IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction.

BACKGROUND: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma. METHODS: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models. RESULTS: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA+ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA+ memory B-cells significantly correlated with clinical features of SAD such as exacerbations. CONCLUSIONS: With this study we demonstrate for the first time a significant association of increased IgA+ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.

Accelerated Dose Escalation with 3 Injections of an Aluminum Hydroxide-Adsorbed Allergoid Preparation of 6 Grasses Is Safe for Children and Adolescents with Moderate to Severe Allergic Rhinitis.

A high-dose, accelerated escalation schedule during subcutaneous allergen-specific immunotherapy (AIT) is safe and well-tolerated in adults. However, there are no data in children and adolescents. The aim of the present trial was to assess safety and tolerability of an accelerated dose escalation schedule of an AIT with a grass pollen allergoid in children and adolescents with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in the One Strength Group included 3 injections with 1 strength B (10,000 TU/mL), whereas the dose escalation scheme for the Standard group included 7 injections with 2 strengths A (1,000 TU/mL) and B (10,000 TU/mL) of an allergoid grass pollen preparation. Overall, n = 50 children (n = 25 in each group; mean age 8.9 + 1.54 years) and n = 37 adolescents (n = 20 and n = 17; 14.2 + 1.62 years) were randomized. For all patients, the mean treatment duration was 59.4 days in the One Strength group and 88.6 days in the Standard group. Treatment-emergent adverse events (TEAEs) related to AIT were reported in 52 and 40% in children and 35 and 35.3% in adolescents, respectively. Systemic allergic reactions occurred in about 5% of our patients and were reported in more patients of the One Strength group (6.7 vs. 2.4%). All systemic reactions were classified as WAO Grade 1. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in children and adolescents with allergic rhinitis with or without asthma.

Accelerated Dose Escalation with Three Injections of an Aluminum Hydroxide-Adsorbed Allergoid Preparation of Six Grasses Is Safe for Patients with Moderate to Severe Allergic Rhinitis.

Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.

TOLLIP and MUC5B modulate the effect of ambient NO2 on respiratory symptoms in infancy.

BACKGROUND: Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes. METHODS: 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO2) and particulate matter ≤10 µm in aerodynamic diameter (PM10) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro, cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid. RESULTS: Significant interaction was observed between modelled air pollution (weekly NO2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation. CONCLUSION: Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution.

Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases.

BACKGROUND: Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects early cystic fibrosis (CF) lung disease. LCI was used as an end-point in single- and multicentre settings at highly experienced MBW centres in preschool children. However, multicentre feasibility of MBW in children aged 2-6 years, including centres naïve to this technique, has not been determined systematically. METHODS: Following central training, 91 standardised nitrogen MBW investigations were performed in 74 awake preschool children (15 controls, 46 with CF, and 13 with other lung diseases), mean age 4.6±0.9 years at investigation, using a commercially available device across five centres in Germany (three experienced, two naïve to the performance in awake preschool children) with central data analysis. Each MBW investigation consisted of several measurements. RESULTS: Overall success rate of MBW investigations was 82.4% ranging from 70.6% to 94.1% across study sites. The number of measurements per investigation was significantly different between sites ranging from 3.7 to 6.2 (p<0.01), while the mean number of successful measurements per investigation was comparable with 2.1 (range, 1.9 to 2.5; p=0.46). In children with CF, the LCI was increased (median 8.2, range, 6.7-15.5) compared to controls (median 7.3, range 6.5-8.3; p<0.01), and comparable to children with other lung diseases (median 7.9, range, 6.6-13.9; p=0.95). CONCLUSION: This study demonstrates that multicentre MBW in awake preschool children is feasible, even in centres previously naïve, with central coordination to assure standardised training, quality control and supervision. Our results support the use of LCI as multicentre end-point in clinical trials in awake preschoolers with CF.