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Allergen immunotherapy (AIT), when continued for 3 years, is the only disease-modifying treatment for AR and asthma. Adherence is a key to ensure effectiveness, and poor adherence is a contraindication for AIT. The objective of this study was to evaluate real-world adherence to AIT with subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) preparations in patients allergic to grass or tree pollen. The impact of AIT on the consumption of asthma and rhinitis medication was also analyzed. In this retrospective cohort analysis of a German longitudinal prescription database, the adherence of a grass and tree pollen allergoid was examined and compared to two sublingual AIT tablets/drops. Patients receiving grass or tree allergen-specific immunotherapy prescriptions were compared with non-AIT patients receiving symptomatic allergic rhinitis (AR) and asthma prescriptions. The study endpoints included therapy adherence, AR progression, and asthma progression. Multivariate regression analyses were used to estimate the effects of SCIT or SLIT, adjusting for variables related to demographics and prescriptions. SCIT adherence was 60.1-61.8% at 2 years and 35.0-37.5% at 3 years for the two allergens. SLIT adherence was distinctly lower (29.5-36.5% and 9.6-18.2%, respectively). Adherence in children was higher compared to adolescents or adults. All products were highly efficacious at reducing symptomatic AR medication consumption. SCIT also reduced asthma medication use for both allergens, whereas for SLIT these results were significant only for grasses but not trees. Subcutaneous AIT in a real-world setting achieved significantly higher adherence rates compared to sublingual administration. SCIT reduced the use of rhinitis and asthma medication significantly for both allergens, while SLIT reduced the use of rhinitis medication for both allergens and the use of asthma medication for grasses only.

Asthma is a chronic inflammatory airway disease, and its treatment is frequently challenging despite detailed national and international guidelines. While basic anti-inflammatory therapy usually consists of inhaled corticosteroids in doses adapted to the asthma severity, add-on treatment with bronchodilators is essential in more severe asthma. Only recently, the long-acting anticholinergic tiotropium was introduced into the GINA guidelines. This review reports on the studies that have been performed with tiotropium in adult asthmatic patients. Following early proof-of-concept studies, several studies with tiotropium as an add-on therapy to inhaled corticosteroids (ICS), with or without a long-acting beta agonist (LABA), demonstrated convincing clinical benefit for patients. Important lung function parameters and quality of life scores significantly improved shortly after onset of the add-on therapy with tiotropium, and some studies even demonstrated non-inferiority against salmeterol. All studies reported an excellent safety profile of tiotropium. The still growing body of tiotropium studies, both in adults and children, will help to identify the position of tiotropium in future asthma guidelines and might also indicate which patients benefit most from an add-on therapy with tiotropium.

The long-tern implications of stress during university for individuals’ mental health are not well understood so far. Hence, we aimed to examine the potential effect of stress while studying at university on depression in later life. We analysed data from two waves of the longitudinal Study on Occupational Allergy Risks. Using the ‘work overload’ and ‘proving oneself’ scales of the Trier Inventory for Chronic Stress and the Patient Health Questionnaire-2 (PHQ-2), participants reported chronic stress during university (2007–2009, mean age 22.2 years, T1) and depressive symptoms ten years later (2017–2018, mean age 31.6 years, T2). We performed linear regression analyses to explore the association between stress during university (T1) and later depressive symptoms (T2). Participants (N = 548, 59% female) indicated rather low levels of stress and depression (PHQ-2 mean score: 1.14 (range: 0–6)). We observed evidence for a linear association between overload at T1 and depression at T2 (regression coefficient (B) = 0.270; 95% confidence interval (CI) = 0.131 to 0.409; standardised regression coefficient (β) = 0.170). Our analyses yielded evidence for an association between chronic stress while studying and risk of depressive symptoms later in life. This finding underlines the importance of implementing sustainable preventive measures against stress among students.

Childhood asthma genes Rates of childhood asthma diagnosis are rising: 6% of children in the United States are sufferers. Both genetic and environmental factors are clearly important. To discover more about the genetic element, Moffatt et al . looked for genes linked to asthma in a genome-wide association scan. More than a third of children with asthma of onset below the age of seven showed variations in expression of the ORMDL3 gene on chromosome 17. Similar genes are found in yeast and other primitive organisms, suggesting that they may be components of an ancient and conserved immune mechanism. Variations in expression of the gene ORMDL3 were found to be associated with development of childhood asthma, suggesting this gene should be examined in more patient groups. Asthma is caused by a combination of poorly understood genetic and environmental factors 1 , 2 . We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P  value of P  < 10 -12 . In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children ( P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort ( P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated ( P  < 10 -22 ) in cis with transcript levels of ORMDL3 , a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum 3 . The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Diagnosing and treating asthma in paediatric patients remains challenging, with many children and adolescents remaining uncontrolled despite treatment. Selecting the most appropriate pharmacological treatment to add onto inhaled corticosteroids (ICS) in children and adolescents with asthma who remain symptomatic despite ICS can be difficult. This literature review compares the efficacy and safety of long-acting β 2 -agonists (LABAs), leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs) as add-on treatment to ICS in children and adolescents aged 4–17 years. A literature search identified a total of 29 studies that met the inclusion criteria, including 21 randomised controlled trials (RCTs) of LABAs versus placebo, two RCTs of LAMAs (tiotropium) versus placebo, and four RCTs of LTRA (montelukast), all as add-on to ICS. In these studies, tiotropium and LABAs provided greater improvements in lung function than LTRAs, when compared with placebo as add-on to ICS. Although exacerbation data were difficult to interpret, tiotropium reduced the risk of exacerbations requiring oral corticosteroids when added to ICS, with or without additional controllers. LABAs and LTRAs had a comparable risk of asthma exacerbations with placebo when added to ICS. When adverse events (AEs) or serious AEs were analysed, LABAs, montelukast and tiotropium had a comparable safety profile with placebo. In conclusion, this literature review provides an up-to-date overview of the efficacy and safety of LABAs, LTRAs and LAMAs as add-on to ICS in children and adolescents with asthma. Overall, tiotropium and LABAs have similar efficacy, and provide greater improvements in lung function than montelukast as add-on to ICS. All three controller options have comparable safety profiles.

Background There are evidence gaps in the management of pediatric cough, particularly for acute pediatric cough. This study had two aims: to identify therapeutic principles and unmet needs in the treatment of cough in pediatric patients (internationally), and to consider the evidence required to address these unmet needs. Methods A MEDLINE/PubMed database search was performed to identify articles describing therapeutic principles in the treatment of pediatric cough. An online survey of international pediatric cough experts was conducted, with questions on the definitions, diagnosis, treatment, and unmet needs in pediatric cough management. Results Cough guidelines have differing definitions of pediatric patients (≤12–18 years), acute pediatric cough (< 2–3 weeks), and chronic pediatric cough (> 4–8 weeks). Similarly, among 18 experts surveyed, definitions varied for pediatric patients (≤10–21 years), acute pediatric cough (< 3–5 days to < 6 weeks), and chronic pediatric cough (> 2–8 weeks). Guidelines generally do not recommend over-the-counter or prescription cough medicines in acute pediatric cough, due to lack of evidence. In the expert survey, participants had differing opinions on which medicines were most suitable for treating acute pediatric cough, and noted that effective treatments are lacking for cough-related pain and sleep disruption. Overall, guidelines and experts agreed that chronic pediatric cough requires diagnostic investigations to identify the underlying cough-causing disease and thereby to guide treatment. There are unmet needs for new effective and safe treatments for acute pediatric cough, and for randomized controlled trials of existing treatments. Safety is a particular concern in this vulnerable patient population. There is also a need for better understanding of the causes, phenotypes, and prevalence of pediatric cough, and how this relates to its diagnosis and treatment. Conclusions Whereas pediatric cough guidelines largely align with regard to the diagnosis and treatment of chronic cough, there is limited evidence-based guidance for the management of acute cough. There is a need for harmonization of pediatric cough management, and the development of standard guidelines suitable for all regions and patient circumstances.

Effector CD8 + T cells convert from IFN-γ + (Tc1) to IL-13 + (Tc2) cells in the presence of IL-4. Underlying regulatory mechanisms are not fully defined. Here, we show that addition of 1,25D3, the active form of vitamin D3, during CD8 + T-cell differentiation prevents IL-4-induced conversion to IL-13-producers. Transfer of 1,25D3-treated CD8 + T cells into sensitized and challenged CD8 + -deficient recipients fails to restore development of lung allergic responses. 1,25D3 alters vitamin D receptor (VDR) recruitment to the Cyp11a1 promoter in vitro and in vivo in the presence of IL-4. As a result, protein levels and enzymatic activity of CYP11A1, a steroidogenic enzyme regulating CD8 + T-cell conversion, are decreased. An epistatic effect between CYP11A1 and VDR polymorphisms may contribute to the predisposition to childhood asthma. These data identify a role for 1,25D3 in the molecular programming of CD8 + T-cell conversion to an IL-13-secreting phenotype through regulation of steroidogenesis, potentially governing asthma susceptibility. Type 2 CD8 + T cells (Tc2) play a role in the development of experimental asthma. Here the authors show that 1,25D3, the active form of vitamin D3, can prevent conversion of CD8 + T cells to a Tc2 phenotype, reducing asthma susceptibility.

Background: Dried ivy leaf extract EA 575® (Prospan®) is commonly used to treat coughs and may help reduce inappropriate antibiotic use for the common cold. This retrospective study investigated whether prescribing EA 575 is associated with reduced subsequent antibiotic use in children and adolescents with the common cold. Repeated EA 575 prescriptions were also analyzed to estimate treatment satisfaction. Methods: Data were sourced from the IQVIA Disease Analyzer database, including patients under 18 diagnosed with a common cold and prescribed either EA 575 or antibiotics between 2017 and 2020 (index date). Propensity score matching controlled for confounding factors. Antibiotic prescriptions were assessed 4–30 and 31–365 days after the index date, along with bacterial infections 4–40 days post-index. Repeated EA 575 prescriptions 2–5 years post-index were analyzed as a proxy for treatment satisfaction. Results: Overall, 10,390 children and adolescents were included in each matched cohort. Compared to antibiotics, EA 575 prescriptions were associated with significantly lower odds of antibiotic use 4–30 days (OR: 0.56; 95% CI: 0.49–0.64; p < 0.001) and 31–365 days (OR: 0.58; 95% CI: 0.54–0.62; p < 0.001) after the index date. The odds of bacterial infection 4–30 days after EA 575 prescription were also lower (OR: 0.67; 95% CI: 0.45–0.99; p = 0.047). Of the 42,677 patients in the EA 575 analysis, 50.5% had at least one repeated prescription, with the highest rates among children aged 0–2 years (54.7%) and the lowest in those aged 13–17 years (19.9%). Conclusions: EA 575 prescription was associated with reduced subsequent antibiotic use in children and adolescents with common colds. Frequent repeated prescription rates emphasize the therapeutic value of EA 575 as a treatment option for cold symptoms, especially in younger children.

Background Long-term effectiveness of asthma control medication has been shown in clinical trials but results from observational studies with children and adolescents are lacking. Marginal structural models estimated using targeted maximum likelihood methods are a novel statistiscal approach for such studies as it allows to account for time-varying confounders and time-varying treatment. Therefore, we aimed to calculate the long-term risk of reporting asthma symptoms in relation to control medication use in a real-life setting from childhood to adulthood applying targeted maximum likelihood estimation. Methods In the prospective cohort study SOLAR (Study on Occupational Allergy Risks) we followed a German subsample of 121 asthmatic children (9–11 years old) of the ISAAC II cohort (International Study of Asthma and Allergies in Childhood) until the age of 19 to 24. We obtained self-reported questionnaire data on asthma control medication use at baseline (1995–1996) and first follow-up (2002–2003) as well as self-reported asthma symptoms at baseline, first and second follow-up (2007–2009). Three hypothetical treatment scenarios were defined: early sustained intervention, early unsustained intervention and no treatment at all. We performed longitudinal targeted maximum likelihood estimation combined with Super Learner algorithm to estimate the relative risk (RR) to report asthma symptoms at SOLAR I and SOLAR II in relation to the different hypothetical scenarios. Results A hypothetical intervention of early sustained treatment was associated with a statistically significant risk increment of asthma symptoms at second follow-up when compared to no treatment at all (RR: 1.51, 95% CI: 1.19–1.83) or early unsustained intervention (RR:1.38, 95% CI: 1.11–1.65). Conclusions While we could confirm the tagerted maximum likelihood estimation to be a usable and robust statistical tool, we did not observe a beneficial effect of asthma control medication on asthma symptoms. Because of potential due to the small sample size, lack of data on disease severity and reverse causation our results should, however, be interpreted with caution.

Background When the coronavirus pandemic 2019 (COVID‐19) emerged, concerns were also raised regarding the safety of allergen immunotherapy (AIT). The German Society for Allergology and Clinical Immunology (DGAKI) conducted a survey to collect real‐world data on the daily routine of administering subcutaneous AIT (SCIT) and sublingual AIT (SLIT) during the COVID‐19 pandemic. Methods A web‐based retrospective survey using the online platform survio with 26 standardized questions was used to survey physicians treating allergic patients during the pandemic. Results Three hundred and forty‐five physicians who regularly offer and perform AIT in German‐speaking countries responded to the questions. 70.4% of the respondents stated that they regularly initiated and dosed up SCIT for inhalant allergies (41.4% venom‐SCIT, 73.6% SLIT), and 85.2% of the respondents stated that they continued SCIT for inhalant allergies during the maintenance phase in a regular way (59.1% venom‐SCIT, 90.4% SLIT) in healthy patients without current symptoms indicating an infection with COVID‐19. With regard to tolerability, there was no evidence for increased occurrence of adverse events in patients without current symptoms of COVID‐19 infection during the pandemic. Conclusions This retrospective study demonstrated adherence to national and international position papers of AIT during the COVID‐19 pandemic in German‐speaking countries. Besides, the survey has confirmed a good tolerability of AIT for both SCIT and SLIT.