Long-term effects of pollen allergoid tyrosine-adsorbed subcutaneous immunotherapy on allergic rhinitis and asthma.

BACKGROUND: Allergen immunotherapy (AIT) may have a long-term disease-modifying effect. The aim of this study was to demonstrate the long-term effects of pollen allergoid tyrosine-adsorbed subcutaneous AIT on allergic rhinitis (AR) and asthma (AA) in clinical practice. METHODS: This retrospective study, funded by an AIT manufacturer, analysed the impact of AIT on AR progression and onset of need for AA medication, using a German database covering ~35% of national prescriptions during 2008-2020. Anonymized prescription data of AR patients aged 5-65 years treated with grass or tree pollen AIT between 2009 and 2013 and followed for at least 2 years after AIT cessation were compared with matched control patients with seasonal AR. RESULTS: 181,496 patients received AIT prescriptions. 5959 fulfilled the inclusion criteria. The median AIT treatment duration was 1092 days and the follow-up duration was 6.4 years. Less patients treated with AIT received prescriptions for symptomatic AR medication in the follow-up versus controls (AIT: OR: 0.37; 95% Confidence Interval (CI) 0.34, 0.40; p < .001, tyrosine-adsorbed AIT: OR: 0.27; 95% CI 0.20, 0.35 p < .001). Less asthmatic patients under AIT received prescriptions for AA medications versus controls (AIT: OR: 0.48; 95% CI 0.41, 0.55; p < .001, tyrosine-adsorbed AIT: OR: 0.48; 95% CI 0.29, 0.79; p = .004). AR and AA medication prescriptions for AIT patients were reduced in the follow-up versus baseline and controls (AIT: AR: 20.0%; 1.5 vs. 0.2 prescriptions; AA: 29.1%; 2.0 vs. 0.6 prescriptions, p < .001; tyrosine-adsorbed AIT: AR: 24.2%, 1.4 vs. 0.2 prescriptions; AA: 35.6%, 2.1 vs. 0.6 prescriptions, p < .001). The probability of AA medication onset in non-asthmatic patients during follow-up was reduced for AIT patients compared to controls (OR: 0.77, 95% CI 0.66, 0.90; p = .001). All endpoints were significant for children/adolescents and adults in stratified analyses. CONCLUSIONS: We found evidence for long-term effects up to 9.5 years for tyrosine-adsorbed AIT.

House dust mite SCIT reduces asthma risk and significantly improves long-term rhinitis and asthma control-A RWE study.

BACKGROUND: The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM subcutaneous AIT (SCIT) products hold approval in Germany and therefore will be available after the scheduled completion of the TAO procedure in 2026. In general, data from clinical trials on the long-term effectiveness of HDM AIT are rare. We evaluated real-world data (RWD) in a retrospective, observational cohort study based on a longitudinal claims database including 60% of all German statutory healthcare prescriptions to show the long-term effectiveness of one of these products in daily life. Aim of this analysis was to provide a per product analysis on effectiveness of mite AIT as it is demanded by international guidelines on AIT. METHODS: Subjects between 5 and 70 years receiving their first (index) prescription of SCIT with a native HDM product (SCIT group) between 2009 and 2013 were included. The exactly 3:1 matched control group received prescriptions for only symptomatic AR medication (non-AIT group); the evaluation period for up to 6 years of follow-up ended in February 2017. Study endpoints were the progression of allergic rhinitis (AR) and asthma, asthma occurrence and time to the onset of asthma after at least 2 treatment years. RESULTS: In total, 892 subjects (608 adults and 284 children/adolescents) were included in the SCIT group and 2676 subjects (1824 adults and 852 children/adolescents) in the non-AIT group. During the follow-up period after at least 2 years of SCIT, the number of prescriptions in the SCIT group was reduced by 62.8% (p < .0001) for AR medication and by 42.4% for asthma medication (p = .0003). New-onset asthma risk was significantly reduced in the SCIT vs non-AIT group by 27.0% (p = .0212). The asthma-preventive effect of SCIT occurred 15 months after start of the treatment. In the SCIT group, the time to onset of asthma was prolonged compared to the non-AIT group (p = .0010). CONCLUSION: In this first product based RWD analysis on SCIT with a native HDM product, patients aged 5 to 70 years benefited from AIT in the long term in terms of reduced progression of AR and asthma after at least 2 years of treatment. The effects seemed to last for up to 6 years after treatment termination. A significantly reduced risk of asthma onset was observed, starting after 15 months of treatment.

Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.

PURPOSE: Primary ciliary dyskinesia (PCD) is a heterogeneous disorder that includes respiratory symptoms, laterality defects, and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance. METHODS: In addition to studies in mouse and planaria, clinical exome sequencing and functional analyses in human were performed. RESULTS: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms. Consistently, we found that Clxn is expressed in mice left-right organizer. Transmission electron microscopy depicted ODA defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1, and DNAI2 from the distal axonemes, and mislocalization or absence of DNAH9. In addition, CLXN was undetectable in ciliary axonemes of individuals with defects in the ODA-docking machinery: ODAD1, ODAD2, ODAD3, and ODAD4. Furthermore, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility. CONCLUSION: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5.

Therapeutic principles and unmet needs in the treatment of cough in pediatric patients: review and expert survey.

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.

Work-related stress and atopic dermatitis: Results from the study on occupational allergy risks.

Chronic stress at work is ubiquitous in modern societies. However, its influence on atopic dermatitis (AD) has hardly been investigated. This study aimed to elucidate the association between work-related stress and AD via a longitudinal study. The analysis comprised data from three phases (2002-2003, 2007-2009, 2017-2018) of the prospective Study on Occupational Allergy Risks (SOLAR), including 1,240 young adults aged 16 to 18 years at baseline (61% female) who were originally recruited for the International Study of Asthma and Allergies in Childhood Phase II in 1995-1996. AD was assessed at all three phases based on self-reports of a physician's diagnosis and symptoms. Work-related stress was measured at all three periods using the work discontent and work overload scales from the Trier Inventory for the Assessment of Chronic Stress with adaptions to school and university. Generalized estimating equations were used to analyze the association between stress and AD, treating work discontent and work overload first as continuous and then as categorical exposure variables. We observed 50 AD cases (4%) at SOLAR I, 48 (4%) at SOLAR II, and 42 (3%) at SOLAR III. A one-point increase in the work discontent score was associated with an odds ratio (OR) for AD of 1.05 (95% confidence interval [CI], 1.00-1.10). The respective increase in the work overload score led to an OR of 1.03 (95% CI, 0.99-1.06). In the categorical analysis, there was no clear indication of elevated odds of AD in the highest vs. lowest exposure group (4th vs. 1st quartile: OR, 1.53; 95% CI, 0.92-2.53 for work discontent; OR, 1.38, 95% CI, 0.83-2.27 for work overload). Altogether, we observed limited to no evidence for an association between work-related stress and AD. Our study's ability to detect stronger evidence may have been compromised by shortcomings such as nondifferential misclassification of the outcome or insufficient statistical precision due to small numbers of AD cases. Another explanation could be that AD predominantly becomes evident in childhood, not in adulthood.

[Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 - published by the German Respiratory Society (DGP) e. V.] / S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma.

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.

Real-world evidence for the long-term effect of allergen immunotherapy: Current status on database-derived European studies.

Randomized controlled trials (RCTs) are the gold-standard for benefit-risk assessments during drug approval processes. Real-word data (RWD) and the resulting real-world evidence (RWE) are becoming increasingly important for assessing the effectiveness of drug products after marketing authorization showing how RCT results are transferred into real life care. The effectiveness of allergen immunotherapy (AIT) has been assessed in several RWE studies based on large prescription databases. We performed a literature search for retrospective cohort assessments of prescription databases in Europe to provide an overview on the methodology, long-term effectiveness outcomes, and adherence to AIT. Thirteen respective publications were selected. AIT was more effective in reducing the progression of allergic rhinitis (AR) compared to a non-AIT control group receiving only symptomatic treatment for AR for up to 6 years. The development and progression of asthma were hampered for most endpoints in patients treated with most preparations compared to the non-AIT group, receiving only anti-asthmatic medication. The results for "time to onset" of asthma were inconsistent. Adherence to AIT decreased during the recommended 3-year treatment period, however, in most studies higher adherence to subcutaneous than to sublingual AIT was shown. The analysis of long-term effectiveness outcomes of the RWE studies based on prescription databases confirms the long-term efficacy of AIT demonstrated in RCTs. Progression of rhinitis and asthma symptoms as well as delayed onset of asthma triggered by different allergens, real life adherence to the treatment shows differences in particular application routes.

Trajectories of asthma and allergy symptoms from childhood to adulthood.

BACKGROUND: Phenotypes of asthma and allergic diseases are mainly studied separately for children and adults. To explore the role of adolescence and young adulthood, we investigated symptom trajectories at the transition from childhood into adulthood. METHODS: Latent class analysis (LCA) was conducted in a population initially recruited for the German arm of Phase II of the International Study of Asthma and Allergies in Childhood and followed-up three times until their early 30s (N=2267). Indicators included in LCA were 12-month prevalences of symptoms of wheeze, rhinoconjunctivitis, and eczema. Latent classes were further characterised regarding important traits such as skin prick tests. Logistic regression models were used to investigate associations with environmental determinants such as smoking and occupational exposures. RESULTS: Six latent classes were identified: an asymptomatic one as well as three with single and two with co-occurring symptoms. All trajectories essentially established between baseline assessment at around 10 years and the first follow-up at around 17 years. Probabilities for symptoms increased from childhood to adolescence, especially for wheeze-related latent classes, while they remained constant in adulthood. Wheeze-related latent classes were also positively associated with exposures during adolescence (e.g. active smoking). CONCLUSION: Distinct trajectories of asthma and allergy symptoms establish from childhood through adolescence and stabilize during early adulthood. This pattern was most notable in wheeze-related latent classes which also showed the strongest positive associations with environmental exposures in adolescence/young adulthood. Therefore, not only childhood but also adolescence is relevant for disease development and offers considerable potential for prevention and health promotion.

Peanut-induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry.

BACKGROUND: Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. METHODS: Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. RESULTS: 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). CONCLUSIONS: The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.