France is leading the other countries. In terms of SU, the four other countries are similar. For costs, Poland is lower than the three others. However, medication use differs largely. For 2018, in SU, intra-nasal corticosteroid is the first treatment in Poland (70.0%), France (51.3%), Spain (51.1%) and Germany (50.3%) whereas the Italian market is dominated by systemic anti-histamines (41.4%) followed by intra-nasal corticosteroids (30.1%). Results of other years were similar. Discussion: There are major differences between countries in terms of rhino-conjunctivitis medication usage.