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Exercise-induced bronchoconstriction (EIB) is a prevalent condition in elite athletes caused by transient airway narrowing during or after exercise. Young athletes nowadays start early to perform high level exercise, highlighting the need to screen for EIB in a younger population. The purpose of this review is to evaluate current evidence of pre-tests with high probability to predict a positive provocation test in young and adolescent athletes, aged 12–24 years and thus indicate whether a young athlete is at risk of having EIB. Up to now, there is no validated screening test available to increase the pre-test probability of a provocation test of EIB in young and adolescent athletes. We would recommend that a clinical guideline committee might consider the development of a flow chart to screen for EIB in adolescent athletes. It could be composed of a symptom-based questionnaire focusing on wheezing during exercise, atopic state, reversibility test (to exclude EIB with asthma) and completed with markers in blood/serum. However, more research is necessary.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL. ispartof: BLOOD ADVANCES vol:7 issue:9 pages:1713-1724 ispartof: location:United States status: published

BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression. (c) 2022 American Academy of Allergy, Asthma & Immunology

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder. ispartof: J Exp Med vol:220 issue:5 pages:e20221755- ispartof: location:United States status: published

Purpose of review The development and progression of chronic respiratory diseases are impacted by a complex interplay between genetic, microbial, and environmental factors. Here we specifically summarize the effects of environmental exposure on asthma, allergic rhinitis, and chronic rhinosinusitis. We furthermore discuss how digital health technology may aid in the assessment of the environmental exposure of patients and how it may be of added value for them. Recent findings It is well established that one gets allergic symptoms if sensitized and exposed to the same allergen. Viruses, bacteria, pollutants, irritants, and lifestyle-related factors modify the risk of getting sensitized and develop symptoms or may induce symptoms themselves. Understanding these processes and how the various factors interact with each other and the human body require big data and advanced statistics. Mobile health technology enables integration of multiple sources of data of the patients' exposome and link these to patient outcomes. Such technologies may contribute to the increased understanding of the development of chronic respiratory disease. Summary Implementation of digital technologies in clinical practice may in future guide the development of preventive strategies to tackle chronic respiratory diseases and eventually improve outcomes of the patient.

Understanding the underlying mechanisms behind IgE-mediated cow’s milk allergy (IgE-CMA) is imperative for the discovery of novel biomarkers and the design of innovative treatment and prevention strategies. Here, we report data on the gut microbiome, metabolome, and lipidome of 81 children affected by food allergies, including CMA and healthy controls. Moreover, we developed a mouse model that mimicked IgE CMA best, BALB/c mice sensitized with ß-lactoglobulin using cholera toxin. During sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid and tryptophan metabolites, that preceded allergic inflammation, while this inflammation was reflected in a disturbed sphingomyelin and histamine metabolism. We endorsed the microbial origin of these metabolites by in vitro colonic digestions and confirmed the microbial dysbiosis in our patient cohort, which was accompanied by metabolic signatures of low-grade inflammation. Our results suggest that gut dysbiosis precedes allergic inflammation, opening new opportunities for future prevention and treatment strategies. Trial: NCT04249973.

Asthma is a heterogeneous disease consisting of several inflammatory phenotypes of which neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids. The development of targeted therapies requires the identification of biomarkers to distinguish these phenotypes. Currently, we lack validated biomarkers for non-eosinophilic asthma. The aim of this study is to examine serum calprotectin (SC) in asthmatics and its potential as biomarker for neutrophilic asthma.Hundred-seventeen severe asthmatics were referred for sputum induction and data were obtained from their medical records. To evaluate the association between SC and asthma phenotypes, patients were divided into subgroups based on sputum cell count (3% eosinophils and 61% neutrophils). Additionally, SC levels of asthmatics were compared with these of patients with chronic obstructive pulmonary disease, non-cystic fibrosis bronchiectasis and healthy controls.Asthmatics (In conclusion, there was no difference in SC levels between the different inflammatory subtypes in asthmatics. Nevertheless, severe asthmatics seemed to have higher SC levels suggesting that SC may be a marker of disease severity rather than a marker for specific inflammatory subtypes in asthmatics. Further research in larger cohorts is necessary to validate SC as biomarker in severe asthmatics.

Adequate nasal breathing is indispensable for athletes, and nasal symptoms have been shown to interfere with their subjective feeling of comfortable breathing and quality of life. Nasal symptoms are caused by either structural abnormalities or mucosal pathology. Structural pathologies are managed differently from mucosal disease, and therefore, adequate diagnosis is of utmost importance in athletes in order to choose the correct treatment option for the individual. Literature suggests that nasal symptoms are more prevalent in athletes compared to the general population and certain sports environments might even trigger the development of symptoms. Given the high demands of respiratory function in athletes, insight into triggering factors is of high importance for disease prevention. Also, it has been suggested that athletes are more neglectful to their symptoms and hence remain undertreated, meaning that special attention should be paid to education of athletes and their caregivers. This review aims at giving an overview of nasal physiology in exercise as well as the possible types of nasal pathology. Additionally, diagnostic and treatment options are discussed and we focus on unmet needs for the management and prevention of these symptoms in athletes within the concept of precision medicine. ispartof: ALLERGY vol:76 issue:9 pages:2716-2729 ispartof: location:Denmark status: published

Background Accurate diagnosis of urinary tract infection is essential as children left untreated may suffer permanent renal injury. Aim To compare the diagnostic values of biomarkers or clinical prediction rules for urinary tract infections in children presenting to ambulatory care. Design and setting Systematic review and meta-analysis of ambulatory care studies. Methods Medline, Embase, WOS, CINAHL, Cochrane library, HTA and DARE were searched until 21 May 2021. We included diagnostic studies on urine or blood biomarkers for cystitis or pyelonephritis in children below 18 years of age. We calculated sensitivity, specificity and likelihood ratios. Data were pooled using a bivariate random effects model and a Hierarchical Summary Receiver Operating Characteristic analysis. Results Seventy-five moderate to high quality studies were included in this review and 54 articles in the meta-analyses. The area under the receiver-operating-characteristics curve to diagnose cystitis was 0.75 (95%CI 0.62 to 0.83, n = 9) for C-reactive protein, 0.71 (95% CI 0.62 to 0.80, n = 4) for procalcitonin, 0.93 (95% CI 0.91 to 0.96, n = 22) for the dipstick test (nitrite or leukocyte esterase ≥trace), 0.94 (95% CI 0.58 to 0.98, n = 9) for urine white blood cells and 0.98 (95% CI 0.92 to 0.99, n = 12) for Gram-stained bacteria. For pyelonephritis, C-reactive protein Conclusions Clinical prediction rules including the dipstick test biomarkers can support family physicians while awaiting urine culture results. CRP and PCT have low accuracy for cystitis, but might be useful for pyelonephritis.

Taste receptors are well known for their role in the sensation of taste. Surprisingly, the expression and involvement of taste receptors in chemosensory processes outside the tongue have been recently identified in many organs including the airways. Currently, a clear understanding of the airway-specific function of these receptors and the endogenous activating/inhibitory ligands is lagging. The focus of this review is on recent physiological and clinical data describing the taste receptors in the airways and their activation by secreted bacterial compounds. Taste receptors in the airways are potentially involved in three different immune pathways (i.e., the production of nitric oxide and antimicrobial peptides secretion, modulation of ciliary beat frequency, and bronchial smooth muscle cell relaxation). Moreover, genetic polymorphisms in these receptors may alter the patients' susceptibility to certain types of respiratory infections as well as to differential outcomes in patients with chronic inflammatory airway diseases such as chronic rhinosinusitis and asthma. A better understanding of the function of taste receptors in the airways may lead to the development of a novel class of therapeutic molecules that can stimulate airway mucosal immune responses and could treat patients with chronic airway diseases. ispartof: CELLS vol:10 issue:11 ispartof: location:Switzerland status: published

PURPOSE: Accurate diagnosis of urinary tract infection in children is essential because children left untreated can experience permanent renal injury. We aimed to assess the diagnostic value of clinical features of pediatric urinary tract infection. METHODS: We performed a systematic review and meta-analysis of diagnostic test accuracy studies in ambulatory care. We searched the PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Health Technology Assessment, and Database of Abstracts of Reviews of Effects databases from inception to January 27, 2020 for studies reporting 2 × 2 diagnostic accuracy data for clinical features compared with urine culture in children aged

Allergic rhinitis (AR) affects 23-30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontrolled. Allergen immunotherapy (AIT) has been shown to improve the level of control up to 84% of patients being controlled by AIT. Recently, new guidelines for AIT have been published, supporting the clinical evidence for effectiveness of various subcutaneous and sublingual products for AIT in patients who are allergic to airborne allergens. AIT in AR patients not only reduces nasal and/or ocular symptoms but also induces tolerance and has preventive potential. Adoption of AIT into daily clinical practice in Belgium and other European countries is hampered primarily by reimbursement issues of each of the single products but also by several patient- and physician-related factors. Patients need to be better informed about the effectiveness of AIT and the different routes of administration of AIT. Physicians dealing with AR patients should inform patients on tolerance-inducing effects of AIT and are in the need of a harmonized and practical guide that supports them in selecting eligible patients for AIT, in choosing evidence-based AIT products and in following treatment protocols with proven efficacy. Therefore, a stepwise and holistic approach is needed for better adoption of AIT in the real-life setting in Belgium. ispartof: CLINICAL AND TRANSLATIONAL ALLERGY vol:9 issue:1 ispartof: location:England status: published

PURPOSE OF REVIEW: The current review describes the role of different types of innate lymphoid cells (ILCs) in the pathogenesis of asthma inflammatory phenotypes by linking findings from murine asthma models with human studies. Novel treatment options are needed for patients with steroid-insensitive asthma. Strategies targeting ILCs, or their upstream or downstream molecules are emerging and discussed in this review. RECENT FINDINGS: In eosinophilic asthma, ILCs, and especially type 2 ILCs (ILC2s), are activated by alarmins such as IL-33 upon allergen triggering of the airway epithelium. This initiates IL-5 and IL-13 production by ILC2, resulting in eosinophilic inflammation and airway hyperreactivity. Type 3 ILCs (ILC3s) have been shown to be implicated in obesity-induced asthma, via IL-1β production by macrophages, leading ILC3 and release of IL-17. ILC1s might play a role in severe asthma, but its role is currently less investigated. SUMMARY: Several studies have revealed that ILC2s play a role in the induction of eosinophilic inflammation in allergic and nonallergic asthmatic patients mainly via IL-5, IL-13, IL-33 and thymic stromal lymphopoietin. Knowledge on the role of ILC3s and ILC1s in asthmatic patients is lagging behind. Further studies are needed to support the hypothesis that these other types of ILCs contribute to asthma pathogenesis, presumably in nonallergic asthma phenotypes. ispartof: CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY vol:19 issue:1 pages:53-60 ispartof: location:United States status: published

Background Exercise-induced bronchoconstriction (EIB) is a transient airway narrowing, occurring during or shortly after intensive exercise. It is highly prevalent in non-asthmatic outdoor endurance athletes suggesting an important contribution of air pollution in the development of EIB. Therefore, more research is necessary to investigate the combination of exercise and pollutants on the airways. Methods Balbc/ByJ mice were intranasally challenged 5 days a week for 3 weeks with saline or 0.2 mg/ml diesel exhaust particles (DEP), prior to a daily incremental running session or non-exercise session. Once a week, the early ventilatory response was measured and lung function was determined at day 24. Airway inflammation and cytokine levels were evaluated in bronchoalveolar lavage fluid. Furthermore, innate lymphoid cells, dendritic cells and tight junction mRNA expression were determined in lung tissue. Results Submaximal exercise resulted in acute alterations of the breathing pattern and significantly improved FEV0.1 at day 24. DEP exposure induced neutrophilic airway inflammation, accompanied with increased percentages of CD11b+ DC in lung tissue and pro-inflammatory cytokines, such as IL-13, MCP-1, GM-CSF and KC. Occludin and claudin-1(Cldn-1) expression were respectively increased and decreased by DEP exposure. Whereas, exercise increased Cldn-3 and Cldn-18 expression. Combining exercise and DEP exposure resulted in significantly increased SP-D levels in the airways. Conclusion DEP exposure induced typical airway neutrophilia, DC recruitment and pro-inflammatory cytokine production. Whereas, intensive exercise induced changes of the breathing pattern. The combination of both triggers resulted in a dysregulation of tight junction expression, suggesting that intensive exercise in polluted environments can induce important changes in the airway physiology and integrity.

Background: Staphylococcus aureus colonization and release of enterotoxin B (SEB) has been associated with severe chronic rhinosinusitis with nasal polyps (CRSwNP). The pathogenic mechanism of SEB on epithelial barriers, however, is largely unexplored. Objective: We investigated the effect of SEB on nasal epithelial barrier function. Methods: SEB was apically administered to air-liquid interface (ALI) cultures of primary polyp and nasal epithelial cells of CRSwNP patients and healthy controls, respectively. Epithelial cell integrity and tight junction expression were evaluated. The involvement of Toll-like receptor 2 (TLR2) activation was studied in vitro with TLR2 monoclonal antibodies and in vivo in tlr2−/− knockout mice. Results: SEB applied to ALI cultures of polyp epithelial cells decreased epithelial cell integrity by diminishing occludin and zonula occludens (ZO)-1 protein expression. Antagonizing TLR2 prevented SEB-induced barrier disruption. SEB applied in the nose of control mice increased mucosal permeability and decreased mRNA expression of occludin and ZO-1, whereas mucosal integrity and tight junction expression remained unaltered in tlr2−/− mice. Furthermore, in vitro SEB stimulation resulted in epithelial production of IL-6 and IL-8, which was prevented by TLR2 antagonization. Conclusion & Clinical relevance: SEB damages nasal polyp epithelial cell integrity by triggering TLR2 in CRSwNP. Our results suggest that SEB might represent a driving factor of disease exacerbation, rather than a causal factor for epithelial defects in CRSwNP. Interfering with TLR2 triggering might provide a way to avoid the pathophysiological consequences of S. aureus on inflammation in CRSwNP. Funding statement: The author’s laboratories are supported by grants from the Belgian Federal Government (IUAP P7/30), IWT (TBM project 130260), and the research council of the KU Leuven (GOA 14/011). RS and DMB are recipients of a senior research fellowship from the Fund of Scientific Research (FWO), Flanders, Belgium. BS is currently a Postdoctoral Fellow of the Fund for Scientific Research Flanders (FWO). Acknowledgements The authors would like to thank Ahmad Kasran, Lieve Coorevits and Ellen Dilissen for their insightful comments and technical advice, Dr. Camille Allonsius for helping with the transfection of HEK cells and Prof. Mark Jorissen (UZ Leuven) for collecting nasal tissue. Additionally, we thank Prof. Pieter Vanden Berghe for his assistance with confocal microscopy (Hercules AKUL/11/37 and FWO G.0929.15). We would like to thank Prof. Olivier Denis from Sciensano, Brussels, Belgium for the tlr2-/- mice. Author contributions: BS and KM performed experiments, acquired data, analyzed data and wrote the manuscript. YAA and SFS conducted experiments. CB, RS, DMB and SL discussed and interpreted findings, and critically revised the manuscript. JLC and BS designed research study and critically revised the manuscript. Funding: The author’s laboratories are supported by grants from the Belgian Federal Government (IUAP P7/30) and the research council of the KU Leuven (GOA 14/011). RS and DMB are recipients of a senior researcher fellowship from the Fund of Scientific Research (FWO), Flanders, Belgium. BS is currently a Postdoctoral Fellow of the Fund for Scientific Research Flanders (FWO).

BACKGROUND: Nasal hyperreactivity (NHR) is a common feature of various rhinitis subtypes and represents a novel phenotype of rhinitis. It is being reported in two-thirds of adult rhinitis patients irrespective of the atopic status. Data on the prevalence of NHR in patients with asthma are lacking, as well as the nature of evoking triggers. METHODS: Postal questionnaires were distributed to an unselected group of asthmatic patients in Leuven (Belgium, n = 190) and completed by 114 patients. In Mexico City (Mexico) and Brasov (Romania), respectively, 97 out of 110 and 80 out of 100 asthmatic patients attending the outpatient clinic completed the questionnaire. Non-asthmatic volunteers were recruited amongst university and hospital co-workers in Leuven (n = 53). The presence of self-reported NHR, the type of triggers evoking nasal and bronchial symptoms, medication use, self-reported allergy, and environmental factors were evaluated. RESULTS: Overall, 69% of asthma patients reported NHR, with 32% having more than 4 triggers evoking NHR. These triggers included mainly exposure to temperature and humidity changes, cigarette smoke, and strong odours. A higher prevalence of NHR was detected in allergic compared to non-allergic asthma patients (73% vs. 53% p

At present, it is unclear which exercise-induced factors, such as myokines, could diminish the negative impact of the reduction in pulmonary function imposed by the exercise in question. In this study, we aim to evaluate the prevalence of exercise-induced bronchoconstriction (EIB) and also to investigate the effect of myokines in the performance of marathon runners presenting EIB or not. Thirty-eight male recreational marathon runners (age 38.8 [33&ndash, 44], height 175.7 [172.0&ndash, 180.3], weight 74.7 [69.3&ndash, 81.6]) participated in this study, and through spirometry tests, a prevalence of 23.6% of EIB was found, which is in agreement with the literature. The volunteers who tested positive to EIB (EIB+) presented lower maximum aerobic capacity compared to those who tested negative (EIB&minus, ) (EIB+ 44.02 [39.56&ndash, 47.02] and EIB&minus, 47.62 [44.11&ndash, 51.18] p = 0.03). The comparison of plasma levels of IL-1&beta, (EIB+ p = 0.296, EIB&minus, p = 0.176, EIB+ vs. EIB&minus, baseline p = 0.190 immediately after p = 0.106), IL-4 (undetectable), IL-6 (EIB+ p = 0.003, EIB&minus, p &le, 0.001, EIB+ vs. EIB&minus, baseline p = 0.301 immediately after p = 0.614), IL-8 (EIB+ p = 0.003, EIB&minus, baseline p = 0.110 immediately after p = 0.453), IL-10 (EIB+ p = 0.003, EIB&minus, baseline p = 0.424 immediately after p = 0.876) and TNF-&alpha, (EIB+ p = 0.003, EIB&minus, baseline p = 0.141 immediately after p = 0.898) were similar in both groups 24 h before and immediately after the marathon. However, negative correlations were found between the marathon finishing time and the levels of IL-8 (r = &minus, 0.81, p = 0.022), and IL-10 (r = &minus, 0.97, p &le, 0.001) immediately after completing the marathon. In conclusion, for the first time, it is shown that the myokines IL-8 and IL-10 are related to improvement of the performance of marathon runners presenting EIB.

Background A high burden of lower airway symptoms is found in elite swimmers. To what extent elite swimmers suffer from upper airway symptoms and how these associate with nasal inflammation is less clear. We here aimed to evaluate upper airway symptoms and nasal inflammation in elite athletes. Methodology Elite swimmers, indoor athletes and age-matched controls were recruited. Upper airway symptoms were assessed by sino-nasal outcome test (SNOT)-22 questionnaire. Visual Analogue score (VAS) for nasal symptoms as well as neurogenic and inflammatory mediators in nasal fluid were assessed at baseline, immediately and 24-hours after sport-specific training. The effect of hypochlorite on nasal epithelial cells was evaluated in vitro. Results Baseline SNOT-22 and VAS for nasal itch and impaired smell were significantly higher in swimmers compared to controls. Nasal substance P and uric acid levels were increased in elite swimmers 24-hours after swimming compared to baseline. In elite swimmers, uric acid levels 24-hours post-exercise correlated with baseline SNOT-22. As increased symptoms and inflammation were found in swimmers but not in indoor athletes, we hypothesized that hypochlorite exposure might be the underlying mechanism. In vitro, the highest dose of hypochlorite decreased nasal epithelial cell integrity and induced release of uric acid. Conclusion Upper airway symptoms are frequently reported in elite swimmers. Intensive swimming resulted in a delayed increase of epithelial injury and neurogenic inflammation.

Physical exercise promotes many health benefits. However, its effects are not well known in a polluted environment. Thus, this study aimed to compare upper airway inflammatory responses between street runners and sedentary individuals. Twenty-eight volunteers were recruited: runners (n = 14) and sedentary individuals (n = 14), who lived and worked in the same metropolitan area of S&atilde, o Paulo, Brazil. Particulate matter (PM) levels were monitored ten weeks before winter (low PM levels) and ten weeks after the beginning of winter (high PM levels) [PM10 (p &lt, 0.0001) and PM2.5 (p &lt, 0.0001)]. The cytokines (TNF-&alpha, IL-6, IL-10, and IL-17A) levels in the nasal lavage and fractional exhaled nitric oxide (FeNO) were taken at the beginning of the winter (baseline) and ten weeks afterwards (after ten weeks of high PM exposure). IL-6 concentration increased in both runners (p = 0.037) and sedentary individuals (p = 0.027) after high PM exposure compared to the baseline. IL-10 concentration increased in sedentary individuals (p = 0.037) while IL-17A levels were increased in runners (p = 0.001) after high PM exposure compared to the baseline. FeNO levels decreased in runners (p = 0.025) after high PM exposure compared to the baseline. Outdoor endurance training acts as an inducer of a differentiated immune response in the upper airways of runners compared to individuals with a sedentary lifestyle from the same community after elevated PM exposure.

The chance to develop celiac disease is five-folds higher in children with severe food allergy than in general population Concomitant autoimmunity and severe IgE-mediated allergy are not uncommon and should alert the physician to exclude more complex diagnoses such as immune dysregulation, polyendocrinopathy, enteropathy-X-linked (IPEX) syndrome, auto immune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or even celiac disease Asthenia in a well-nourished allergic child should be taken seriously and deserves a thorough workup

Although regular exercise-training improves immune/inflammatory status, the influence of air pollutants exposure during outdoor endurance training compared to a sedentary lifestyle has not yet been clarified. This study aimed to compare the immune/inflammatory responses in the airways of street runners and sedentary people after acute and chronic particulate matter (PM) exposure. Forty volunteers (street runners (RUN, n = 20), sedentary people (SED, n = 20)) were evaluated 1 (acute) and 10 (chronic) weeks after PM exposure. Cytokines [interferon (IFN)-&gamma, tumor necrosis factor (TNF)-&alpha, interleukin (IL)-6, IL-10, IL-13, and IL-17A] in nasal lavage fluid, salivary antibacterial peptides (lactoferrin (LTF), cathelicidin (LL-37), defensin-&alpha, 1&ndash, 3), and secretory immunoglobulin A (SIgA), plasma club cell protein (CC16), and fractional exhaled nitric oxide (FeNO) were analyzed. After acute exposure, the RUN group showed lower levels of IL-13, IL-10, and FeNO, but higher defensin-&alpha, than the SED group. After chronic exposure, the RUN group showed elevation of IFN-&gamma, IL-10, IL-17A, and a decrease of FeNO levels, whereas the SED group showed elevation of TNF-&alpha, IL-6, IL-10, and a decrease of IL-13 levels. Comparing these groups, the RUN group showed higher levels of SIgA and LTF, and lower FeNO levels than the SED group. In relation to the Th immune response analysis after acute and chronic PM exposure, the RUN group showed a pattern associated with Th1, while in the SED group, a Th2 pattern was found. Both groups showed also a Th17 immune response pattern. Our results allow us to suggest that the immune/inflammatory status of the respiratory tract after acute and chronic PM exposure was improved by the long-standing regular practice of outdoor endurance exercise compared to a sedentary lifestyle.

BACKGROUND: A defective epithelial barrier is found in patients with allergic rhinitis (AR) and asthma; however, the underlying mechanisms remain poorly understood. Histone deacetylase (HDAC) activity has been identified as a crucial driver of allergic inflammation and tight junction dysfunction. OBJECTIVE: We investigated whether HDAC activity has been altered in patients with AR and in a mouse model of house dust mite (HDM)-induced allergic asthma and whether it contributed to epithelial barrier dysfunction. METHODS: Primary nasal epithelial cells of control subjects and patients with AR were cultured at the air-liquid interface to study transepithelial electrical resistance and paracellular flux of fluorescein isothiocyanate-dextran (4 kDa) together with mRNA expression and immunofluorescence staining of tight junctions. Air-liquid interface cultures were stimulated with different concentrations of JNJ-26481585, a broad-spectrum HDAC inhibitor. In vivo the effect of JNJ-26481585 on mucosal permeability and tight junction function was evaluated in a mouse model of HDM-induced allergic airway inflammation. RESULTS: General HDAC activity was greater in nasal epithelial cells of patients with AR and correlated inversely with epithelial integrity. Treatment of nasal epithelial cells with JNJ-26481585 restored epithelial integrity by promoting tight junction expression and protein reorganization. HDM-sensitized mice were treated with JNJ-26481585 to demonstrate the in vivo role of HDACs. Treated mice did not have allergic airway inflammation and had no bronchial hyperreactivity. Moreover, JNJ-26481585 treatment restored nasal mucosal function by promoting tight junction expression. CONCLUSION: Our findings identify increased HDAC activity as a potential tissue-injury mechanism responsible for dysregulated epithelial cell repair, leading to defective epithelial barriers in AR. Blocking HDAC activity is a promising novel target for therapeutic intervention in patients with airway diseases. ispartof: Journal Of Allergy And Clinical Immunology vol:144 issue:5 pages:1242-1253.e7 ispartof: location:United States status: published

ObjectiveAcute infection is the most common presentation of children to hospital. A minority of these infections are serious, but early recognition and adequate management are essential. We aimed to develop improved tools to assess children attending ambulatory hospital care, integrating clinical features with point-of-care C reactive protein (CRP).DesignProspective observational diagnostic study.Setting and patients5517 acutely ill children (1 month–16 years) presenting to 106 paediatricians at six outpatient clinics and six emergency departments in Belgium.Index testPoint-of-care CRP alongside vital signs and objective symptoms measurements.Main outcomeHospital admission for >24 hours with a serious infection ResultsAn algorithm was developed consisting of clinical features and CRP. This achieved 97.1% (95% CI 94.3% to 98.7%) sensitivity and 99.6% (95% CI 99.2% to 99.8%) negative predictive value, excluding serious infections in 36.4% of children. It stratifies patients into three groups based on CRP level: high-risk group with CRP >75 mg/L (26.8% risk of infection), intermediate-risk group with CRP 20–75 mg/L and at least one of seven clinical features (8.1%), and lower risk group with CRP ConclusionsConducting a CRP test may first enable children to be stratified into three risk groups, guiding assessment of clinical features that could be performed by junior doctors or nurses. In one-third of acutely ill children, the algorithm could exclude serious infection. Prospective validation of the algorithm is needed.Clinical trial registrationNCT02024282(post-results).

Background: Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. Objective: We sought to investigate the role of histamine and TH2 cells in driving epithelial barrier dysfunction in AR. Methods: Air-liquid interface cultures of primary nasal epithelial cells were used to measure transepithelial electrical resistance, paracellular flux of fluorescein isothiocyanate-dextran 4 kDa, and mRNA expression of tight junctions. Nasal secretions were collected from healthy control subjects, AR patients, and idiopathic rhinitis patients and were tested in vitro. In addition, the effect of activated TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-γ and TNF-α on mucosal permeability was tested in vivo. Results: Histamine as well as nasal secretions of AR but not idiopathic rhinitis patients rapidly decreased epithelial barrier integrity in vitro. Pretreatment with histamine receptor-1 antagonist, azelastine prevented the early effect of nasal secretions of AR patients on epithelial integrity. Supernatant of activated TH1 and TH2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ and TNF-α enhanced mucosal permeability in mice. Antagonizing IL-4 prevented mucosal barrier disruption and tight junction downregulation in a mouse model of house dust mite allergic airway inflammation. Conclusions: Our data indicate a key role for allergic inflammatory mediators in modulating nasal epithelial barrier integrity in the pathophysiology in AR., SCOPUS: ar.j, info:eu-repo/semantics/published

Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas., SCOPUS: ar.j, info:eu-repo/semantics/published

The evidence of exercise-induced bronchoconstriction (EIB) without asthma (EIBwA ) occurring in athletes led to speculate about different endotypes inducing respiratory symptoms within athletes. Classical postulated mechanisms for bronchial obstruction in this population include the osmotic and the thermal hypotheses. More recently, the presence of epithelial injury and inflammation in the airways of athletes was demonstrated. In addition, neuronal activation has been suggested as a potential modulator of bronchoconstriction. Investigation of these emerging mechanisms is of major importance as EIB is a significant problem for both recreational and competitive athletes and is the most common chronic condition among Olympic athletes, with obvious implications for their competing performance, health and quality of life. Hereby, we summarize the latest achievements in this area and identify the current gaps of knowledge so that future research heads toward better defining the etiologic factors and mechanisms involved in development of EIB in elite athletes as well as essential aspects to ultimately propose preventive and therapeutic measures.

Background: Exercise-induced bronchoconstriction (EIB) is a transient airway narrowing, occurring during or shortly after intensive exercise in non-asthmatic elite athletes. Often, these athletes are also exposed to harmful environmental conditions such as diesel exhaust particles (DEP) at high ventilation rates during intensive training. Objective: To develop a mouse model of EIB and to investigate the influence of DEP-induced exacerbations on acute respiratory responses, lung inflammation and lung physiology in this model. Methods: Balb/c mice were intranasally challenged 5 days a week for 3 weeks long with saline or 0.2 mg/ml DEP, prior to an incremental running protocol or resting period. Once a week, early respiratory responses were measured using a double chamber plethysmograph. At day 24, mice were sacrificed to determine lung function, such as airway resistance, FEV0.1 and FVC. Broncho-alveolar lavage was performed to determine airway inflammation and involvement of cytokines and DAMPS. Results: Submaximal exercise resulted in a decreased peak inspiratory flow (immediately after exercise) and an improved FEV0.1, which were both not influenced by DEP exposure. Yet, DEP induced neutrophilic airway inflammation but it was not enhanced when combining with exercise. However, DEP uptake in lung macrophages appears to be higher in combination with exercise. Conclusion: Changes in acute respiratory responses, such as PIF, indicate that submaximal exercise results in EIB, independently from DEP exposure. Moreover, exercising mice did not show an exacerbation response upon DEP exposure. However, more research is needed to identify underlying mechanisms of exercise-induced acute responses.

Background: Staphylococcus aureus colonization and release of enterotoxin B (SEB) has been shown to contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), but the pathogenic mechanisms are largely unknown. Methods: We investigated the effect of SEB on nasal epithelial function in vitro on primary polyp and nasal epithelial cells of patients with CRSwNP and healthy controls respectively, and in vivo in a mouse model by measuring epithelial integrity and tight junction expression. The involvement of TLR2 signaling was studied in vitro by using TLR2 monoclonal antibodies and in vivo in tlr2-/- transgenic mice. Findings: We found that in vitro stimulation with SEB decreased polyp epithelial integrity by reducing occludin and ZO-1 protein expression. This impaired barrier function was associated with elevated expression of epithelial TLR2 and antagonizing TLR2 triggering prevented SEB-induced barrier disruption in vitro. In wild type mice, SEB applied in the nose increased mucosal permeability and decreased occludin and ZO-1 mRNA expression, whereas tlr2-/- mice had an intact mucosal barrier and normal tight junction expression after SEB exposure. Furthermore, in vitro SEB stimulation resulted in epithelial production of IL-6, IL-8 and TNF, which was prevented when TLR2 triggering was antagonized. Interpretation: Our results indicate that SEB impairs epithelial barrier function in CRSwNP via TLR2 activation. Interfering with TLR2 activation may provide a way to avoid the pathophysiological consequences of S. aureus colonization in CRSwNP. Funding Statement: The author’s laboratories are supported by grants from the Belgian Federal Government (IUAP P7/30), IWT (TBM project 130260) and the research council of the KU Leuven (GOA 14/011). PWH, RS and DMB are recipients of a senior researcher fellowship from the Fund of Scientific Research (FWO), Flanders, Belgium. BS is currently a Postdoctoral Fellow of the Fund for Scientific Research Flanders (FWO). Declaration of Interests: The authors declare no competing interest related to this work. Ethics Approval Statement: All experiments were approved by the Medical Ethical Committee of the University Hospitals Leuven. Murine experiments were approved by the Ethical Committee for Animal Research at the KU Leuven.

Recent advances in both murine models and clinical research of neutrophilic asthma are improving our understanding on the etiology and pathophysiology of this enigmatic endotype of asthma. We here aim at providing an overview of our current and latest insights on the pathophysiology and treatment of neutrophilic asthma.Activation of the NLRP3 inflammasome pathway with increased IL-1β has been demonstrated in various studies involving patients with asthma. It has been suggested that type 3 innate lymphoid cells are implicated in the inflammatory cascade leading to neutrophilic inflammation. The role of neutrophil extracellular traps is only at the start of being understood and might be an attractive novel therapeutic target. A diverse panel of nonallergic stimuli, such as cigarette smoke, intensive exercise, cold air or saturated fatty acids, have been linked with neutrophilic airway inflammation. Azithromycin treatment could reduce asthma exacerbations and quality of life in patients with persistent asthma.Research of the last few years has accelerated our insights in mechanisms underlying neutrophilic asthma. This is in stark contrast with the lack of efficacy of different therapies targeting neutrophil chemotaxis and/or signalling cascade, such as IL-17A or CXCR2. Macrolide therapy might be a useful add-on therapy for patients with persistent asthma.

MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was—even after major histocompatibility complex class I upregulation—insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8−CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. Significance Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL-mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell-based research for immunotherapy.

BACKGROUND The use of the internet as a source of information has grown exponentially in the last decade. YouTube is currently the second most visited website and a major Web-based educational resource for medical students. OBJECTIVE The aim of this study was to evaluate the quality, accuracy, and attractiveness of the information acquired from YouTube videos about 2 central concepts in immunology. METHODS YouTube videos posted before August 27, 2018 were searched using selected keywords related to either antigen presentation or immunoglobulin gene rearrangement. Video characteristics were recorded, and the Video Power Index (VPI) was calculated. Videos were assessed using 5 validated scoring systems: understandability and attractiveness, reliability, content and comprehensiveness, global quality score (GQS), and a subjective score. Videos were categorized by educational usefulness and by source. RESULTS A total of 82 videos about antigen presentation and 70 about immunoglobulin gene rearrangement were analyzed. Videos had a mean understandability and attractiveness score of 6.57/8 and 5.84/8, content and comprehensiveness score of 9.84/20 and 5.84/20, reliability score of 1.65/4 and 1.53/4, GQS of 3.38/5 and 2.76/5, and subjective score of 2.00/3 and 2.00/3, respectively. The organized channels group tended to have the highest VPI and GQS. CONCLUSIONS YouTube can provide medical students with some useful information about immunology, although content wise it cannot substitute textbooks and academic courses. Students and teachers should be aware of the educational quality of available videos if they intend to use them in the context of blended learning.

Several studies have already identified atopy as a risk factor for the development of exercise-induced bronchoconstriction (EIB) in adult elite athletes (1-3). Skin prick test or serum specific IgE to common aero-allergens is used to determine the patient's atopy status (4). In 2009, Bonini M et al. introduced a screening tool to predict atopy in elite adult athletes, namely the Allergy Questionnaire for Athletes or short the AQUA© questionnaire (5). This article is protected by copyright. All rights reserved. ispartof: PEDIATRIC ALLERGY AND IMMUNOLOGY vol:29 issue:6 pages:648-650 ispartof: location:England status: published

Physical exercise requires proper function of the upper and lower airways in order to meet exertional ventilatory requirements. Athletes performing frequent intensive exercise experience more sino-nasal symptoms and demonstrate objective decreases in sino-nasal function when compared with the general population. Sino-nasal dysfunction is known to interfere with sport performance. Nasal epithelial injury, neutrophilic influx, and decreased mucociliary clearance have been associated with intensive training. In this review, the authors provide a comprehensive overview of the prevalence of sino-nasal disease in athletes, the possible underlying pathophysiologic mechanisms, and a summary of diagnostic and treatment options. ispartof: IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA vol:38 issue:2 pages:259-+ ispartof: location:United States status: published

SummaryBackground Data from birth cohort studies suggest that increased cord blood total IgE and reduced cord blood regulatory T cells increase the risk of developing allergic sensitization and atopic dermatitis. Objective We here addressed whether serum total IgE and hen's egg-specific IgE levels at birth and at age 1 year differed between healthy and allergic children in a Belgian birth cohort (FONIA). We furthermore studied whether these parameters as well as cord blood Foxp3/CD3γ mRNA levels might predict the allergic outcome. Methods and results Children (n = 84) were clinically assessed at the ages of 6, 12, 18, and 24 months and at 6 years. Cord blood total IgE levels above 0.35 kU/L predicted early (i.e. before or at the age of 2 years) allergy development. Presence of serum IgE antibodies to hen's egg (cut-off 0.05 Ua/mL) at the age of 1 year was associated with early as well as late (i.e. between the age of 2 and 6 years) allergy development. Cord blood Foxp3/CD3γ mRNA ratios were significantly lower in early allergic children and levels below 0.32 predicted the allergic outcome. Conclusions and clinical Relevance Low cord blood Foxp3/CD3γ mRNA ratios are highly predictive for early allergy development, whereas specific IgE levels to hen's egg white above 0.05 Ua/mL at age 1 year predict allergy development in general.